CURRENT ISSUES IN CARDIOLOGY
CONTENTS
Preface
xi
Jonathan A. Abbott
Dedication
xiii
Jonathan A. Abbott
Advances in Echocardiography
1083
Mark A. Oyama
Echocardiography is an exceptionally useful technique for diag-
nosing cardiovascular disease in small animals. It is noninvasive
and provides a wealth of data concerning cardiac morphology
and function. For many patients, echocardiography is the definitive
diagnostic tool. A well-performed study coalesces the findings of
the physical examination, electrocardiogram, and radiographs into
a clearly defined diagnosis on which treatment decisions can be
based. More so than other diagnostic techniques, echocardiography
is highly operator dependent and relies on the proper acquisition
and interpretation of results by an examiner who is familiar with
the principles, capabilities, and limitations of ultrasound imaging.
This article reviews the basics of echocardiography, measurement
of cardiac dimensions, and assessment of cardiac function. Within
these sections, emerging technologies that expand the capabilities
of the echocardiographic examination are introduced.
Neuroendocrine Evaluation of Cardiac Disease
1105
D. David Sisson
Current evidence favors the view that regardless of etiology, there
is a predictable sequence of neuroendocrine activation that oper-
ates in most dogs and cats with progressive heart disease and that
it is largely, but not entirely, independent of etiology. The natriuretic
peptides and sympathetic nervous system seem to be early respon-
ders to developing cardiac and hemodynamic perturbations in
VOLUME 34
Æ
NUMBER 5
Æ
SEPTEMBER 2004
v
both species. Brain natriuretic peptide (BNP) plays a particularly
prominent role in cats, possibly as a reflection of disease etiology.
Shortly thereafter, plasma endothelin concentrations rise, reflecting
the impact of the hemodynamic alterations on the vasculature.
Endothelin and the natriuretic peptides directly suppress plasma
renin release but have divergent effects on aldosterone. Activation
of the tissue renin-angiotensin-aldosterone system (RAAS) may
operate early on to further the progression of heart failure, but
evidence of plasma RAAS activation occurs comparatively late and
near the time of development of overt congestive heart failure
(CHF). Finally, in animals with severe CHF that are prone to hypo-
tension, vasopressin levels may also rise, contributing to the reten-
tion of free water and congestion that is refractory to diuretics.
Although oversimplified, this scenario seems to be consistent with
data obtained in human, canine, and feline patients. These observa-
tions provide some impetus for evaluating angiotensin-converting
enzyme (ACE) inhibitors in cats and b-receptor–blocking drugs in
dogs and cats. Perhaps we are also a little closer to identifying useful
biochemical markers that can aid in the diagnosis of heart disease,
guide therapy, and improve our understanding of the biologic pro-
cesses occurring in our patients.
Management of Atrial Fibrillation
1127
Anna R.M. Gelzer and Marc S. Kraus
Atrial fibrillation (AF) is the most common clinically important
arrhythmia in veterinary medicine. Electrical cardioversion of AF
to sinus rhythm is feasible, but pharmacologic rate control is an
effective and achievable treatment strategy for most veterinary
patients. Recent human trials suggest that rate control and rhythm
control are almost equally beneficial. Nevertheless, AF can be a
challenging arrhythmia to manage, because most affected animals
have numerous other concurring problems associated with the
underlying heart disease that dictate or influence the clinician’s
choice of treatment and monitoring strategy for each patient.
Use of Pimobendan in the Management of Heart Failure
1145
Virginia Luis Fuentes
Pimobendan is an oral inodilator compound producing a positive
inotropic effect and peripheral vasodilation. It possesses the novel
feature of calcium sensitization as well as inhibiting phosphodies-
terase III. In studies with human patients, improvements were seen
in hemodynamic function and exercise tolerance, without evidence
of proarrhythmia. Studies of pimobendan in dogs with congestive
heart failure caused by dilated cardiomyopathy or mitral valve
disease have demonstrated improvements in clinical status and
survival when compared with placebo and similar effects or better
when compared with angiotensin-converting enzyme inhibitors.
vi
CONTENTS
Beta-Blockade in the Management of Systolic
Dysfunction
1157
Jonathan A. Abbott
Heart failure is a clinical syndrome that results from systolic or dia-
stolic cardiac dysfunction. Current evidence supports the view that
chronic activation of the adrenergic nervous system is maladaptive
and partly responsible for the progression of myocardial dysfunc-
tion. The use of b-adrenergic antagonist (BAA) is now standard
therapy for people who develop heart failure due to systolic dys-
function. Possibly, beta-blockade has a role in the management of
dogs with heart failure. This review addresses the pathophysiolo-
gic basis for the use of BAA in heart failure and the potential role
of BAA in veterinary patients with systolic dysfunction.
Interventional Catheterization for Tachyarrhythmias
1171
Kathy N. Wright
Catheter ablation of cardiac tachyarrhythmias is unique among our
therapeutic armamentarium because it offers the ability to cure
certain tachyarrhythmias permanently without implanted devices.
Tachycardia-induced cardiomyopathy that is not distinguishable
from idiopathic dilated cardiomyopathy clinically can also resolve
once the underlying tachyarrhythmia is eliminated. The equipment
and expertise required limit the availability of this treatment
modality in veterinary medicine. Its success with supraventricular
tachyarrhythmias (particularly those secondary to accessory path-
ways), however, makes it a viable option for many owners, even
if they must travel some distance to reach a center performing these
procedures.
Dilated Cardiomyopathy: An Update
1187
Michael R. O’Grady and M. Lynne O’Sullivan
Dilated cardiomyopathy (DCM) continues to be an important
cause of morbidity and mortality in the dog. The progression of
DCM is described by three distinct stages, normal, occult DCM,
and overt DCM. This review focuses on the natural history of
occult and overt DCM, predictors of outcome, and management.
New Insights into Degenerative Mitral Valve Disease in
Dogs
1209
Jens Ha¨ggstro¨m, Henrik Duelund Pedersen, and Clarence
Kvart
Degenerative mitral valve disease (DMVD) is the most common
cardiac disease in dogs. Although the disease is frequently
described in the veterinary literature, many aspects are still
unknown or controversial. Based on recent research findings, this
article addresses the etiology, pathogenesis, inheritance, diagnosis
of early DMVD, diagnosis of mild decompensated heart failure,
CONTENTS
vii
and efficacy of early medical intervention in clinically compensated
dogs.
Feline Hypertrophic Cardiomyopathy: An Update
1227
Catherine J. Baty
This article reviews the recent advances in the clinical assessment,
natural history, and treatment of feline hypertrophic cardiomyopa-
thy. A brief summary regarding investigations of the genetic etiol-
ogy of the disease is also provided.
Boxer Dog Cardiomyopathy: An Update
1235
Kathryn M. Meurs
Boxer dog cardiomyopathy is an inheritable form of myocardial
disease characterized most commonly by ventricular tachycardias,
syncope, and, sometimes, systolic dysfunction and heart failure.
Careful evaluation of boxer dog cardiomyopathy by several inves-
tigators has demonstrated that the disease may be best classified as
arrhythmogenic right ventricular cardiomyopathy. Affected dogs
have a variable prognosis; although some succumb to sudden
cardiac death, many can remain asymptomatic or be successfully
managed on antiarrhythmics for years.
Feline Arterial Thromboembolism: An Update
1245
Stephanie A. Smith and Anthony H. Tobias
Arterial thromboembolism (ATE) in cats is a devastating complica-
tion of several diseases, with cardiac disease being the most
common. Cats presenting with acute appendicular ATE are in
considerable pain and distress and are frequently in shock. Acute
management includes administration of oxygen, analgesics, and
heparin as well as a diagnostic evaluation for manifestations of
underlying cardiac disease. The mortality rate during an acute
ATE episode is high. Long-term thromboprophylaxis is an impor-
tant goal in patients that survive the initial ATE episode as well
as in cats with diseases that predispose to ATE. Practical, safe,
and truly effective methods to prevent ATE in cats remain elusive.
Index
1273
viii
CONTENTS
FORTHCOMING ISSUES
November 2004
Neuromuscular Diseases II
G. Diane Shelton, DVM, PhD, Guest Editor
January 2005
Topics in Feline Medicine
James Richards, DVM, Guest Editor
March 2005
Emergency Medicine
Kenneth J. Drobatz, DVM, Guest Editor
RECENT ISSUES
July 2004
Clinical Nephrology and Urology
India F. Lane, DVM, MS,
S. Dru Forrester, DVM, MS,
Shelly L. Vaden, DVM, PhD, Guest Editors
May 2004
Ocular Therapeutics
Cecil P. Moore, DVM, MS, Guest Editor
March 2004
Ear Disease
Jennifer L. Matousek, DVM, MS, Guest Editor
The Clinics are now available online!
Access your subscription at:
www.theclinics.com
Preface
Current Issues in Cardiology
Guest Editor
It has been six years since the Veterinary Clinics of North America: Small
Animal Practice
has addressed topics in cardiology. Although the expression
‘‘information explosion’’ is somewhat hackneyed, it is also apt; in the
30-some years since the birth of modern veterinary cardiology, knowledge
has expanded at an astonishing rate. Therefore, when asked to compile and
edit an issue that could take its place in the venerable Clinics series, I was
initially at a loss. I was struck not only by the magnitude of recent advances,
but also by their diversity. To emphasize a single topic in cardiology might
serve to diminish important findings in other areas. Possibly, this approach
would also lead to an ultimately unrewarding digression into esoterica. In-
stead, this issue addresses a broad range of subjects in an attempt to provide
an overview of current topics in veterinary cardiology.
The initial articles outline recent advances in cardiovascular diagnosis.
The use of neuroendocrine biomarkers in the diagnosis of cardiovascular
disease is addressed, and then recent advances in the practice of echocardiol-
ogy are reviewed. Subsequent articles address current issues in cardiovascu-
lar therapy: the use of the inodilator pimobendan is reviewed, the potential
of beta-blockade in the management systolic dysfunction is evaluated, and
the growing field of minimally invasive techniques is represented by a review
of interventional antiarrhythmic therapy. The therapeutic challenges posed
by atrial fibrillation are the focus of another article. Finally, in a series of
updates, current issues in the diagnostic and therapeutic management of
specific disorders are addressed. The reader is fortunate that prominent
experts were willing to share their views on such vital and exciting topics
Jonathan A. Abbott, DVM
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.06.004
Vet Clin Small Anim
34 (2004) xi–xii
in veterinary cardiology. As Guest Editor, I was fortunate that such accom-
plished clinical scientists gave freely of their time and expertise. I wish to
acknowledge these authors and express sincere thanks for their willingness
to contribute to this issue.
Jonathan A. Abbott, DVM
Department of Small Animal Clinical Sciences
VMRCVM, Virginia Tech
Phase II Duckpond Drive
Blacksburg, VA 24061, USA
E-mail address:
xii
J.A. Abbott / Vet Clin Small Anim 34 (2004) xi–xii
Dedication
To my parents, DA and JA, and, of course, to ARA, MHA, and SJA.
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.06.003
Vet Clin Small Anim
34 (2004) xiii
Advances in echocardiography
Mark A. Oyama, DVM
Department of Veterinary Clinical Medicine, College of Veterinary Medicine,
University of Illinois, 1008 West Hazelwood Drive, Urbana, IL 61802, USA
Echocardiography is an exceptionally useful technique for diagnosing
cardiovascular disease in small animals. It is noninvasive and provides
a wealth of data concerning cardiac morphology and function. For many
patients, echocardiography is the definitive diagnostic tool. A well-
performed study coalesces the findings of the physical examination, electro-
cardiogram, and radiographs into a clearly defined diagnosis on which
treatment decisions can be based. More so than other diagnostic techniques,
echocardiography is highly operator dependent and relies on the proper
acquisition and interpretation of results by an examiner who is familiar with
the principles, capabilities, and limitations of ultrasound imaging. This
article reviews the basics of echocardiography, measurement of cardiac
dimensions, and assessment of cardiac function. Within these sections,
emerging technologies that expand the capabilities of the echocardiographic
examination are introduced. It is not within the scope of this article to
provide a comprehensive review of ultrasound principles or technique, and
the interested reader is referred to several additional resources
Principles of ultrasound
Sound is propagated through media in the form of a wave with
a characteristic frequency and wavelength. Ultrasound is not detected by
the human auditory apparatus because of a much higher frequency than that
of audible sound (ultrasound frequency [20,000 Hz versus audible sound
frequency of 50–12,000 Hz). The high frequency of ultrasound permits
focusing and directional control of the sound beam and reflection by small
objects in the submillimetric range. The interaction between ultrasound and
tissue consists of wave reflection, refraction, transmission, and attenuation
(
). Waves that are reflected back to the transducer are detected,
E-mail address:
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.004
Vet Clin Small Anim
34 (2004) 1083–1104
converted into electrical signals, amplified, and displayed as video pixels of
variable brightness.
Resolution, attenuation, and ultrasound frequency
When performing an echocardiographic examination, the user is attempt-
ing to discern small structures of the heart that may only be several
millimeters apart. The ability of ultrasound to distinguish these features is
referred to as the resolution of the system. More specifically, axial resolution
is the ability to discern between two objects lying parallel to the direction of
the beam and is dependent on the frequency and duration of the ultrasound
signal. In general, beams with a higher frequency (and shorter wavelength)
have a greater axial resolution (
). Therefore, ultrasound waves are
better suited for image acquisition than are sound waves in the auditory
range, and ultrasound waves with higher frequencies possess greater re-
solution than those with lower frequencies.
Fig. 1. The interaction of ultrasound waves with tissue involves reflection of waves back toward
the transducer, refraction or bending of waves, transmission of waves to greater depths, and
attenuation of waves as a result of energy loss in the form of wave scatter and heat production.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
Attenuation refers to the loss of energy of the ultrasound wave as it travels
through media. Attenuation is the result of energy absorption and pro-
duction of heat as well as scattering of the ultrasound beam in directions that
cannot be recovered by the transducer. Attenuation is greatest when using
ultrasound beams of high frequency, and the paradoxic relation between
beam resolution and attenuation gives rise to one of the great limitations of
ultrasound examination. Wave attenuation is significant because it restricts
examination of structures deeper within the viewing field, and the examiner is
faced with the dilemma of enhancing beam penetration at the expense of
resolution and vice versa.
Echocardiographic examination
Instrumentation
Newer ultrasound machines are typically equipped with broadband
transducers capable of imaging at several different frequencies. Transducers
that generate a fan-shaped beam (sector scan) are most practical when
attempting to interrogate veterinary patients with a relatively small trans-
thoracic cardiac window. Transducer frequency is selected based on the
highest frequency that can adequately penetrate to the structures of interest,
thus achieving a reasonable balance between resolution and penetration.
Most large-breed dogs are imaged using a transducer frequency between 3.0
and 5.0 MHz (1 MHz = 1
10
6
Hz). Smaller dogs are imaged at a higher
frequency, usually between 5.0 and 8.0 MHz, and cats are imaged at
a frequency between 7.0 and 10 MHz. After the proper transducer frequency
is selected, images are idealized by adjusting machine gain, gray scale, field
depth, beam focusing, reject, and postprocessing filters.
Fig. 2. The interaction of an ultrasound wave of low (A) and high (B) frequency with a series of
objects displays the association between axial resolution and wave frequency. The high-
frequency wave demonstrates superior axial resolution by virtue of its ability to discern the close
relation of objects along its axis.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
Echocardiographic modalities
Virtually all echocardiographic units are equipped with M-mode and two-
dimensional (2D) sector scanning capabilities. Many higher end units also
provide spectral and color-flow Doppler imaging. M-mode echocardiogra-
phy is one of the oldest imaging modalities, and its application toward
cardiac evaluation is extensive. The M-mode study is generated from a single
line of ultrasound, providing an ‘‘ice-pick’’ view of the heart; the linear
echoes persist on the screen so that cardiac motion is displayed over time.
The examiner orients the study by positioning a cursor across a simultaneous
2D image. Advantages of M-mode study include high pulse-repetition
frequency, which results in excellent temporal resolution, high axial
resolution, ease of image acquisition, and reproducibility of measurements.
The 2D sector scanning displays cardiac structures in a familiar anatomic
fashion and is more intuitive than the M-mode study. A 2D examination
forms the basis of diagnostic echocardiography, and achievement of tech-
nically adequate images is imperative for successful evaluation.
Doppler echocardiography reveals the pattern of blood flow within the
cardiac chambers and great vessels and is typically separated into spectral
and color-flow modalities. Cardiac abnormalities cause disruptions in flow
that can be identified via a Doppler study. Spectral Doppler echocardiog-
raphy displays the velocity and direction of blood flow in a graphics format
displayed separately from the M-mode or 2D image. Color-flow Doppler
superimposes color-coded Doppler information over the gray scale 2D
image, permitting rapid appreciation of the location and direction of blood
flow in relation to cardiac structures. Flow toward and away from the
transducer is displayed as red or blue, respectively. Turbulent blood flow is
displayed as a mosaic pattern of light blue, yellow, or green as selected by the
operator. A color-flow study is often used to identify areas of abnormal blood
flow, which are then further examined by the spectral Doppler modality.
Acquisition of echocardiographic images
A persistent source of frustration for the echocardiographer is ultrasound
artifact. Artifact can involve distortion of echo signals (eg, reverberation,
‘‘ring-down’’ artifact), display of false echo signals (eg, reverberation, mirror
images, side-lobe artifact), or removal of real echo signals (eg, attenuation,
scatter, shadowing artifact). The improvement of image quality and sup-
pression of ultrasound sound artifact is one of the primary goals of new
ultrasound technology.
Tissue harmonic imaging
Tissue harmonic imaging (THI) is a way to improve image quality in
technically demanding cases in which the patient is a poor echocardiographic
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
subject (ie, obese or barrel-chested dogs). THI reduces ultrasound artifact; by
doing so, it amplifies the reflective properties of the myocardial–blood pool
interface, enhances the delineation of the endocardial borders, and improves
the confidence and repeatability of cardiac measurements
. THI is made
possible by the nonlinear nature of sound wave propagation through biologic
media
. As ultrasound waves travel through tissue, they induce small
amounts of compression and expansion, thereby changing the density of the
tissue, the velocity of propagation, and the shape of the sound wave. This
effect is magnified as the sound wave penetrates deeper into the tissue,
producing reflective frequencies that are multiples of the original transmitted
frequency (harmonics) (
). The generation of harmonic signals is
cumulative and in direct proportion to beam depth, which is radically
different than the progressive attenuation of the fundamental ultrasound
wave. Generation of harmonic waves is greatest for tissues directly on the
main axis of the ultrasound beam. THI enhances the conspicuity of these
tissues while decreasing the detection of reflected signals from off-axis
sources, reverberation, scatter, or side-lobes. When compared with the
fundamental frequency, THI results in detection of ultrasound waves with
a superior signal-to-noise ratio and improvement in image clarity (
THI takes advantage of wideband transducer technology. When using
second harmonic THI, the ultrasound unit transmits using a fundamental
frequency (f
0
) but only receives and processes reflected echoes at the higher
second harmonic frequency (2f
0
). In this manner, THI benefits from the use
of a low-frequency fundamental wave, with deep tissue penetration and
image reconstruction based on a higher second harmonic frequency with
greater resolution. In clinical practice, THI substantially improves image
Fig. 3. Theoretic ultrasound spectrum demonstrating the fundamental frequency (f
0
) and its
second (2f
0
), third (3f
0
), and fourth (4f
0
) components. Tissue harmonic imaging transmits at the
fundamental frequency but only receives and constructs the ultrasound image from the
harmonic components.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
quality, and for many echocardiographers, the degree of improvement
warrants the exclusive use of THI when performing 2D examinations.
Two-dimensional frame rate
The frame rate of the ultrasound study is defined as the number of images
displayed per second, with higher rates offering greater temporal resolution
of cardiac events. For example, if the mitral valve moves from an open to
closed position in one twentieth of a second and the frame rate of the system
is 20 frames per second, the valve is open in the first frame and closed in the
next. A higher frame rate of 100 frames per second contains 3 intermediate
frames with information regarding the intervening course of mitral valve
excursion and provides greater temporal resolution. An ultrasound unit’s
maximum frame rate depends on the density of the raw data it can collect.
Ultrasound machines generate a certain amount of data per unit time, and
this information has to be divided among the video frames that are ultimately
displayed. Thus, excessively high frame rates risk diluting out the available
ultrasound data to the point of poor image quality. Newer ultrasound units,
Fig. 4. Right parasternal long-axis view of the left ventricular outflow tract and aorta using
fundamental two-dimensional imaging (A) and second harmonic tissue imaging (B). Left apical
view of the left ventricle and left atrium using fundamental imaging (C) and second harmonic
tissue imaging (D). All studies were performed using a transmitted frequency of 2 MHz. Studies
B and D display improved clarity of image, particularly with regard to the endocardial–blood
pool border and the aortic (B) and mitral (D) valves.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
by shortening the duration of transmitted ultrasound pulses, increase the
density of returned information per unit time (known as the line repetition
frequency), and the construction of a large number of frames per second
without substantial sacrifice in image quality is achievable. As a result, 2D
studies with outstanding resolution and image quality can now be performed
at frame rates in excess of 100 frames per second versus 25 to 30 frames per
second just years ago.
Measurement of cardiac dimensions
Cardiac disease causes change in cardiac geometry and dimensions. An
invaluable use of echocardiography is quantification of cardiac size with
respect to chamber dimension and wall thickness. Traditionally, measure-
ments of the left atrium and left ventricle (LV) are derived from M-mode
images obtained from the right short- and long-axis views
. From these
measurements, indices of global LV systolic function, such as percent
fractional shortening and ejection fraction, can be calculated. It is apparent
that the determination of cardiac function relies on accurate measurement of
cardiac dimensions, and technical difficulties, such as improper alignment,
poor image quality, and inadequate delineation of the endocardial–blood
pool interface, can lead to erroneous results. With regard to these issues,
three specific developments are particularly relevant, including harmonic
imaging as previously discussed, anatomic M-mode (AMM), and 2D men-
suration of left atrial diameter (LAD).
Anatomic M-mode
Proper M-mode measurement of the LV is performed along a line that is
perpendicular to the short or long axis of the heart; yet, in many patients, this
alignment is difficult to achieve. The AMM generates M-mode studies from
2D cine loops; however, unlike the conventional M-mode, whose scan line
must lie along the axis of the ultrasound beam, the AMM is able to produce
images independent of the orientation of the ultrasound beam. This allows
the examiner to align the study based on the direct spatial orientation of the
heart as seen on the 2D image (
). AMM studies are constructed from
raw 2D digital data before conversion to an analogue video signal and benefit
from the high frame rates and superior resolution available in newer
ultrasound units
. The sharpness of the AMM study is comparable to
that of the conventional M-mode study, and detection of the endocardial–
blood pool interface is readily accomplished (
). The AMM reduces the
variability of LV measurements and improves correlation with measure-
ments made directly from the 2D image
. In clinical practice, the
AMM can increase reproducibility of measurements, improve accuracy, and
permit evaluation of regional cardiac function from a single 2D study.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
Fig. 5. Examples of the orientation of conventional and anatomic M-mode (AMM) studies of
the left ventricle from the right parasternal long-axis (A) and short-axis (B) views, and the
diameter of the aorta and left atrium from the right parasternal short-axis view (C). The origin
of the conventional M-mode study (dotted line) is fixed at the apex of the sector scan and cannot
be positioned perpendicular to the axis of the left ventricle (A, B) or incorporate the widest
portion of the left atrium (C). In contrast, the AMM study (solid line) can be detached from the
sector apex and properly positioned across the ventricle (A, B) and placed across the main body
of the left atrium (C).
Measurement of left atrial size
Insofar as cardiac disease leads to increased atrial filling pressures and the
development of congestive heart failure, the LAD is a crucial index of disease
severity. Veterinary ultrasonographers are familiar with the typical orienta-
tion of the canine heart when attempting to perform M-mode studies of the
LAD, and they realize that many M-mode studies do not include the widest
portion of the left atrial chamber, resulting in M-mode measurements that
underestimate true atrial size (see
). In contrast, the main body and
widest portion of the left atrium are readily appreciated from the 2D right
Fig. 6. Conventional M-mode (A) and anatomic M-mode (AMM) (B) studies of the left
ventricle from the right parasternal short-axis view. The image quality of the AMM study is
comparable to that of the conventional M-mode study. The inset displays the orientation of the
AMM study based on the two-dimensional image.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
parasternal short-axis view at the level of the heart base. The AMM and 2D
methods use this view to improve measurement of the LAD. First, the AMM
enables the examiner to detach the M-mode cursor from the ultrasound
beam’s point of origin and to align the study across the widest portion of the
atrium (see
). Second, measurements of left atrial size can be directly
made from the 2D image and may include the circumference or area of the
atrial chamber as well as the diameter (
. These measurements
more closely approximate the maximum size of the atrium and are more
likely accurate and representative of disease severity. Studies have demon-
strated that the LAD and resulting LAD/aortic root diameter (Ao) ratio are
underestimated using conventional M-mode techniques compared with
either AMM or 2D measurement
. This bias is increasingly exaggerated
as the LAD increases, suggesting that AMM or 2D measurements possess
greater sensitivity for left atrial enlargement versus conventional M-mode
measurements
. The use of 2D-derived LAD and the LAD/Ao ratio is
widespread; in many laboratories, it is the basis for left atrial evaluation in
dogs, although it is only recently that 2D measurement of the LAD/Ao ratio
has been systematized and normative data published (
.
Beginning echocardiographers should be aware of the limitations of M-mode
measurement and consider incorporating one of the 2D (or AMM)
techniques into their routine echocardiographic examination.
Indexing measurements of cardiac dimension
Cardiac dimensions have generally been referenced against values that are
based on the patient’s body weight. Many references incorrectly assume that
the relation between heart size and body weight is linear, leading to ‘‘normal’’
ranges that are ineffectually wide, especially at the extremes of body weight,
both small and large
. Studies have demonstrated that the relation
between length and body weight is best described as nonlinear. In fact, body
weight is proportional to length cubed, and this finding significantly
influences the interpretation of cardiac measurements and greatly diminishes
the clinical utility of reference ranges based on linear regression
Attempts to address this problem have included the development of
weight-based reference ranges derived from exponential, logarithmic, or
polynomial models (
) or the use of shape-based indexes. The use of
indexing is attractive from several standpoints. Indexes (1) eliminate the need
for a large table of normal values that span a range of weights, (2) are
independent of the size of the animal, (3) are easily calculated, and (4) seem to
be valid over a range of species. Brown et al
have proposed an indexing
system based on the Ao, which is similar in theory to the familiar LAD/Ao
ratio. By indexing one measure of length (ie, LV internal dimension) against
another (ie, Ao), a nondimensional unitless ratio is formed that is in-
dependent of animal size. These so-called ‘‘shape ratios’’ are valid across
animals of differing size so long as their basic shape (anatomic proportion-
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
ality) remains the same. In its simplest iteration, M-mode dimensions of the
LV and atrium are divided by the M-mode dimension of the aortic root, and
a preliminary range of indexed values based on examination of 53 normal
dogs has been published (
)
. Alternatively, the cardiac dimensions
can be indexed against a theoretic Ao based on the cube root of the patient’s
Fig. 7. Examples of four different methods to measure the left atrial diameter (LAD) and aortic
root diameter (Ao) from the right parasternal short-axis view. (A) The Ao is measured along
a line formed by the commissure of the noncoronary and right coronary aortic valve cusps from
the inner edge to inner edge of the aortic wall. The LAD is measured along a line extending
from the commissure of the noncoronary and left coronary aortic valve cusps from the inner
edge to inner edge of the left atrial wall. (B) The circumference and area of the left atrium and
aortic root are derived by tracing a line along the inner edge of the aortic and atrial walls. (C)
The LAD is measured perpendicular to a line that bisects the atrium from an apicobasilar
orientation and parallel to the mitral valve annulus. The LAD measurement is made halfway
between the plane of the mitral valve and roof of the atrium from the inner edge to the inner
edge of the left atrial wall. The LAD/Ao ratio is calculated by using the Ao measurement
obtained via method A. (D) The Ao is measured along a line extending from the midpoint of the
right aortic valve sinus to the commissure of the noncoronary and left coronary aortic valve
cusps. The LAD is measured by extending this line to the inner edge of the opposite left atrial
wall. (A–C adapted from Rishniw M, Erb HN. Evaluation of four 2-dimensional
echocardiographic methods of assessing left atrial size in dogs. J Vet Intern Med
2000;14:429–35; with permission. D adapted from Hansson K, Haggstrom J, Kvart C, Lord
P. Left atrial to aortic root indices using two-dimensional and M-mode echocardiography in
Cavalier King Charles spaniels with and without left atrial enlargement. Vet Radiol Ultrasound
2002;43:568–75; with permission.)
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
body weight, which accounts for the nonlinear relation between measures of
diameter and weight (Ao diameter = kW
1/3
, where k = a species-specific
constant and W = body weight). Readers who are specifically interested in
the derivation and methodology of the weight-based aortic diameter index
are referred to the original published work by Brown et al
. Compared
with its applicability in dogs, shape-based indexing offers less advantage over
conventional reference ranges in cats. This is most likely a result of the more
homologous somatotype (ie, shape) of cats of different breeds, ages, and
genders, for example. The indexing of cardiac dimensions has a future impact
on the practice of echocardiography by providing uniformity of method and
facilitating the comparison of study results between different examiners,
particularly within species with a wide variety of conformations. Across
different animal species, the use of shape-based indexing has the potential for
comparative physiologic study and provision of additional insight into the
response of heart size to cardiac disease.
More recently, Cornell et al
investigated the use of allometric scaling
in the development of normative echocardiographic data. In this context, the
allometric equation describes the relation between cardiac dimensions and
body weight adjusted by a proportionality constant and a scaling exponent.
These investigators determined that cardiac dimensions were generally
proportional to body weight raised to an exponent that was close to one
third. This result was consistent with the logical assumption that body weight
is related to the cube of linear dimensions. M-mode variables indexed to the
body weight raised to their scaling exponent were used to propose reference
intervals.
Table 1
Descriptive statistics for the left atrium–to-aorta diameter ratio in 36 normal dogs (study 1)
and 56 normal Cavalier King Charles Spaniels (study 2)
Percentiles
Study 1
5
25
50
75
95
Diameter (
0.86
1.18
1.31
1.42
1.57
Circumference (
1.51
1.83
1.98
2.20
2.35
Area (
1.76
2.20
2.83
3.30
3.68
Diameter (
)
1.11
1.53
1.66
1.80
1.99
Study 2
Mean
SD
95% range
Diameter (
)
1.03
0.09
0.85–1.21
See text and
for description of method.
a
Adapted from
Rishniw M, Erb HN. Evaluation of four 2-dimensional echocardiographic
methods of assessing left atrial size in dogs. J Vet Intern Med 2000;14:429–35; with permission.
b
Data from
Hansson K, Haggstrom J, Kvart C, Lord P. Left atrial to aortic root indices
using two-dimensional and M-mode echocardiography in Cavalier King Charles spaniels with
and without left atrial enlargement. Vet Radiol Ultrasound 2002;43:568–75.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
Assessment of ventricular diastolic function
The normal diastolic function of the heart allows filling of the ventricles
without an increase in atrial pressure. During diastole, filling of the heart
occurs in two distinct phases. Early filling is achieved via a combination of
active (energy-dependent) myocardial relaxation and the passive elastic recoil
of the ventricle as it ‘‘rebounds’’ from systole. These events cause ventricular
pressure to fall, open the atrioventricular valves, and commence atrial-to-
ventricular blood flow. It is during this early phase that most diastolic filling
occurs (approximately 80%). The remaining 20% of ventricular filling is
achieved in late diastole via contraction of the atrial myocardium. For any
individual, the balance between early and late filling depends on the rate of
active relaxation, the elastic nature of the myocardium, and the atrial-
ventricular pressure gradient. In patients with diastolic dysfunction, the rate
of myocardial relaxation is slowed and the balance of filling shifts toward late
diastole
. If diastolic function continues to deteriorate, atrial pressure
increases in an effort to maintain effective filling of the ventricles, and the
increased atrial-ventricular pressure gradient shifts the pattern of diastolic
blood flow back toward predominantly early filling.
Diastolic dysfunction is common in veterinary medicine, particularly in
cats with myocardial disease. In cats with hypertrophic and restrictive
cardiomyopathy, the rate of myocardial relaxation and compliance of the
Fig. 8. The relation between body weight and the left ventricular diastolic internal dimension
(LVIDd) displaying the mean and 95% confidence intervals of regressions based on linear
(dotted line) and nonlinear (solid line) equations. The linear regression possesses wider
confidence intervals and overestimates the LVIDd at small and large body weights when
compared with the more appropriate nonlinear analysis. (Adapted from Brown DJ, Rush JE,
MacGregor J, et al. M-mode echocardiographic ratio indices in normal dogs, cats, and horses:
a novel quantitative method. J Vet Intern Med 2003;17:653–62; with permission.)
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ventricle are abnormal, leading to elevations in atrial pressure and de-
velopment of congestive heart failure
. Insofar as the extent of
diastolic dysfunction contributes to morbidity and mortality, quantification
of diastolic performance is of particular interest to the clinician. Diastolic
function can be measured using a variety of parameters, including mitral and
pulmonary vein inflow velocity and, more recently, Doppler imaging of the
mitral valve annulus and color-flow M-mode imaging of mitral valve inflow.
Mitral inflow velocity
Interrogation of mitral inflow using spectral Doppler imaging reveals the
two phases of ventricular filling, identified as the early wave (E) and the late
atrial wave (A). The peak velocity of these waves is a surrogate measure of
the amount of left ventricular filling that occurs during each component of
diastole. Thus, a normal patient displays a greater E velocity compared with
A velocity, and an E-to-A velocity ratio (E/A) greater than 1. Patients with
early diastolic disease possess impaired early relaxation of the LV and have
a reduction of E velocity as compared with A velocity, resulting in an E/A
less than 1 (
). In subjects with an impaired relaxation pattern, the left
atrial pressure is usually normal or only slightly increased, and congestive
heart failure is typically absent; however, as diastolic function continues to
deteriorate, the pattern of mitral inflow velocity changes. Increased atrial
pressure results in early opening of the mitral valve, augmented early filling,
high E velocity, and a rapid rise in ventricular pressure. Late in diastole, A
velocity is diminished because of ventricular pressure that is already
Table 2
Mean value and 95% reference range of M-mode–derived cardiac dimensions indexed to the
diameter of the aortic root in 53 healthy dogs
Indexed parameter
Mean
SD
95% range
Canine
IVSd
0.440
0.077
0.286–0.594
IVSs
0.598
0.101
0.396–0.800
LVPWd
0.413
0.068
0.277–0.549
LVPWs
0.615
0.100
0.415–0.815
LVDd
1.608
0.202
1.204–2.012
LVDs
1.055
0.171
0.713–1.397
LAD
1.012
0.139
0.734–1.290
The reference ranges provided should be considered a general guideline only; the clinical
utility of this mensuration method has not been prospectively evaluated.
Abbreviations:
IVSd, interventricular septal thickness in diastole; IVSs, interventricular
septal thickness in systole; LAD, left atrial diameter; LVDd, left ventricular chamber diameter
in diastole; LVDs, left ventricular chamber in systole; LVPWd, left ventricular posterior wall
thickness in diastole; LVPWs, left ventricular posterior wall thickness in systole.
Adapted from
Brown DJ, Rush JE, MacGregor J, et al. M-mode echocardiographic ratio
indices in normal dogs, cats, and horses: a novel quantitative method. J Vet Intern Med
2003;17:653–62; with permission.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
abnormally elevated. This pattern of mitral inflow indicates restrictive
diastolic filling and is characterized by elevated E velocity, decreased A
velocity, and an E/A much higher than 1 (see
). Patients with
a restrictive pattern often demonstrate elevated atrial pressures in the form
of congestive heart failure. Assessment of diastolic function based on mitral
inflow velocity seems straightforward; however, the transition from impaired
relaxation to restrictive filling involves a phase during which mitral velocity
profiles resemble those of a normal patient. Specifically, this pseudonormal
pattern displays normal E and A velocities and an E/A greater than 1 (see
). In patients with a pseudonormal filling pattern, the development of
moderately elevated atrial pressure masks the presence of underlying
impaired ventricular relaxation, leading to an erroneous clinical assumption
of normal diastolic function. Because of this and other limitations of the
mitral inflow velocity method, thorough assessment of diastolic function
Fig. 9. Schematic demonstrating Doppler studies of mitral inflow and mitral valve annular
motion over the course of diastolic heart disease. Mitral inflow studies are performed using
conventional Doppler imaging, whereas mitral annular studies are performed using Doppler
tissue imaging (DTI). In normal subjects, the velocity profile of mitral inflow and mitral annular
motion display velocities in early diastole (E and E
DTI
) is greater than in late diastole (A and
A
DTI
). In patients with impaired relaxation, the velocity profile reverses, demonstrating greater
A and A
DTI
velocities than E and E
DTI
velocities. As diastolic function worsens, left atrial
pressure (LAP) rises and the mitral inflow pattern undergoes pseudonormalization, resulting in
a profile similar to that in normal subjects (E > A). In contrast, the velocity profile of the mitral
annulus remains abnormal (E
DTI
\ A
DTI
). In patients with restrictive diastolic filling and
markedly elevated LAP, mitral inflow study demonstrates E velocity much higher than A
velocity (E
A), whereas the mitral annular study continues to indicate poor diastolic function
(E
DTI
\ A
DTI
).
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
typically includes simultaneous interrogation of pulmonary venous inflow or
a relatively new ultrasound technology called Doppler tissue imaging (DTI).
Doppler tissue imaging
In contrast to a conventional Doppler study that interrogates blood flow
velocity, DTI examines the motion of cardiac tissue, particularly the diastolic
velocity of the mitral valve annulus
. The velocity of the annulus
represents the rate of change of ventricular length during diastolic filling.
Abnormalities of diastolic function alter early and late diastolic annular
velocity (E
DTI
and A
DTI
, respectively). The interpretation of DTI studies
mirrors that of mitral inflow velocity in that poor diastolic function is
revealed by a decreased E
DTI
, elevated A
DTI
, and an E
DTI
/A
DTI
less than 1;
however, unlike a conventional Doppler study, DTI is relatively insensitive
to the effects of left atrial pressure and is useful in differentiating the
pseudonormal pattern from normal (see
. In cases of
moderate to advanced diastolic dysfunction, increased left atrial pressure
does not affect the balance between early and late annular motion, and the
Fig. 10. Mitral valve annulus motion obtained from the left apical view using Doppler tissue
imaging. The studies demonstrate the relation between early and late diastolic motion in
a normal subject (E
DTI
> A
DTI
) (A) and in a patient with impaired diastolic relaxation and
reversal of the velocity profile (E
DTI
\ A
DTI
) (B).
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
E
DTI
/A
DTI
typically remains less than 1. DTI has been studied in a variety of
veterinary populations, including normal cats and dogs
; cats with
hypertrophic and restrictive cardiomyopathy
; and dogs with mitral
regurgitation, dilated cardiomyopathy, and subaortic stenosis
. The
results of these studies have demonstrated that (1) acquisition of DTI studies
is feasible in the dog and cat; (2) DTI measures correlate well with traditional
invasive measures of diastolic function; (3) DTI provides information
concerning the relative effects of relaxation, ventricular compliance, and
filling pressures on diastolic function; and (4) patients with cardiac disease
demonstrate altered diastolic tissue velocities compared with normal
patients. The full clinical application of DTI has yet to be realized. The
promise of DTI is development of a rapid, easily obtainable, accurate, and
quantitative measure of diastolic heart function, which has been lacking
previously in clinical echocardiography. In addition to furthering our
understanding of diastolic abnormalities and their progression during the
course of disease, it is anticipated that DTI can help to test the efficacy of new
treatment strategies.
Color Doppler M-mode imaging
Color M-mode imaging superimposes a color-flow Doppler study over
a conventional M-mode study, permitting the study of blood flow in relation
to the anatomic structures. Unlike the 2D color-flow study, which is
displayed as a series of images run over time, the use of M-mode permits
the display of blood flow over time on a single image. Color M-mode
interrogation of the early inflow of blood from the left atrium to LV (early
mitral inflow) represents the velocity of blood flow (centimeters per second)
along the length of the LV throughout the entire early portion of diastole
Similar to the aforementioned DTI parameters, this measure of mitral inflow
propagation velocity, V
p
, is relatively independent of atrial filling pressures
and possesses a strong correlation with LV relaxation; hence, its suitability as
an index of diastolic heart function. V
p
decreases in patients with poor
ventricular relaxation and is recognized as a decrease in the slope of the color-
flow M-mode signal (
). In healthy anesthetized cats, V
p
possesses good
correlation with invasive measures of LV relaxation and was superior to
other echocardiographic indices, including velocity of the mitral valve
annulus in early diastole (E
a
)
. In practice, the clinical application of V
p
has been hindered by a large degree of variability based on measurement
technique, machine settings, and influence of systolic function on measured
values
. Nonetheless, the recent study of a variety of noninvasive
indices of LV relaxation speaks to the growing emphasis on diastolic heart
function and its role in the development of cardiac disease.
One particularly intriguing application of indices of LV relaxation
involves the noninvasive estimation of left atrial pressure through the
combined use of mitral inflow and DTI or V
p
values
. As previously
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
discussed, the velocity of mitral blood flow as determined by conventional
Doppler echocardiography (E) is affected by LV relaxation and left atrial
pressure, whereas E
a
and V
p
are primarily indices of ventricular relaxation.
By combining the values as either E/E
a
or E/V
p
, the effects of LV relaxation
can be theoretically removed from E, leaving in its place a relatively pure
index of atrial pressure. In healthy anesthetized cats, E/V
p
possessed
moderate correlation (R
2
= 0.64) with LV end-diastolic pressure (a surro-
gate measure of left atrial pressure)
, and in anesthetized dogs with acute
mitral regurgitation, E/E
a
possessed a similar correlation (R
2
= 0.71) to
mean left atrial pressure
. The ability to measure atrial pressure
noninvasively would have profound clinical implications in the diagnosis
and treatment of heart failure. Determination of atrial pressure would greatly
facilitate assessment of dyspneic patients with suspected cardiac disease,
would enable the monitoring of response to therapy, and would be useful in
determining the efficacy of new treatment strategies.
Assessment of severity of mitral valve disease
Degenerative mitral valve disease (MVD) is the most common acquired
heart disease in dogs. MVD causes mitral regurgitation; ventricular and
atrial enlargement; and in cases of severe disease, morbidity and mortality as
a result of exercise intolerance, fainting, and congestive heart failure. The
Fig. 11. Color M-mode study of mitral inflow demonstrating the measurement of mitral inflow
propagation velocity (V
p
) in a normal patient (A) and in a patient with suspected impaired left
ventricle relaxation (B). A line is drawn along the first color-aliasing boundary of the early wave
of mitral inflow. The slope of the line represents V
p
in units of centimeters per second and is
reduced in the patient with suspected diastolic function.
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
severity of MVD is proportional to the volume of regurgitation, and the ideal
determination of severity involves calculation of the regurgitant stroke
volume, regurgitant fraction, and regurgitant orifice area
. Because of the
relative complexity of attaining volumetric measurements, ultrasonogra-
phers often assess severity via surrogate echocardiographic parameters,
including the gross appearance of the mitral valve leaflets on 2D study, M-
mode and 2D measurement of left ventricular and atrial size, and color-flow
Doppler evaluation of the relative size and extent of the regurgitant blood
flow jet. These semiquantitative measures classify patients into categories of
mild, moderate, or severe disease but possess inadequate sensitivity to detect
significant changes in regurgitant volume. To increase sensitivity and
improve monitoring of disease progression in dogs with MVD, a color-flow
Doppler technique known as the proximal isovelocity surface area (PISA)
method has been investigated
Proximal isovelocity surface area method
During ventricular systole, blood flow moves from the LV toward the
mitral valve regurgitant orifice with increasing velocity. The velocity of the
blood flow is a function of its distance from the mitral valve. In an idealized
environment, the acceleration of blood toward the valve creates a series of
concentric hemispheres on whose surface are blood elements all moving at
the same velocity. The radius of a hemisphere extends from the surface of the
Fig. 12. Color-flow Doppler image from a dog with mitral valve regurgitation demonstrating
the proximal isovelocity surface area (PISA) method used to quantify the severity of disease.
The image was frozen in midsystole and displays blood flow moving toward the plane of the
mitral valve regurgitant orifice (dotted line). The color-flow Doppler settings were adjusted to
code blood flow yellow when velocity reached 0.84 m/s. A hemisphere of yellow above the
mitral valve annular plane can be identified and represents a shell of blood elements all moving
at 0.84 m/s. The radius (r) of the hemisphere is drawn from the edge of the hemisphere to the
plane of the mitral valve annulus. Blood flow through the mitral valve is calculated as the
product of hemisphere surface area and velocity (flow = velocity
2pr
2
).
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M.A. Oyama / Vet Clin Small Anim 34 (2004) 1083–1104
hemisphere to the level of the mitral valve regurgitant orifice (
). The
blood flow through the regurgitant orifice can be calculated as the product of
hemisphere surface area and the velocity that defines its radius (flow =
velocity
2pr
2
). Once calculated, blood flow can be multiplied by the
duration of mitral regurgitation (seconds) to yield regurgitant volume
(volume = flow
time). Regurgitant orifice area can be calculated as the
flow rate divided by the peak velocity of the mitral regurgitant jet. The PISA
method has been validated in dogs with mitral regurgitation and can track
serial changes in regurgitant volume in dogs treated with vasodilators
. As with all echocardiographic techniques, and perhaps even more
so, proper use of the PISA method relies on accurate alignment and
meticulous attention to image quality. Eccentrically directed regurgitant jets
can hinder measurement of the hemisphere radius, as can poor image quality,
improper filter settings, and deformation of the hemisphere caused by the
lateral constraining effect of the ventricular walls
. Another important
source of error involves the need for accurate identification of the plane of
the regurgitant orifice, especially because error of the radius measurement is
compounded to the second power. In clinical practice, the PISA method has
potential application for evaluation of disease progression, testing of drug
efficacy and treatment regimens, and improving our understanding of the
pathophysiology of mitral regurgitation.
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Neuroendocrine evaluation of cardiac
disease
D. David Sisson, DVM
Veterinary Teaching Hospital Cardiology Service, Department of Veterinary Clinical
Medicine, University of Illinois, 1008 West Hazelwood Drive, Urbana, IL 61802, USA
Heart failure is a complex clinical syndrome wherein reduced systolic or
diastolic performance of the heart results in increased activity of the
adrenergic nervous system, overexpression of atrial (ANP) and brain
(BNP) natriuretic peptides, activation of the renin-angiotensin-aldosterone
system (RAAS), increased synthesis and release of endothelin and arginine
vasopressin (AVP), and amplified expression of proinflammatory cytokines,
such as tumor necrosis factor-a, interleukin-1, and interleukin-6
Neuroendocrine responses to developing heart failure have been well
documented in human patients, and recently conducted studies support the
assertion that qualitatively similar responses operate in dogs and cats with
heart disease. Understanding these complex systems is vital to understanding
the modern treatment of heart failure, which is largely based on the concept
of blunting or otherwise modifying the excessive operation of certain
maladaptive neuroendocrine responses, such as the adrenergic system and
the RAAS. It is becoming increasingly evident that measurement of
particular neuroendocrine markers offers diagnostic, prognostic, and ther-
apeutic information not easily obtained by routine clinical evaluation,
sophisticated imaging, or hemodynamic assessments.
Plasma catecholamines
When cardiac output is depressed and blood pressure falls, the adrenergic
nervous system is activated. This results in an elevated heart rate, augmented
myocardial contractility, and the selective redirecting of blood flow to vital
centers. The systemic effects of generalized sympathetic stimulation include
arteriolar constriction, which helps to maintain tissue perfusion pressures.
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Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.005
Vet Clin Small Anim
34 (2004) 1105–1126
Myocardial performance, already compromised by underlying heart disease,
is negatively affected by the resulting mismatch of afterload to contractility.
This consequence is exaggerated in patients with chronic heart failure,
wherein downregulation of cardiac b
1
-receptors further diminishes the
contractile response. Adrenergic venous constriction results in increased
venous return (preload) augmenting cardiac output, but the resulting
increases in venous and capillary pressures aid in the development of
symptomatic congestion. Chronic exposure to high norepinephrine levels
contributes to pathologic vascular and cardiac remodeling, promotes
arrhythmogenesis, and induces premature death of myocytes
. More-
over, increased sympathetic discharge is a potent stimulus of the RAAS and
contributes to elevated circulating concentrations of AVP and endothelin
. The interactions of these systems are sufficiently complex that
unintended and unpredicted consequences may be observed in individual
patients in varying circumstances. For example, administration of a b-
receptor–blocking drug removes the adrenergic stimulus for renin release,
but renin levels may paradoxically increase if the negative chronotropic and
inotropic effects of beta-blockade serve to diminish effective renal perfusion.
Norepinephrine and epinephrine are small-molecular-weight hormones
synthesized by sequential modification of the amino acid,
L
-tyrosine. The
adrenal medulla synthesizes and stores norepinephrine and epinephrine and
releases them into the circulation in response to acute stress. Lacking the
enzyme phenylethanolamine N-methyltransferase, peripheral nerves do not
synthesize or release epinephrine (
). Norepinephrine (but not epineph-
rine) plays a central role as a neurotransmitter and is constantly released
from terminal sympathetic nerve endings. Despite reuptake and inactivation
of most of the norepinephrine released in this fashion, a small portion leaks
into the circulating blood so that plasma levels of norepinephrine, measured
at rest can serve as a useful index of sympathetic nervous system activity.
Plasma norepinephrine concentrations in human congestive heart failure
(CHF) patients correlate with the severity of heart failure and are inversely
related to survival
. In addition, rising concentrations of norepinephrine in
human patients treated for CHF correlate with a decline in clinical status
.
Importantly, catecholamine plasma concentrations rise in many circum-
stances other than heart failure, including emotional stress and physical
exertion, emphasizing the rather poor specificity of such measures. For these
reasons, interpretation of plasma catecholamine levels in individual animals
is always likely to be problematic. Obtaining suitable resting samples from
dogs and cats in a clinical setting is challenging, and there is large variation in
such measurements even in patients appropriately categorized according to
the severity of underlying heart disease.
For reasons already mentioned, blood sampling for measurement of
plasma catecholamine levels is ideally accomplished via preplaced indwelling
catheters from rested and relaxed subjects. Mean plasma epinephrine and
norepinephrine levels obtained and measured in this fashion in healthy
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
research cats are 221 and 424 pg/mL, respectively (D.F. Hogan, DVM, D.D.
Sisson, DVM, unpublished observations). When blood is obtained via
jugular venipuncture from unsedated client-owned cats, mean plasma
epinephrine and norepinephrine levels are greater than 250 and 1000 pg/
mL, respectively
. There can be little doubt that cats experience blood
sampling at a veterinary teaching hospital as a stressful event even when
attempts are made to minimize excitement and taxing distractions. The
requirements for sample handling are also rigorous, because plasma
catecholamines are subject to oxidation, necessitating the use of antioxidants
Fig. 1. Norepinephrine and epinephrine are synthesized by sequential modification of the amino
acid,
L
-tyrosine. The enzyme phenylethanolamine N-methyltransferase is present in the adrenal
medulla but not in the peripheral nerves, which neither synthesize nor release epinephrine. For
this reason, plasma norepinephrine levels are a better indicator of basal sympathetic nervous
system activity than epinephrine, which tends to rise more in response to acute stressors.
1107
D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
to preserve the samples before analysis, cold centrifugation, and storage at
temperatures less than 0(. Plasma epinephrine and norepinephrine concen-
trations are best determined by high-pressure liquid chromatography
(HPLC), which is cumbersome and expensive to perform, generally limiting
such measures to a research environment.
Limited studies of circulating catecholamine concentrations in dogs and
cats with spontaneously occurring heart disease have been conducted, but the
value of plasma norepinephrine as an independent predictor of mortality in
dogs or cats has not been determined. In cats with CHF or systemic
thromboembolism caused by hypertrophic cardiomyopathy (HCM) and
restrictive cardiomyopathy (RCM), we found that plasma epinephrine and
norepinephrine concentrations are greater than 2000 and 2500 pg/mL,
respectively
. In cats with HCM or RCM that are not in heart failure,
plasma epinephrine and norepinephrine concentrations are above 1500 and
1700 pg/mL, respectively
. In 1990, Ware et al
reported significantly
elevated plasma norepinephrine levels in dogs with heart failure caused by
dilated cardiomyopathy (DCM) and degenerative valve disease (DVD)
compared with normal dogs. In this study, plasma concentrations of
norepinephrine correlated directly with the severity of heart failure; they
tended to be higher in dogs with DCM compared with dogs with DVD.
Plasma epinephrine levels in dogs with heart failure were also slightly higher
than those measured in control dogs, but the difference was not statistically
significant. Observations from a much larger population of dogs (D.D.
Sisson, DVM, unpublished data) indicate that plasma norepinephrine and
epinephrine concentrations are significantly elevated in dogs with CHF (New
York Heart Association [NYHA] class III and IV) caused by DCM and
DVD. More modest elevations are found in dogs with more modest disease
(NYHA class I and II). These results provide convincing evidence of
increased sympathetic nervous system activity in dogs and cats with naturally
occurring heart disease not unlike that observed in human patients with
chronic heart failure
. Given the established adverse consequences of
chronic exposure to adrenergic stimulation and the proven efficacy of beta-
blockers in human trials, there is overwhelming evidence supporting the need
for carefully designed clinical trials evaluating the efficacy of b-receptor–
blocking drugs in dogs and cats.
Natriuretic peptides
ANP and BNP (B-type) are initially elaborated from cardiac mRNA as
long peptide sequences, termed pre-proANP and pre-proBNP, respectively
. Removal of a signal peptide from each yields shorter peptides, termed
proANP
and proBNP, which, in healthy animals, are stored in membrane-
bound granules in the atria for later release. The mature active ANP and
BNP hormones are cleaved from the carboxy- or C-terminal ends of the
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
proANP and proBNP molecules and released into the circulation together
with their respective amino- or N-terminal fragments, usually termed NT-
proANP
and NT-proBNP. The structures of mature ANP and BNP are
similar in that both contain a 17–amino acid ring closed by a disulfide bond
between two cysteine residues. The sequence and number of amino acids
comprising ANP and BNP are dissimilar, however, because they are encoded
by different genes
. In healthy human beings, cats, and dogs, circulating
forms of BNP and ANP are probably derived mainly from the atria
A third natriuretic peptide, C-type or CNP, is found primarily in the brain
and vascular endothelium. Circulating levels of CNP are much lower than
those of ANP and BNP in healthy animals and human beings, suggesting
that it acts in a paracrine fashion, inducing local relaxation of vascular
smooth muscle and inhibiting vascular remodeling.
Sudden rises in plasma ANP and BNP levels are accomplished by their
release from atrial storage granules mainly by the stimulus of atrial stretch.
Sustained increases in circulating ANP and BNP, as seen in patients with
heart disease, are accomplished by increased mRNA expression in different
regions of the heart
. In some species, plasma BNP concentrations rise
dramatically and often surpass ANP levels as the major site of BNP
production switches from the atria to the ventricles
. We found that
cats with HCM demonstrate marked increases in the expression of BNP in
the atria and ventricles
. Others studying dogs with experimental pacing-
induced heart failure reported that ventricular BNP expression remains
rather modest and that the atria remain the predominant source of most
circulating BNP
. Some caution is warranted in the interpretation of such
studies, because gene expression is difficult to quantify and tissue levels do
not necessarily reflect the amount of peptide synthesized and released.
Nonetheless, a growing body of experimental evidence indicates that the
patterns of ANP and BNP gene expression vary in different species and in
relation to the type of underlying heart disease
The physiologic actions of ANP and BNP generally oppose those exerted
by the RAAS
. ANP and BNP act via the A-type natriuretic peptide
receptor (NPR-A) to induce natriuresis and diuresis by inhibiting tubular
sodium transport in the inner medullary collecting duct of the kidney. This
same receptor type mediates vasorelaxation of systemic and pulmonary
arterioles, thereby decreasing systemic and pulmonary vascular resistance.
Additional actions of ANP and BNP mediated by NPR-A include direct
inhibition of the release of renin by the kidney and the release of aldosterone
from the adrenal cortex. A second receptor, the B-type natriuretic peptide
receptor (NPR-B), responds to ANP and BNP but preferentially mediates
vasodilation from locally produced CNP. Mature ANP and BNP are
removed from the circulation by the clearance receptor, C-type natriuretic
peptide receptor (NPR-C), which internalizes ANP and delivers it to
lysosomes for degradation, and by a membrane-bound ectoenzyme, neutral
endopeptidase, which cleaves ANP into inactive peptide fragments. Neutral
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
endopeptidase shows greater activity for ANP than for BNP, and NPR-C
exhibits greater selectivity for ANP than for BNP, offering an explanation
for the longer plasma half-life of BNP
. N-terminal fragments of
proANP (NT-proANP) and proBNP (NT-proBNP) are removed more
slowly from the circulation than their C-terminal counterparts, because
clearance of these peptides is more dependent on renal excretion. As a result,
NT-proANP and NT-proBNP plasma levels are higher than and not as labile
as their C-terminal counterparts. In general, the N-terminal peptides are
more sensitive markers of heart disease, and their levels tend to correlate
more closely with the severity of underlying heart disease
. Impor-
tantly, assays measuring N-terminal fragments are also more likely to be
affected by altered renal function; thus, this variable must be taken into
consideration when interpreting plasma levels of an individual patient.
The amino acid sequence of active C-terminal ANP is remarkably similar
in different species (
). Human, canine, feline, bovine, porcine, and ovine
ANP share the same 28–amino acid sequence
. Although more variable,
there is also sufficient homology between the N-terminal amino acid sequence
of ANP such that some of the assays developed to measure NT-proANP in
human beings can be used for the same purpose in dogs and cats
. For
example, NT-proANP radioimmunoassay (RIA) kits designed for use in
human beings (Biotop OY, Turku, Finland) can be used in dogs and cats,
because the antibody employed in this kit is directed to amino acid residues 80
to 96 of human ANP, a sequence identical to that observed in canine and
feline NT-proANP over this region. This assay is a coated-tube RIA and does
not require chemical extraction, simplifying the assay procedure. In contrast
to the homology demonstrated by ANP in different species, the structure of
BNP is quite variable in different mammals
. The amino acid sequences of
mature BNP in dogs and cats are markedly different from the human BNP
sequence (
). For this reason, assays designed to measure BNP in human
Fig. 2. The amino acid sequence of mature atrial natriuretic peptide (ANP) is highly conserved
in mammals. The amino acid sequence of mature ANP is identical in human beings, dogs and
cats, and there is considerable homology in the N-terminal fragments of proANP peptide as
well. Thus, many ANP assays developed for use in human patients can be used to measure ANP
in canine and feline plasma samples.
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
beings tend not to work well in dogs and cats. We have used a commercially
available RIA kit (Phoenix Pharmaceuticals, Mountain View, CA), that
employs antibodies specific for the 32–amino acid carboxy-terminus of canine
BNP to measure mature peptide concentrations in dogs and cats. The
structure of mature feline BNP is sufficiently homologous with canine BNP to
Fig. 3. The amino acid sequence of mature brain (B-type) natriuretic peptide (BNP) is not as
highly conserved in mammals as that of atrial natriuretic peptide. The amino acid sequence of
mature BNP in dogs and cats varies considerably from that in human beings. Those amino acids
that are different from their counterparts in the human BNP molecule are identified by an
interrupted envelope. The sequences of canine and feline BNP are similar enough to allow
measurement by a radioimmunoassay using antibodies directed against canine BNP.
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
permit the use of the canine antibody assay, but feline-specific BNP
antibodies should improve the sensitivity and specificity of the assay.
The prospect of screening veterinary patients suspect for possible heart
disease or heart failure is an exciting possibility, but much technical work and
clinical verification remain to be accomplished before natriuretic peptide
assays can be incorporated into routine practice. The only method currently
available to measure canine or feline BNP is an RIA, and this method is
tedious to perform. Blood is ideally collected in chilled tubes, and aprotinin is
added to inhibit proteolysis. The plasma is separated by cold centrifugation,
and the sample is stored at
ÿ70(C until the assay is performed. The sample
must then be subjected to a time- and labor-intensive extraction process
before the RIA can be performed. Clearly, such laborious procedures do not
lend themselves to routine clinical testing. Nonetheless, if measurement of
BNP levels is shown to have sufficient clinical merit, it is quite feasible to
develop a user-friendly sandwich BNP enzyme-linked immunosorbent assay
(ELISA) that could be performed in any veterinary practice setting.
Heart failure in human patients is characterized by substantial elevations
of ANP and BNP, and a large number of studies of human subjects have
shown that measurement of plasma natriuretic peptide concentrations,
especially BNP, are helpful for discriminating patients with dyspnea caused
by heart failure from those with pulmonary disease or other disorders
. Two assays, one measuring BNP and the other NT-proBNP, have been
approved by the US Food and Drug Administration (FDA) for identifying
human patients with heart failure. The BNP assay is a bedside test, whereas
the NT-proBNP is an automated assay suitable for simultaneous processing
of large numbers of samples
. Which assay is superior is a matter for
debate, but the BNP assay has been evaluated in greater numbers of patients
in more studies. In the Breathing Not Properly Multinational Study, a BNP
level lower than 50 pg/mL had a negative predictive value of 96%, whereas
a BNP level greater than 100 pg/mL was 90% sensitive for detecting heart
failure in human patients
. The mean BNP concentrations of patients
with NYHA class III and IV heart failure were 8- to 10-fold fold higher than
the cutoff value for subjects without heart failure
. In a recently reported
study of cats with myocardial disease, measures of plasma BNP levels seem
to have similar diagnostic potential
. Plasma BNP levels elevated more
than 10-fold distinguished cats with heart failure from control cats better
than plasma ANP levels, which were increased 4- to 5-fold. The diagnostic
potential of plasma BNP levels does not seem as promising in dogs. Plasma
BNP concentrations do not increase markedly until the later stages of heart
failure (NYHA class III and IV) in dogs with DVD, and the magnitude of the
change is less dramatic than that observed in cats and human beings
.
We have observed similar patterns in dogs with DVD and DCM, suggesting
that there may be a species difference in the magnitude of BNP expression. In
contrast to cats and human beings, plasma NT-proANP levels are currently
more useful than BNP levels as a marker of heart disease and heart failure in
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
dogs
. It is not clear at the present time whether this finding reflects
a species-related difference in natriuretic peptide physiology or whether it is
simply an artifact of a primitive BNP assay. This observation was first noted
in Cavalier King Charles spaniels with DVD
, and our laboratory
subsequently confirmed it to be true in other breeds with DVD or DCM. In
a recently completed study of dogs presented for dyspnea, we found that
plasma NT-proANP was better than plasma BNP or endothelin (ET)-1 for
identifying dogs with CHF and that all three peptide assays outperformed
serum troponin as markers of CHF in dogs
. We are currently testing the
hypothesis that BNP is the superior marker of CHF in cats in a prospective
study of similar design.
In humans, circulating BNP concentrations are elevated in asymptomatic
patients with systolic left ventricular (LV) dysfunction, in patients with LV
diastolic dysfunction, in patients with ventricular hypertrophy caused by
systemic or pulmonary hypertension, and in patients with HCM
Some have even advocated using circulating BNP levels to screen patients for
early LV dysfunction. Based on our preliminary data, it is likely that the
measurement of plasma BNP will aid in the early identification of cats with
HCM. Such testing also might clarify the status of cats with equivocal results
when evaluated by other diagnostic modalities, including echocardiography.
The ultimate clinical utility and prognostic value of natriuretic peptide assays
remain uncertain in dogs and cats. Studies of human patients with CHF have
proven that plasma BNP levels are particularly useful in formulating an
accurate prognosis, particularly when measured before and after therapy
In one study, treatment guided by BNP monitoring was superior
to that based solely on other clinical methods of evaluation
Renin-angiotensin-aldosterone system
The major circulating form of renin is prorenin, which is formed in
juxtaglomerular cells in the kidney from preprorenin by removal of a signal
peptide and by glycosylation during transport through the rough endoplas-
mic reticulum
. Prorenin is an inactive prohormone that is converted to
the active renin enzyme by removal of a 43–amino acid segment within
intracellular storage granules or after release into the circulation. The half-
life of activated plasma renin is on the order of 10 to 20 minutes
. Major
stimuli for the release of the renin from the juxtaglomerular apparatus
include b
1
-adrenergic stimulation, decreased effective renal perfusion, and
reduced sodium reabsorption by the renal tubules
. Angiotensin II
inhibits renin, exemplifying the phenomenon of classic feedback inhibition.
The main action of renin is to accelerate the conversion of the large
prohormone, angiotensinogen, to the decapeptide, angiotensin I, which is
subsequently converted to the octapeptide, angiotensin II, via angiotensin-
converting enzyme (ACE;
). The precursor of angiotensin II and III,
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
angiotensinogen, is a globular glycoprotein produced in the liver and released
into the circulating plasma, which serves as the primary storage reservoir
.
In human beings, and presumably in domestic animals, the production of
angiotensinogen is upregulated and plasma levels are increased by infection,
thyroid administration, and hyperadrenocorticism
. Conversely, pro-
duction is downregulated in hypothyroidism and Addison’s disease.
ACE is a membrane-bound zinc metallopeptidase that is present in
virtually all tissues and body fluids. It is a long single-chain protein with
more than a thousand peptide residues complexed with large amounts of
sugar in the form of fucose, mannose, galactose, and N-acetyl-glucosamine as
well as with sialic acid
. The sugar content varies depending on the source
of isolation. ACE acts by cleaving terminal dipeptides from the C-terminus of
the substrate peptide; hence, it is a dipeptidyl carboxypeptidase. The
selectivity of ACE is such that it cleaves any substrate peptide, R1-R2-R3-
OH, where R1 is a protected
L
-amino acid, R2 is any
L
-amino acid except
proline, and R3 is any
L
-amino acid with a free carboxy-terminal. Thus, ACE
converts angiotensin I to active angiotensin II and also inactivates the potent
vasodilator, bradykinin. Although the conversion of angiotensin I to
angiotensin II occurs mainly via the action of ACE, it can also be
accomplished by the actions of cathepsin G, elastase, tissue plasminogen
activator, chymase, and chymostatin-sensitive AII-generating enzyme
(CAGE)
. The importance of these alternate pathways is species
Fig. 4. The conversion of the large prohormone, angiotensinogen, to the decapeptide,
angiotensin I (ANG I), is catalyzed by the enzyme renin. ANG I is subsequently converted to
the octapeptide, angiotensin II (ANG II), mainly via angiotensin-converting enzyme. Other
tissue enzymes, including cathepsin G, elastase, tissue plasminogen activator, chymase, and
chymostatin-sensitive AII-generating enzyme, may also mediate the conversion of ANG I to
ANG II.
1114
D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
dependent
. Sequential actions of aminopeptidase and ACE acting on
angiotensin I also produce angiotensin III, a seven–amino acid peptide
(heptapeptide) that has actions similar to but less potent than angiotensin II
. In addition to its recognized prominence in the kidney, local tissue
renin-angiotensin systems have been demonstrated in a number of different
organs, including the brain, heart, blood vessels, and adrenal glands
These local renin-angiotensin systems play an important role
in the development of the constellation of changes constituting pathologic
remodeling, including vascular and myocardial hypertrophy, inflammation,
and fibrosis.
The physiologic actions of angiotensin II have been thoroughly explored
and reported
. All the important physiologic effects of angiotensin
II are mediated by angiotensin-1 receptors (ARBs), which are abundantly
located in the blood vessels, kidneys, liver, heart, and pituitary and adrenal
glands
. In addition to its role as a potent vasoconstrictor, angiotensin
II promotes sodium and water retention via direct effects on the renal tubules
and contributes to this effect by stimulating aldosterone production and
release from the adrenal glands. The half-life of circulating angiotensin II is
on the order of 1 or 2 minutes because it is rapidly hydrolyzed by circulating
and tissue angiotensinases to inactive peptide fragments. From an evolu-
tionary perspective, angiotensin II and aldosterone are seen to play essential
roles in regulating sodium and water balance and maintaining vascular
pressure when the circulating blood volume is compromised by hemorrhage
or salt and water deprivation. When inappropriately elevated for excessive
periods, as in chronic heart failure, angiotensin II and aldosterone induce
detrimental vascular and ventricular remodeling processes
. The
end result of these processes is further damage to an already compromised
heart, accelerating the clinical deterioration and premature demise of
patients with heart disease. Advances in the treatment of heart failure and
systemic hypertension realized in the last decade have resulted largely from
the use of compounds that prevent the formation of angiotensin II via
inhibition of ACE and block the interaction of angiotensin II with ARBs or
antagonize the actions of aldosterone. The benefits of these treatment
strategies include longer survival times and an improved quality of life. Of
these agents, only ACE inhibitors are approved for the treatment of heart
failure in dogs and people, although aldosterone antagonists and ARBs
certainly have demonstrated efficacy in improving outcome in human
patients with CHF.
Major stimuli for aldosterone production and release include angiotensin
II, elevated plasma potassium levels, and corticotropin (ACTH) as well as the
dominant physiologic effect of aldosterone related to its effects on the kidney.
Aldosterone acts on epithelial cells of the distal collecting ducts, where it
diffuses into the cytoplasm and binds to cytoplasmic mineralocorticoid
receptors (MRs)
. After its entry into the nucleus, activated MR
induces a cascade of events that ultimately increases absorption of sodium
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
ions and excretion of potassium. Aldosterone mediates similar sodium-
conserving processes in the sweat and salivary glands and in the colon. This
sodium-conserving effect constitutes the classic view of aldosterone as an
integral component of the RAAS. Based on extensive studies conducted over
the last decade, the role of aldosterone, like angiotensin II, is now better
understood
. Other messengers, including plasma catecholamines,
ET-1, and AVP, promote the production and release of aldosterone into the
tissues and blood
. In this context, the failure of ACE inhibitors to
restore and maintain normal plasma aldosterone concentrations uniformly in
patients with CHF is understandable
. Moreover, aldosterone pro-
duction is not confined to the adrenal gland. MRs are more widely
distributed than previously realized, and aldosterone exerts important
physiologic effects in addition to those related to sodium, water, and
potassium homeostasis. In patients with heart failure, aldosterone contrib-
utes to generalized vasoconstriction via direct MR-mediated stimulation of
sympathetic nervous system activity, via inhibition of norepinephrine uptake
and degradation in the periphery, and via other complex actions promoting
endothelial cell dysfunction
. Aldosterone also contributes to
baroreceptor dysfunction in heart failure, enhancing the activity of the
sympathetic nervous system and diminishing the activity of the parasympa-
thetic limb. Aldosterone produced locally in tissues like the brain, vascula-
ture, and myocardium mediates important biologic processes that are still
only partly understood. Of particular importance is the emerging role of
aldosterone as a mediator of inflammation and fibrosis in the processes of
pathologic remodeling in the vasculature, kidney, and heart
Commercial assays of all the various components of the RAAS are
routinely performed at only a few specialized diagnostic laboratories. Plasma
renin activity (PRA) rather than renin concentration is typically used to
evaluate the initiating action in the of renin-angiotensin-aldosterone cascade
. PRA assays typically measure the rate of formation of angiotensin I
generated by the action of the enzyme renin acting on angiotensinogen. In
our laboratory, the rate of angiotensin I formation is determined via
a competitive binding RIA. Like renin, ACE assays determine enzyme
activity rather than the quantity of circulating ACE. The techniques used and
the utility of measurements of plasma ACE activity are controversial. A
variety of substrates, including furylacryloyl-Phe-Gly-Gly, Hip-His-Leu,
Phe-His-Leu, Hip-Gly-Gly, and angiotensin I, are mixed with a plasma
sample, and the rate of the reaction is determined via spectrophotometric,
fluorometric, or radiochemical detection hardware
. The results
obtained from different assays are not comparable. If repeated sampling is
anticipated or when groups or individuals are to be compared, it is advisable
to use a single validated assay from a reliable laboratory. Hamlin and
Nakayama
used an ultraviolet kinetic assay to measure ACE activity in
dogs but did not specify the substrate. In their evaluation of the pharma-
cokinetics and pharmacodynamics of benazepril in dogs and cats, King et al
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
validated a commercial radioassay kit based on the substrate H-Hip-
Gly-Gly. When assessing the degree of plasma ACE inhibition, it is advisable
to measure other components of the RAAS
. Plasma angiotensin II levels
should fall, whereas renin levels and the ratio of angiotensin I/angiotensin II
should rise with effective ACE inhibition
. Most importantly, all
these assays are underused in veterinary clinical studies and in clinical
practice given their value for assessing owner compliance and dose response
to an administered ACE inhibitor.
Measurement of angiotensin levels and various metabolites in plasma is
probably best accomplished by HPLC-RIA
. With this method, peptides
are first separated by liquid chromatography, and RIA techniques then are
used to quantify the peptides of interest. Because this technique is difficult
and expensive, measurement of angiotensin I and angiotensin II levels is
often accomplished using competitive RIA or enzyme immunoassay kits
Although these kits show little cross-reactivity between angiotensin I and
angiotensin II, peptides like angiotensin III do cross-react. Depending on the
information desired, this may or may not be problematic. By comparison,
serum or plasma aldosterone concentrations are relatively easily and
accurately determined using commercially available competitive binding
RIA kits
Interpretation of the results of all the various RAAS assays can be
problematic in individual human beings or animals. CHF is but one of many
patient circumstances causing increased release of renin from the kidney.
Low-salt diets, dehydration, blood loss, and vigorous exercise stimulate renin
release from the juxtaglomerular apparatus as a consequence of diminished
renal blood flow. More interestingly, PRA and aldosterone concentrations
are not always elevated in patients with overt CHF
. As already
mentioned, the physiologic effects of the RAAS include volume expansion
and vasoconstriction, both of which serve to diminish renin production. As
a result, operation of the RAAS tends to be phasic and to conceal its
activation. Accordingly, it is not surprising that there is uncertainty
regarding the initiation of RAAS overexpression in dogs and cats with heart
disease. There is fairly uniform agreement that the RAAS is activated in dogs
and cats with cardiomyopathy and signs of CHF, particularly if diuretics
have been administered
. There is disagreement regarding the
presence of RAAS activation before the onset of overt CHF. Ha¨ggstro¨m et al
reported low plasma concentrations of angiotensin II and aldosterone in
Cavalier King Charles Spaniels with valvular heart disease 1 year before, 1 to
6 months before, and at the time of onset of overt CHF. These investigators
concluded that fluid retention in the early stages of developing heart failure
may not be caused by activation of the plasma RAAS and that other
mechanisms may be responsible for early sodium and water retention in dogs
with mitral regurgitation (MR). They further hypothesized that increased
circulating concentrations of ANP effectively suppress the plasma RAAS in
dogs with early compensated DVD. In apparent contradiction, Pedersen and
1117
D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
his colleagues
reported increased PRA and elevated concentrations of
aldosterone in asymptomatic and mildly symptomatic Cavalier King Charles
Spaniels with DVD, even when diet was taken into account. Studies
conducted in our laboratory show substantial elevations of PRA and serum
aldosterone levels in dogs with overt CHF caused by MR and DCM as well
as in cats with HCM or RCM. Activation of the RAAS is particularly
marked in dogs and cats with acquired heart disease when furosemide is used
to alleviate congestive signs. In most dogs and cats with less severe heart
disease (NYHA class I and II), PRA and aldosterone concentrations are
within the normal range or only slightly elevated.
Endothelin
Vascular tone is modulated by the endothelium-derived vasodilators,
nitric oxide (NO) and prostacyclin, and by the complex actions of the potent
endothelium-derived vasopeptide, endothelin.
Three related peptides,
ET-1, ET-2 and ET-3, comprise the endothelin family
. Circulating
endothelins are derived from larger peptides produced by vascular endothe-
lial cells (myocytes and a variety of other cells) in a sequence of steps
analogous to that described for natriuretic peptides
. Thus, preproen-
dothelin gives rise to biologically inactive proendothelin, also termed big
endothelin
, which, in turn, is cleaved at the N-terminus to yield the mature
peptide. The active mature peptide, ET-1, is derived from inactive big ET-1 by
the action of a membrane-bound metallopeptidase, endothelial-converting
enzyme (ECE), and is the predominant circulating form of endothelin
produced by endothelial cells. The mature peptide has two intramolecular
disulfide bridges linking cysteine residues, producing a double-ring structure
(
). ET-1 mRNA expression and ET-1 production are stimulated by
hypoxia and mechanical factors, including stretch and low shear stress; by
vasoactive substances, such as angiotensin II, AVP, norepinephrine, and
bradykinin; and by growth factors and cytokines, including transforming
growth factor-b, tumor necrosis factor-a, and interleukin-1
. Other
vasoactive endothelin derivatives are produced by the action of tissue
chymases, but the biologic importance of this and other alternate pathways
is not yet clear
ET-1 acts via two receptors, ET
A
and ET
B
, to exert complex biologic
effects serving to maintain normal vascular tone
. Vasoconstriction of
smooth muscle, increases in myocardial contractility, and aldosterone
secretion are among the more prominent effects mediated by ET
A
receptor
stimulation. Chronic stimulation of ET
A
receptors and persistently elevated
ET-1 levels cause proliferation and hypertrophy of vascular smooth muscle
and myocardial hypertrophy. Thus, ET-1 is one of several mitogenic
substances incriminated in the pathologic remodeling of the vasculature
and heart in response to chronic hypertension and heart failure. Vasodila-
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
tion, mediated by increased NO production, and aldosterone secretion result
from stimulation of endothelial cell ET
B
-receptors. Increased NO levels, in
turn, inhibit ET-1 synthesis, exemplifying a negative-feedback mechanism.
After intravenous injection of ET-1, blood pressure first declines transiently
and then increases, reflecting the action of these two receptor subtypes. The
interactions of endothelin and the RAAS are complex, but the net effect is
suppression of renin production and stimulation of aldosterone secretion
In healthy people and animals, most circulating ET-1 is derived from the
vasculature and ET-1 levels are low, reflecting its paracrine role in the
maintenance of normal vascular tone. Increased plasma concentrations of
ET-1 and big ET-1 have been documented in human patients with heart
failure, and their levels seem to correlate with disease severity
Moreover, plasma endothelin levels have been shown to correlate inversely
with survival
. Myocardial ET-1 production is thought to substantively
contribute to the approximately twofold elevation of circulating endothelin
levels observed in patients with CHF
. ET-1 concentrations are also
consistently elevated in patients with pulmonary hypertension and some
forms of renal disease but, interestingly, not in patients with systemic
hypertension
The structure of the 21–amino acid sequence of ET-1 is highly conserved
in mammals such that canine ET-1 is identical to human ET-1 and feline ET-
1 differs by only 1 amino acid switch at position 7, where leucine is
substituted for methionine (see
. The biologic significance of
this switch is uncertain. We recently identified and validated a sandwich
ELISA assay designed for use in human subjects that uses antibodies directed
at amino acids 8 through 21 of human ET-1, which are identical to amino
acids 8 through 21 of dogs and cats
. Using this assay, we
Fig. 5. The amino acid sequence of mature endothelin-1 (ET-1) is highly conserved in
mammals. The amino acid sequence of mature ET-1 is identical in human beings and dogs.
Interestingly, feline ET-1 differs by only one amino acid switch at position 7, where leucine is
substituted for methionine. Despite this difference, human assays for ET-1 work well on plasma
from dogs and cats.
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
demonstrated that plasma ET-1 levels more than double in dogs with CHF
caused by DVD or DCM and increase more than threefold in cats with
cardiomyopathy and CHF or systemic thromboembolism
. Significant
but more modest elevations are observed in dogs and cats with less severe
disease. In a recently reported study of dogs presented for dyspnea, we
confirmed that plasma ET-1 levels were elevated in dogs with CHF, although
they were less accurate than plasma NT-proANP for differentiating dogs
with CHF from those with dyspnea from other causes
. Therapeutic
strategies based on blocking ET receptors and inhibition of ECE have not
produced convincing clinical benefits as yet, but several studies are still in
progress
. Interestingly, in a small number of dogs with overt CHF, we
observed that plasma endothelin levels declined substantially after treatment
with conventional therapy (digoxin, furosemide, and an ACE inhibitor).
Vasopressin and adrenomedullin
AVP, often referred to as antidiuretic hormone (ADH), is a nonapeptide
with the amino acid arginine at position 8
. The amino acid sequence
of the mature peptide is highly conserved in most mammals and is identical in
human beings, dogs, and cats
. Interestingly, the amino acid structure of
vasopressin differs from that of oxytocin (OT) at two amino acid positions,
suggesting that the encoding genes of these two peptides arose from
a common precursor
. Provasopressin is produced by neurons whose
cell bodies are located in the hypothalamus. This propeptide is derived from
preprovasopressin and consists of the mature vasopressin peptide linked via
a short processing signal to neurophysin II and its associated copeptin.
Provasopressin is processed into the mature peptide, vasopressin, in vesicles
that are transported along the length of axon to the posterior pituitary, where
they become secretory granules containing the active peptide within the nerve
endings
. Release of vasopressin from the neurohypophysis into the
circulation is stimulated by increased plasma osmolality or hypovolemia.
When plasma volume is reduced, stretch receptors in the atria and large veins
decrease their firing rate, stimulating release of AVP
. Sympathetic
stimulation and angiotensin II also stimulate AVP release
. After its
release, vasopressin reacts with V
1A
receptors in the vasculature and heart,
mediating weak vasoconstrictive and inotropic actions, and with V
2
receptors in the kidney, stimulating water reabsorption
. This latter
effect is accomplished via regulation of the number of aquaporin-2 water
channels inserted into the luminal membrane of cells in the renal collecting
ducts
. Baroreceptor V
2
receptors respond to elevated plasma AVP
levels by augmenting baroreceptor reflexes, which lower the heart rate to
maintain arterial blood pressure in the normal range.
Elevated plasma AVP levels are detectable in some human patients with
CHF, particularly those with severe heart failure and dilutional hypona-
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
tremia
. The paradox of increased AVP release in the face of reduced
plasma osmolality and high filling pressures may be a result of baroreceptor
signaling caused by low arterial blood pressure
. Whatever the mecha-
nism, selective V
2
or combined V
1A
/V
2
receptor antagonists have been shown
to normalize plasma sodium concentrations and to alleviate congestive signs
in affected patients
. Conivaptan, a combined V
1A
/V
2
blocker, has
shown efficacy in dogs with experimentally induced heart failure and in
human patients with severe symptomatic CHF
. Few data are
available regarding circulating AVP levels in dogs or cats with spontaneously
occurring heart disease, but this knowledge deficit will likely be remedied in
the near future.
Adrenomedullin (ADM) is a potent natriuretic and vasodilating 52–amino
acid peptide detected in a variety of tissues, including the adrenal medulla,
heart, lung, and kidney
. ADM production is stimulated by a variety of
chemical and mechanical stimuli, including a number of inflammatory
stimuli, suggesting an important role for ADM in inflammation and patients
with endotoxic shock
. Circulating levels of ADM are elevated in human
patients with CHF, and ADM immunoreactivity is increased in failing
human and canine ventricles
. Current consensus favors an autocrine/
paracrine function for ADM [96(97)]. Interestingly, ADM exerts an inotropic
effect on myocardial cells and attenuates myocardial hypertrophy and
collagen production.
Summary
Current evidence favors the view that regardless of etiology, there is
a predictable sequence of neuroendocrine activation that operates in most
dogs and cats with progressive heart disease and that it is largely but not
entirely independent of etiology. The natriuretic peptides and sympathetic
nervous system seem to be early responders to developing cardiac and
hemodynamic perturbations in both species. BNP plays a particularly
prominent role in cats, possibly as a reflection of disease etiology. Shortly
thereafter, plasma endothelin concentrations rise, reflecting the impact of the
hemodynamic alterations on the vasculature. Endothelin and the natriuretic
peptides directly suppress plasma renin release but have divergent effects on
aldosterone. Activation of the tissue RAAS may operate early on to further
the progression of heart failure, but evidence of plasma RAAS activation
occurs comparatively late and near the time of development of overt CHF.
Finally, in animals with severe CHF that are prone to hypotension,
vasopressin levels may also rise, contributing to the retention of free water
and congestion that is refractory to diuretics. Measurement of vasopressin
levels in dogs and cats with heart disease must be accomplished to confirm
this hypothesis. Although oversimplified, this scenario seems to be consistent
with data obtained in human, canine, and feline patients. These observations
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D.D. Sisson / Vet Clin Small Anim 34 (2004) 1105–1126
provide some impetus for evaluating ACE inhibitors in cats and b-receptor–
blocking drugs in dogs and cats. Perhaps we are also a little closer to
identifying useful biochemical markers that can aid in the diagnosis of heart
disease, guide therapy, and improve our understanding of the biologic
processes occurring in our patients.
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Management of atrial fibrillation
Anna R.M. Gelzer, Dr med vet*,
Marc S. Kraus, DVM
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University,
Ithaca, NY 14853, USA
Atrial fibrillation (AF) is one of the most common arrhythmias
encountered in veterinary medicine. The wide spectrum of presentation
can challenge even the savviest clinician. Management concerns encompass
diagnostic studies, rate control, cardioversion, and management of un-
derlying heart disease. This article is intended to provide a measured
approach to this often ‘‘irregular’’ topic.
Epidemiology
In dogs, AF is the most common clinically significant cardiac arrhythmia.
Different authors have reported incidences between 0.04% and 0.18% and
5.9%
, and AF represents 10% of all arrhythmias
. The incidence of
AF is greater in large-breed dogs than in small-breed dogs
. AF is rare
in dogs less than 12 months of age, with the earliest onset reported in 1- to
2-year-old giant-breed dogs
. AF is most common in giant-breed dogs,
such as the Irish Wolfhound, Great Dane, and Newfoundland
, with
Irish Wolfhounds being most frequently affected with this arrhythmia, with
an incidence of 21% in 500 animals examined by Vollmar
and 10.5% of
496 animals in a study by Brownlie
. At the time of onset of congestive
heart failure, nearly 100% of these Irish wolfhounds had AF
The overall prevalence of AF increases with age and the severity of
congestive heart failure caused by dilated cardiomyopathy (DCM) or
valvular heart disease, with male dogs more frequently affected than female
dogs
. Giant-breed dogs, such as the Irish Wolfhound, Groenendal, or
Mastiff, can be affected with AF in the absence of underlying heart disease
or clinical signs secondary to heart disease
. This is called idiopathic
* Corresponding author.
E-mail address:
(A.R.M. Gelzer).
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.001
Vet Clin Small Anim
34 (2004) 1127–1144
or lone AF. The frequency of lone AF is small (less than 0.05% in Irish
Wolfhounds)
, and the age of first diagnosis varies from 1 to 14 years of
age, with male dogs more frequently affected with lone AF than female dogs
In cats, AF is rare and only found in conjunction with severe atrial
enlargement associated with significant underlying heart disease. Idiopathic
or lone AF has not been reported, presumably because normal feline atria
are too small to allow AF to be sustained.
Etiology
AF occurs most often in conditions associated with atrial dilation. The
common causes of AF in dogs include primary myocardial disease, that is,
DCM or heart disease associated with atrial dilation caused by volume
overload, including chronic degenerative atrioventricular (AV) valve disease
or congenital heart diseases, such as uncorrected patent ductus arteriosus,
atrial septal defect, or mitral and tricuspid valve dysplasia
. Cats with AF
have significant left atrial or biatrial enlargement secondary to hypertrophic
or restrictive cardiomyopathy and associated diastolic dysfunction.
Patient evaluation
Physical examination
Auscultation of patients with AF reveals an irregularly irregular heart
rate ranging from 70 to 270 beats per minute depending on the severity of
the underlying heart disease and the autonomic tone. The irregularity of the
heart rate is an important characteristic of AF but can also be associated
with ventricular arrhythmias or atrial tachyarrhythmias. The intensity of S1
is variable, and S2 may or may not be audible depending on the preceding
RR interval, heart rate, and concurrent heart disease. Auscultatory esti-
mates of heart rate may thus be inaccurate because of the nature of varying
heart sounds in this condition
. Likewise, the femoral pulse quality varies
from beat to beat depending on the diastolic interval and stroke volume, and
pulse deficits can often be appreciated.
Clinical signs
Clinical signs of animals with AF depend largely on the presence and
severity of an underlying heart disease. Dogs may present with congestive
heart failure with signs of coughing, dyspnea, ascites, weakness, lethargy,
and loss of appetite as a result of an advanced stage of DCM, AV valve
insufficiency, or cardiac enlargement as a result of left-to-right shunting. In
giant-breed dogs, AF may be an incidental finding with no clinical signs
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
pertaining to the cardiovascular system. Cats with AF may present with
dyspnea, lethargy, or acute hind limb paralysis as a result of aortic
thromboembolism associated with various forms of cardiomyopathy.
Diagnostic tests
Electrocardiogram
An electrocardiogram (ECG) is the gold standard for diagnosis of AF.
An ECG should be obtained on any animal with suspected AF to establish
the diagnosis, rule out other dysrhythmias, and look for signs of other
cardiac changes suggested by the QRST morphology (bundle branch block,
left or right ventricular hypertrophy). Several rules can help to establish the
correct diagnosis on the ECG. First, the RR intervals are almost always
irregularly irregular during AF. When the heart rate is extremely fast or
extremely slow during AF, the RR intervals can appear regular on a quick
visual inspection; thus, running the paper speed at 50 mm/s and using
calipers may prove helpful in demonstrating irregularity. The rate of the
ventricular response to AF depends on the electrophysiologic properties
of the AV node, the level of vagal and sympathetic tone, and the action of
drugs. Regular RR intervals are possible in the presence of AV block or
interference by ventricular or junctional tachycardia. A rapid, irregular,
sustained, wide QRS-complex tachycardia can be a diagnostic dilemma.
True irregularity typically rules out ventricular tachycardia and leaves
a diagnosis of supraventricular tachycardia (ie, AF with aberrant ventricular
conduction). Second, AF is further recognized by the replacement of
consistent P waves by rapid oscillations or fibrillatory (F) waves, which
vary in size, shape, and timing. In some cases, particularly in cats, the atrial
activation is so rapid and of such low voltage that F waves are not always
visualized on the ECG; conversely, baseline noise or artifact on the ECG
can sometimes simulate these waves in animals that are not in AF. The
absence of P waves helps to exclude other supraventricular arrhythmias,
such as multifocal atrial tachycardia, that can also appear irregular.
Differential diagnosis
AF can be isolated or associated with other arrhythmias (ie, atrial flutter,
ventricular arrhythmias, various forms of AV block). Atrial flutter is more
organized than AF with a saw-tooth pattern of regular atrial activation
(flutter waves) on the ECG. The atrial rate ranges from 350 to 600 beats per
minute in the dog. A two-to-one or three-to-one AV block is common,
producing a ventricular rate of 180 to 300 beats per minute. Atrial flutter
can degenerate into AF, or the ECG pattern can alternate between atrial
flutter and AF, reflecting changes in atrial activation. Ventricular tachycar-
dia is usually a regular wide-complex tachycardia, whereas AF with a bundle
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
branch block demonstrates gross or, occasionally, subtle irregularity of the
RR intervals when scrutinized closely. Atrial tachycardia can be mistaken
for AF because it often appears irregular, and the P waves may vary in size
or shape and be hiding in preceding QRST complexes as a result of the rapid
ventricular rate. AF associated with intermittent and inappropriately long
diastolic intervals suggests AV nodal disease (second-degree AV block) or
complete AV block if the RR intervals are regular and the rate is less than 40
to 60 beats per minute.
Chest radiograph
A chest radiograph should be obtained in cases of new-onset AF,
particularly if there are clinical signs suggestive of heart disease. The size
and shape of the cardiac silhouette may hint at cardiomyopathy or valvular
heart disease. Lung patterns may reveal pulmonary edema, primary lung
disease, or the presence of pleural effusion.
Echocardiography
Echocardiography is a valuable tool to delineate cardiac abnormalities
and evaluate the presence of valvular or myocardial pathologic changes,
atrial enlargement, and left ventricular function. Echocardiography helps to
stratify animals that might be affected with lone AF (ie, no significant
cardiac abnormalities are documented) and might be successfully converted
(and remain) in sinus rhythm. Left atrial size as assessed by echocardiog-
raphy may predict the outcome of cardioversion and subsequent mainte-
nance of sinus rhythm
.
Management of atrial fibrillation
Rhythm control versus rate control
There are two treatment methods for AF: to restore and maintain sinus
rhythm with electrical or pharmacologic cardioversion or to control the
ventricular rate with antiarrhythmic drugs, allowing AF to persist. Reasons
for restoration and maintenance of sinus rhythm in dogs would primarily
include avoidance of tachycardiomyopathy, improved left ventricular
function, and a reduction in clinical signs. In most dogs and cats with
AF, however, conversion to and maintenance of sinus rhythm is not an
obtainable goal, because structural pathologic findings, namely, atrial
dilation, are advanced and irreversible. Therefore, improvement of clinical
signs as a primary therapeutic goal in patients with AF and a fast ventricular
response is usually achieved by rate control. Dogs with a slow ventricular
rate can pose a dilemma for the clinician. The option of restoring sinus
rhythm in a patient with lone AF or AF secondary to mild heart disease is
intuitively appealing granted that a long-term AF-free interval follows the
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
episode. At this time, there are no data proving that dogs with AF and slow
ventricular rates have higher morbidity and mortality than dogs that are
converted to sinus rhythm. Alternatively, such cases are sometimes left
untreated altogether, and patient management is focused on monitoring for
development or progression of cardiac disease. In our clinic, we have
followed giant-breed dogs with AF and inherently slow ventricular rates on
no medication for years without ever documenting a change in cardiac
function and chamber dimensions.
summarize the main
advantages and disadvantages of rhythm control and rate control. Lifelong
drug administration for rate control requires significant owner compliance,
and the cost for medications for large- or giant-breed dogs can be
considerable. Therefore, a reduction in cost for medication and patient
monitoring may seem like an argument for rhythm control. Electrical
cardioversion requires short general anesthesia and hospitalization, how-
ever, and maintenance of sinus rhythm may also necessitate long-term
antiarrhythmic medication and serial follow-up evaluations similar to the
required aftercare for dogs on rate control. In human patients with AF,
restoration and maintenance of sinus rhythm historically were considered
superior to rate control in terms of improved quality of life and reduction of
morbidity and mortality. This convention has been challenged recently,
however, on the basis of several randomized controlled clinical trials in
people comparing rate control therapy with rhythm control therapy, using
as end points quality of life, cardiac performance, morbidity, and mortality.
The data propose that rate control is at least as efficacious if not more so
than rhythm control in most patients, and a trend toward lower mortality in
the rate control group was found
. Patients in the rhythm control
groups were more likely to be hospitalized and had longer hospitalizations,
mostly as a result of repeated cardioversions and antiarrhythmic drug
initiations. So what should veterinarians do for the management of AF? The
answer is not straightforward (
), and without appropriate clinical
trials, the question may never be answered satisfactorily.
Table 1
Advantages and disadvantages of rhythm control: electrical or pharmacologic cardioversion
Advantages
Disadvantages
Avoidance of tachycardiomyopathy
Requires general anesthesia (EC)
Improved left ventricular function
Requires hospitalization (EC)
Reduction in clinical signs
Risk of cardiac arrest from shock (EC)
Improved exercise tolerance
Side effects from antiarrhythmic drugs (EC
þ PC)
High rate of recurrence of AF (EC
þ PC)
Owner compliance (need for continued
antiarrhythmic drug administration to
maintain sinus rhythm (EC
þ PC)
Cost for cardioversion (EC)
Abbreviations:
AF, atrial fibrillation; EC, electrical cardioversion; PC, pharmacologic
cardioversion.
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
How to determine heart rate during atrial fibrillation in dogs
Although a decrease in heart rate is a simple and objective measurement
to make, it remains a surrogate end point, when the definitive end point of
rate control should be improvement in clinical signs of the patient, quality of
life, and mortality. In veterinary medicine, we are lacking clinical studies
that address these important questions, and we do not currently know how
beneficial drug therapy is in reducing heart rate and improving clinical signs
in dogs with spontaneous AF. Two experimental studies in normal Beagle
Table 2
Advantages and disadvantages of rate control: pharmacologic control of the ventricular rate
Advantages
Disadvantages
Avoidance of tachycardiomyopathy
Heart rate control not ‘‘perfect’’
as compared with sinus rhythm
Improved left ventricular function
Side effects from antiarrhythmic drug therapy:
hypotension, gastrointestinal signs
Reduction in clinical signs
Worsening of heart failure: negative inotropic
effects of antiarrhythmic drugs
No hospitalization
Periodic blood screening required
(digoxin levels, kidney/liver function)
Low-maintenance long-term
management by veterinarian
Owner compliance (need for lifelong
antiarrhythmic drug administration)
Cost for lifelong antiarrhythmic medication
and
Atrial fibrillation
Conversion to
sinus rhythm
Control heart
rate
Chest radiograph/ Echocardiogram
Significant heart disease
(CHF)
Normal cardiac function
No therapy
Chronic
therapy
Acute
therapy
Electric
cardioversion
Pharmacologic
cardioversion
?
?
?
or
?
Diltiazem IV
Esmolol IV
Atenolol PO
Digoxin PO
DilacorXR PO
Diltiazem PO
Amiodarone PO*
Flecainide PO*
Propafenone PO*
Sotalol PO*
Monophasic shock: 50-360 J
Biphasic shock: 30-200 J*
Fig. 1. Management algorithm for dogs with atrial fibrillation. This algorithm is intended to
supplement rather than to substitute for clinical judgment and may be changed based on
a patient’s individual needs. Drugs are listed alphabetically and not in order of suggested use.
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
dogs with induced acute AF determined the single diltiazem dosage
administered intravenously or orally (1.938 mg/kg administered intrave-
nously and 5 mg/kg administered orally, respectively) that was optimal to
reduce heart rate and achieve similar cardiac performance and myocardial
oxygen consumption as observed during sinus rhythm
. Extrapolation
of such data to dogs with naturally occurring chronic AF and varying
degrees of underlying heart disease may not be ideal, however. One study in
dogs with spontaneous AF caused by significant heart disease found a heart
rate of 130 to 145 beats per minute to be optimal, using a decrease in
respiratory rate as a surrogate for degree of severity of congestive heart
failure
. The technique of heart rate measurement used in that study
(auscultation of dogs by owners at home) needs to be regarded somewhat
critically, however. Heart rate measurements recorded by owners should be
used cautiously, considering that even veterinary students and residents
experience a significant inaccuracy of heart rate estimates as compared with
more experienced veterinarians
. At this time, it is not known what rate
control means in numeric terms and what levels of ventricular rates would
minimize myocardial oxygen consumption and atrial pressures but sustain
appropriate systemic blood pressure and cardiac output in dogs and cats
with spontaneous AF. If concurrent heart failure is present, a dog may
require a relatively higher mean heart rate to maintain adequate cardiac
output than a dog with uncompromised ventricular function.
An additional limitation to our understanding of optimal heart rate
of animals with AF stems from the technique of rate assessment mostly
practiced in veterinary medicine. In our experience, a short ‘‘in-hospital’’
ECG is insufficient for accurate rate assessment when compared with 24- to
48-hour continuous monitoring as demonstrated in several studies in dogs
. Ideally, a 24-hour ambulatory ECG recording (Holter) gives the
clearest appreciation of heart rate and rhythm during rest and activity in the
familiar home environment
. Additionally, dogs in sinus rhythm
showed significantly lower average heart rates in Holter recordings as
compared with in-hospital ECGs
. This discrepancy can be of particular
importance for patients with AF. The ventricular rate of dogs can vary
greatly during AF depending on the severity of the underlying heart disease,
AV nodal conduction properties, and autonomic tone. In our clinical
experience, most ECGs of dogs with AF obtained in the hospital setting
produce heart rates in the range of 150 to 220 beats per minute, to a large
degree, independent of the dogs’ underlying heart disease but more likely
associated with required restraint and the personality of the patient. In
contrast, the heart rate obtained from 24-hour Holter recordings in the same
dogs can easily range from 50 to 250 beats per minute, with an average of
100 beats per minute. Therefore, we prefer the use of Holter recordings
acquired in the home environment, combined with a pet owner diary
describing the dog’s activity and sleep pattern, to establish average heart
rates and assess drug efficacy for rate control in dogs with AF.
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
When is therapy for atrial fibrillation indicated?
Based on 24-hour Holter recordings, we find that dogs with AF
associated with significant heart disease have average heart rates that often
exceed 170 beats per minute and can be as high as 220 beats per minute.
Average heart rates in normal large-breed dogs during sinus rhythm
commonly are less than 90 beats per minute. Dogs with lone AF as well
as dogs with mild or occult underlying heart disease may present with heart
rates similar to dogs in sinus rhythm. Cats with AF invariably have severe
underlying heart disease and elevated heart rates in the range of 200 to 300
beats per minute.
In our clinic, we usually recommend medical rate control in dogs with AF
when the average heart rate from Holter recordings is greater than 150 beats
per minute. In giant-breed dogs with slow ventricular response rates, it may
not be necessary to reduce the ventricular rate any further. Some dogs with
no or minimal cardiac changes at the time of diagnosis of AF go on to
develop signs of heart failure later in life, however. Administration of
digoxin or a beta-blocker alone in dogs with ‘‘normal’’ ventricular rates may
improve long-term outcome and is usually of no detriment to the patient.
Alternatively, cardioversion to sinus rhythm may be successful in this group
of patients and preferable for the reasons mentioned in
. Prospective
studies to clarify the impact of AF with slow ventricular response rates
versus sinus rhythm on morbidity and mortality in this group of patients are
warranted. The epidemiology and natural history of each case need to be
considered in the clinical decision-making process.
In cats with AF and intact AV nodal conduction, rate control is almost
always indicated.
Rate control
Pharmacologic approach
Negative chronotropic therapy in AF is based mainly on depression of
conduction across the AV node. Dosages and routes of administration of
currently used drugs for rate control in veterinary medicine are presented in
. The first-choice therapy to control heart rate in dogs with AF has
traditionally been digoxin. Orally administered digoxin has a slow onset time
and a potential for toxicity. It is thus important to monitor digoxin serum
levels in dogs using a ‘‘trough sample’’ obtained 8 to 10 hours after pilling
after approximately 3 to 7 days of therapy
. Even if the recommended
dosage is administered, digoxin serum levels can be somewhat unpredictable
in our experience, possibly because of altered renal function or gastrointes-
tinal absorption in patients with heart failure. Therefore, appropriate
adjustments in the dosage can be made based on serum levels. Digoxin
may decrease the ventricular response rate by its indirect vagal effects on the
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
AV node
. Although digoxin may successfully control heart rate in some
dogs, particularly if the ventricular response rate is not excessively high
the efficacy is limited and often not optimal during exercise, excitement, or
endogenous stress as a result of congestive heart failure. Heightened
sympathetic tone during these periods may override the vagal effects of
digoxin and result in excessive heart rates
. The clinician should ask
the question: ‘‘If this dog were in sinus rhythm, would it have sinus
tachycardia?’’ If the answer is yes, digoxin alone is unlikely to control the
ventricular rate. In such instances, digoxin is considered more effective when
used in combination with other drugs, such as calcium channel blockers or
beta-blockers. These drugs act directly by slowing AV nodal conduction
properties; therefore, their efficacy is less influenced by the patient’s
autonomic tone. For dogs with AF and rapid ventricular rates, the calcium
channel blocker diltiazem is quite useful because its negative dromotropic
effect occurs quickly and dose dependently, and unlike digitalis, diltiazem
slows heart rate effectively even during exercise. In dogs with AF and
significant underlying heart disease, we commonly use it in combination with
digoxin (
), because most of these patients might benefit from digoxin
for other reasons in addition to rate control. Although diltiazem has to be
given three times daily, we prefer to use diltiazem XR because it can be
Table 3
Agents for rate control in patients with atrial fibrillation: oral and intravenous routes of
administration
Drug
Administration per os
Intravenous administration
Digoxin
(Lanoxin)
0.005–0.01 mg/kg BID
(\15 kg) or 0.22 mg/m
2
BID (>15 kg)
0.0025 mg/kg bolus, repeat
every 1 hour, up to
maximum of 0.01 mg/kg
as needed
Diltiazem
(Cardizem)
0.5 mg/kg TID titrated up
(maximum: 1.5–2 mg/kg TID)
Cat: 7.5 mg BID to TID
0.1–0.2 mg/kg bolus, then
CRI 2–6 lg/kg/min
Diltiazem
XR (Dilacor)
1.5–6 mg/kg SID to BID
Cat: 30–60 mg SID to BID
Propranolol
(Inderal)
0.1–0.2 mg/kg TID titrated up
(maximum: 0.5 mg/kg TID)
Cat: 2.5–10 mg BID to TID
0.01–0.1 mg/kg as a slow
bolus
Atenolol
(Tenormin)
0.25–1 mg/kg SID to BID
Cat: 6.25 mg SID to BID
Esmolol
(Brevibloc)
50–100 lg/kg bolus (repeat up
to maximum: 500 lg/kg),
50–200 lg/kg/min CRI
Amiodarone
(Cordarone)
10 mg/kg BID for 1 week
(loading dose)
5 mg/kg SID (maintenance dose)
Abbreviations:
BID, twice daily; CRI, continuous rate infusion; SID, once daily; TID, three
times daily.
a
Recommended dose range in veterinary medicine is testimonial and variable
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
administered every 12 hours, improving owner compliance. The currently
recommended dose range is wide (1.5–6 mg/kg); thus, initiating treatment at
the low end of the dose range may require some titrating of the dose up to the
desired effect on heart rate. Conversely, we typically do not exceed 4 mg/kg
twice daily, because we have experienced AV block as well as hypotension in
our patients. AV block can occur as an unwanted effect of pharmacologic
intervention with digitalis glycosides, calcium channel blockers, or beta-
blockers. In unstable patients (rapid AF with signs of overt congestive heart
failure), the use of intravenous diltiazem may improve left ventricular
performance by rapidly slowing ventricular rate and increasing diastolic
filling time as well as by lowering myocardial oxygen demand
, which,
in return, contributes positively to the management of congestive heart
failure. Diltiazem is administered as intravenous boluses to effect and then
repeated every 4 to 6 hours as needed. Heart rate and blood pressure should
be carefully monitored to avoid bradycardia and hypotension, however. In
a small study in people, intravenous digoxin for acute therapy of AF led to
similar improvements in ejection fraction compared with intravenous
diltiazem, despite a slower onset and less potent heart rate slowing effect
; thus, even though we have no personal experience with it, intravenous
digoxin therapy may merit consideration.
Before diltiazem became widely available, beta-blockers alone or in
combination with digoxin were used if digoxin monotherapy was not
Fig. 2. Graphic display of heart rate over 24 hours acquired by means of a Holter recording
from a Doberman Pinscher with atrial fibrillation and dilated cardiomyopathy. The gray
(purple in the web version) vertical lines represent the minimum and maximum RR intervals of
consecutive 1-minute segments. (A) The average heart rate over 24 hours before therapy was
215 beats per minute (baseline). (B) The follow-up Holter recording was acquired after rate
control with digoxin and diltiazem was instituted. Drug therapy resulted in a reduction of the
average heart rate over 24 hours to 125 beats per minute.
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
effective for rate control in dogs
. Some clinicians prefer the use of beta-
blockers over calcium channel blockers in the management of patients with
AF because of their beneficial effects on myocardial oxygen demand and
their favorable effects on mortality as shown in people. Clinical trials failed
to produce any survival benefit of beta-blocker therapy in human patients
with poor systolic function and atrial fibrillation
, however. The
dosage of beta-blockers required for rate control usually has negligible
negative inotropic effects, which are offset by the positive effects of heart
rate reduction, resulting in prolonged diastole, improved filling pressures,
and reduced myocardial oxygen consumption. To avoid peripheral vaso-
constriction in dogs with impaired cardiac output, selective beta-1–blockers
may be superior to nonselective beta-blockers. Atenolol, an oral selective
beta-1–blocker, would be our first choice, often used in conjunction with
digoxin. For acute therapy of AF with rapid ventricular response rates,
intravenous esmolol (b
1
-selective) is effective and can be titrated closely to
a desired effect. After administration of an initial slow bolus, a continuous
rate infusion can be used to maintain rate control in an unstable patient.
Because of its ultrashort half-life, undesired side effects can be corrected
within minutes after discontinuing the infusion. Compared with intravenous
diltiazem, esmolol is quite costly.
In dogs with naturally occurring AF, diltiazem alone has been shown to
be more effective than the combination of propranolol with digoxin for rate
control
. It is not recommended to use diltiazem in conjunction with
beta-blockers for rate control, however, because of their combined effects on
cardiac contractility and systemic arterial blood pressure, which can lead to
a serious decrease in cardiac output and worsening of heart failure
. In
dogs with refractory tachycardia, despite combination therapy with digoxin
and a beta-blocker or calcium channel blocker, amiodarone has been used
for rate control in select cases. Amiodarone is slower in onset and con-
sidered less effective than diltiazem for rate control in people with AF but
has less associated hypotension in critically ill patients and few or no
negative inotropic side effects and thus seems to be relatively safe in dogs
with congestive heart failure and left ventricular dysfunction
. The
drug is well tolerated in the short term, but disadvantages include cost,
variable effectiveness, and side effects, which can be significant if given long
term
In cats with AF and a rapid ventricular rate, we generally recommend
atenolol or diltiazem XR for rate control.
Atrioventricular nodal ablation and ventricular pacing
Transvenous radiofrequency ablation of the AV node and permanent
pacemaker implantation is a highly effective means of achieving rate control
in human patients in whom a rapid ventricular rate cannot be controlled
adequately with drugs
. It is an irreversible treatment and creates
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a lifelong pacemaker dependency. Ablation procedures carry a risk of
sudden death. Although this treatment modality has been performed in
dogs, to date, the benefits and risk for veterinary patients with spontaneous
AF are unknown. Even in people with AF, the precise role of pacemaker
therapy to regulate the ventricular rate remains controversial
.
Rhythm control: cardioversion
Cardioversion of AF to sinus rhythm can be achieved by means of drugs
or electrical shock. Before electrical cardioversion became a more standard
procedure, drugs were commonly used. Electrical cardioversion is more
effective than pharmacologic cardioversion, but the former requires general
anesthesia, whereas the latter does not and may even be achieved out of the
hospital. Cardioversion can be a challenge, even in dogs with minimal
cardiac changes and AF with slow ventricular response rates. An important
factor influencing the success of cardioversion is the duration of AF in an
individual patient and the degree of underlying heart disease. Similar to
horses
, human patients with unsuccessful cardioversion have a longer
duration of AF
Pharmacologic conversion of atrial fibrillation to sinus rhythm
Pharmacologic cardioversion is most promising in recent-onset AF (\7
days in people)
. Unfortunately, the time of onset of AF is usually
unknown in small animals; AF may be an incidental finding during a routine
evaluation if clinical signs are absent or diagnosed as a complication of heart
failure. Unlike the situation in horses
, the success of pharmacologic
restoration of sinus rhythm in small animals is limited at this time.
Quinidine has been used successfully for cardioversion of veterinary patients
with mild underlying heart disease (5–20 mg/kg administered orally every 2–
6 hours), although side effects can be significant, including weakness, ataxia,
seizures, and proarrhythmia
. Because of its vagolytic effects,
quinidine may cause increased conduction across the AV node and an
accelerated ventricular response rate. During attempted cardioversion with
quinidine, addition of a calcium channel blocker, beta-blocker, or digoxin
may avoid this complication and improve the success of cardioversion
.
Risk of proarrhythmia with quinidine therapy includes prolongation of the
QT interval and torsade de pointes ventricular tachycardia. Propafenone,
flecainide, dofetilide, ibutilide, and amiodarone are alternative options for
pharmacologic cardioversion in people
, but their effectiveness in
dogs with spontaneously occurring AF is unreported. Intravenous ibutilide
seems to be the most successful agent for cardioversion in people with recent
onset of AF (human dose: 0.01 mg/kg administered intravenously over 10
minutes, with a maximum of 1 mg)
. Monotherapy with oral amiodar-
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
one, propafenone, or sotalol has not resulted in successful conversion of AF
to sinus rhythm in the authors’ experience.
Electrical cardioversion
Transthoracic electrical cardioversion, used alone or in combination with
pharmacologic loading with a class III (ibutilide sotalol, or amiodarone) or
class IC (propafenone or flecainide) antiarrhythmic drug is most effective for
restoration of sinus rhythm in human patients
. Success in veterinary
patients is also limited, however, and recurrence of AF is common im-
mediately or shortly after conversion. Direct-current cardioversion in-
volves an electrical shock synchronized with the intrinsic activity of the
heart (R wave). This ensures that the electrical stimulation does not occur
during the vulnerable phase of the cardiac cycle (T wave), which could result
in ventricular fibrillation. Reasons for failure of electrical cardioversion in
dogs include high transthoracic impedance (large chest in giant-breed dogs),
insufficient shock energy, position and size of the electrode paddles, output
waveform of the defibrillator, and advanced atrial pathologic findings.
Successful cardioversion requires defibrillation of a critical mass of the
atria, which is achieved with specific anatomic paddle placement. Ideal
paddle placement has not been determined in dogs. In people, the overall
success of cardioversion was greatest with an anterior-posterior configura-
tion (sternum-left scapula)
. Because of the anatomic location of the
atria in the canine thorax, paddle positions dorsolaterally on both lateral
chest walls may be more effective than sternal (ventral) placement. We
position the anesthetized dog in a cradle on its back, extend and attach the
front limbs cranially to the table, thus exposing the entire lateral thoracic
surface. The chest hair should be clipped. Several different paddle place-
ments should be attempted before abandoning the procedure. Paddles need
to be placed at least a few inches apart from each other to avoid ineffective
shorting (‘‘arching’’) of current across the surface of the dog. Maintenance
of good paddle-to-patient interface achieved by using plenty of contact gel
and application of firm pressure of the paddles to the chest may reduce
impedance and increase the chances of successful cardioversion. Recent
studies suggest that a rectilinear biphasic waveform shock has equal or
better success for cardioversion compared with a monophasic waveform
shock
. In a small study in horses with spontaneous AF, biphasic
defibrillation resulted in restoration of sinus rhythm
. The biphasic
defibrillators deliver a rectilinear constant current through the heart,
delivering significantly lower energy levels, thus reducing burning of the
skin, postshock myocardial damage, and potential proarrhythmic effects.
Using a monophasic defibrillator, we administer an initial shock of 50 to 100
J depending on the size of the dog. If cardioversion is unsuccessful, the
energy is increased by increments of 50 to 100 J. In some dogs, it does
require up to 360 J to achieve sinus rhythm. It can be argued that multiple
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A.R.M. Gelzer, M.S. Kraus / Vet Clin Small Anim 34 (2004) 1127–1144
unsuccessful lower energy shocks are worse for the patient than a single
high-energy shock. Success of cardioversion in people with an initial single
shock was 95% if 360 J was used, whereas only 14% converted with 100 J
and 39% converted with 200 J
Future alternative approaches to the treatment of atrial fibrillation
More advanced techniques to restore sinus rhythm are used in certain
human patients. Pulmonary vein foci that can trigger AF have been
discovered with endocardial three-dimensional mapping catheters
.
Surgical therapy involves isolation of the pulmonary veins and atrial
appendage (maze procedure) to reduce the electrical atrial surface area
and thereby abolish re-entry
. Radiofrequency ablation in or around the
pulmonary veins or the surgical maze procedure has been shown to
accomplish the aim of the curative treatment of AF
. Preventative atrial
pacing and antitachycardia pacing integrated with an atrial defibrillator may
offer an attractive alternative option for the management of paroxysmal AF
in people
. In the clinical setting, these therapeutic approaches have not
been tested in animals. Whether these treatment modalities will reach
clinical relevance in veterinary medicine is unknown.
Prevention of atrial fibrillation
Familial is AF is documented in people and is associated with a defect on
chromosome 10
. The high prevalence of AF in certain canine breeds,
such as the Irish Wolfhound, would support the hypothesis that a genetic
predisposition may be a risk factor for development of AF. Pedigree
analysis of canine breeds with an exceptionally high prevalence of AF
should be done to provide breeding recommendations. At this time, the
authors believe that owners should be advised to refrain from using
individual dogs affected with AF for breeding.
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Use of pimobendan in the management
of heart failure
Virginia Luis Fuentes, MA, VetMB, PhD, CertVR,
DVC, MRCVS
Department of Veterinary Clinical Sciences, Royal Veterinary College, Hawkshead Lane,
Hatfield, Hertfordshire, AL9 7TA United Kingdom
Medical options for management of heart failure in small animals have
tended to parallel practice in human patients, but pimobendan is a new
therapy that has not been licensed for human use in the United States and
Europe; however, it has been licensed for use in canine heart failure since
1999 in many European countries. It is also currently licensed for use in
dogs in Australia and Canada.
Pimobendan has properties in common with the phosphodiesterase
(PDE) inhibitors amrinone and milrinone, but it has the additional novel
effect of calcium sensitization. Together these effects result in both positive
inotropic effects and vasodilation. It is an oral compound that can be
combined with other heart failure treatments and is likely to play an
increasing role in canine heart failure therapy in the future.
Pharmacology
Pimobendan is a benzimidazole-pyridazinone derivative with positive
inotropic and vasodilatory properties. Pimobendan inhibits phosphodies-
terase III (eg, amrinone and milrinone), thus reducing breakdown of cyclic
adenosine monophosphate (cAMP). This increases myocardial contractility
and relaxation by potentiating the adrenergic signal transduction pathway,
increasing release and reuptake of calcium. The vascular effects of PDE III
inhibition are cAMP-mediated arteriodilation and venodilation. The sys-
temic and pulmonary vasculature is affected. The positive inotropic effect is
Funding was received from Boehringer Ingelheim vetmedica gmbh for the study cited in
reference 42 and for consultation work for Boehringer Ingelheim vetmedica.
E-mail address:
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.018
Vet Clin Small Anim
34 (2004) 1145–1155
jointly caused by inhibition of PDE III and calcium sensitization, whereas
the vasodilatory effects result from PDE III (and partly PDE V) inhibition.
Pimobendan is water insoluble, and oral absorption is rapid, with peak
plasma levels achieved within an hour of administration. Oral bioavailability
is around 60% to 65% but is reduced in the presence of food
. It is highly
protein bound (90%–95%) and is eliminated in the feces by biliary excretion
. In dogs and human beings, pimobendan is metabolized in the liver to
UDCG-212, which is a more potent inhibitor of PDE III than pimobendan. In
human patients, the plasma elimination half-life of pimobendan is less than 30
minutes and the half-life of UDCG-212 is around 2 hours; yet, the
pharmacodynamic effects persist for more than 8 hours
In vitro effects
The myocardial effects of pimobendan have been widely studied in
skinned and intact myocyte preparations and excised hearts. Studies have
consistently shown that pimobendan causes an increase in the L-type Ca
2
þ
current and the developed tension in isolated myocytes. The maximal
contractile effect is reduced in failing myocytes, although there is still a
cAMP-independent positive inotropic effect. This is associated with a shift
in the Ca
2
þ
tension relation, indicating increased sensitivity of the
contractile proteins to Ca
2
þ
. This calcium sensitization is produced by
an increase in the Ca
2
þ
affinity of the regulatory binding sites of troponin C
and is mainly associated with the L-isomer of pimobendan
Studies on excised hearts have been performed to examine the effects
of pimobendan on ‘‘contractile economy’’ in terms of the relation of
myocardial oxygen consumption to the increase in contractility. Pimoben-
dan’s effect on contractility as assessed by end-systolic elastance was similar
to that produced by dobutamine in normal and failing canine hearts
.
Goto and Hata
showed little difference in the oxygen cost of contractility
between the two drugs in normal myocardium, but dobutamine caused
a significant increase in oxygen cost in failing myocardium. In contrast, the
oxygen cost of pimobendan was similar in normal and failing hearts. Other
studies in guinea pig papillary muscle preparations showed that the energy
demand (measured as heat liberated and representing use of adenosine
triphosphate [ATP]) was much greater for isoproterenol than for pimoben-
dan for a given increase in tension
.
Pimobendan in normal dogs
The effects of pimobendan in normal dogs include moderate reductions in
systemic and pulmonary vascular resistance, a marked reduction in left
ventricular end-diastolic pressure, and moderate increases in heart rate and
cardiac output
. The effects of pimobendan in normal dogs on
1146
V. Luis Fuentes / Vet Clin Small Anim 34 (2004) 1145–1155
contractility, vascular resistance, and heart rate are similar to those observed
with amrinone or milrinone, although pimobendan seems to have a greater
effect in increasing myocardial blood flow
. In addition to its positive
inotropic and vasodilatory effects, pimobendan has favorable effects on
diastolic function. The left ventricular isovolumic time constant of relaxation
(tau) is decreased, indicating improved left ventricular relaxation
Pimobendan in canine models of heart failure
The use of pimobendan has been examined in a number of canine heart
failure models. Pimobendan produced a dose-dependent improvement in
cardiac performance in dogs with propranolol-induced myocardial de-
pression, with an increase in stroke volume and left ventricular maximal
rate of increase in pressure with time (LV dP/dt
max
) and a decrease in
pulmonary capillary wedge pressure. At higher doses of pimobendan, there
was a slight decrease in arterial pressure and slight increase in heart rate,
with an increase in renal blood flow. In ischemic heart disease models,
pimobendan increased LV peak dP/dt
max
and contractility was increased
even in myocardium with postischemic dysfunction
. Pimobendan also
improved left ventricular systolic function in canine pacing-induced heart
failure. A dose-dependent increase was seen in end-systolic elastance less
than that produced in normal dogs but without any increase in heart rate
There seemed to be no attenuation of the positive lusitropic effect in failing
hearts, with the extent of improvement in left ventricular relaxation being
the same in normal and failing hearts
. A comparison of pimobendan and
amrinone in dogs with pacing-induced heart failure showed that pimoben-
dan resulted in significantly greater improvements in systolic function
compared with amrinone (increased end-systolic elastance, LV dP/dt
max
,
stroke volume, and decreased end-systolic volume). This study used doses of
pimobendan and amrinone that resulted in equivalent effects on systolic
function in normal dogs. At these doses, pimobendan also resulted in
greater reductions in left atrial and left ventricular end-diastolic pressures
than amrinone. An equivalent decrease in systemic vascular resistance was
seen with both drugs, but a much greater improvement in left ventricular
relaxation was seen with pimobendan (with a significant decrease in the time
constant of relaxation)
. It has been suggested that the greater
attenuation of positive effects of the pure PDE III inhibitors in failing
hearts is a result of downregulation of the adrenergic signal transduction
pathways, with reduced basal cAMP production, b-adrenergic receptor
downregulation, activation of b-adrenergic receptor kinase, and an increase
in the inhibitory Gia subunit of the G-protein complex
Pimobendan in human heart failure
The promising results of pimobendan in animal studies led to clinical
trials in human patients with heart failure. Single oral doses of pimobendan
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V. Luis Fuentes / Vet Clin Small Anim 34 (2004) 1145–1155
consistently resulted in increased stroke volume index and cardiac index and
decreased systemic and pulmonary vascular resistance
. The effect on
arterial pressure and heart rate was more variable, with some studies
showing no effect on these variables and others showing a reduction in
arterial pressure or increase in heart rate
. Administration of
pimobendan over a 4-week period to patients with moderate to severe heart
failure already receiving diuretics and digoxin resulted in sustained
hemodynamic improvements, with increases in cardiac index and decreases
in pulmonary capillary wedge pressure
.
Human heart failure patients have shown an improvement in exercise
duration in several long-term placebo-controlled trials of pimobendan
. Kubo et al
looked at 198 patients with severe heart failure
(New York Heart Association [NYHA] class III and IV) already receiving
treatment. They were randomized to pimobendan (at 2.5, 5, or 10 mg/d) or
placebo for 12 weeks. The medium-dose group showed a significant increase
in exercise duration and improvement in quality of life based on the
Minnesota Living with Heart Failure questionnaire. There were significantly
fewer hospitalizations for heart failure in the pimobendan-treated patients,
and a similar percentage of patients died in both groups. In the study by
Remme et al
, 242 patients in NYHA class II or III were randomized to
receive pimobendan or enalapril in addition to diuretics and digoxin. Similar
improvements in exercise tolerance and NYHA class were seen in both
groups as well as similar rates of hospitalization for heart failure.
The Pimobendan in Congestive Heart Failure (PICO) trial
proved to
be an influential trial in terms of subsequent use of pimobendan in human
patients. The primary end point was exercise capacity, and 317 patients were
recruited with stable chronic heart failure and a low ejection fraction (69%
had ischemic heart disease). All were receiving an angiotensin-converting
enzyme (ACE) inhibitor and diuretics, and patients were randomized to
receive placebo or pimobendan at 2.5 or 5 mg/d in addition for at least 24
weeks. Pimobendan (at both doses) resulted in increased exercise duration
compared with placebo, and this effect continued to increase until 12 weeks
of treatment and was sustained thereafter. In the placebo-treated patients,
4% had an improved NYHA classification compared with 10% in the
pimobendan groups (P = 0.06). There was no difference in quality-of-life
scores between the two groups. There was a nonsignificant tendency toward
higher mortality in the pimobendan groups, with 11 deaths out of 108
patients in the placebo group, 20 deaths out of 106 patients in the low-dose
pimobendan group, and 16 deaths out of 103 patients in the high-dose
pimobendan group, with a combined hazard ratio for the two groups of 1.8
(95% confidence interval [CI]: 0.9–3.5). Hazard ratios for the combined end
point of death or hospitalization for cardiovascular reasons were 1.5 (95%
CI: 0.9–2.5) for the low-dose pimobendan group and 1.2 (95% CI: 0.7–2.1)
for the high-dose pimobendan group (ie, not significantly different from
placebo). Although not statistically significant, more of the deaths occurred
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in patients receiving digoxin (8 receiving placebo, 15 receiving low-dose
pimobendan, and 12 receiving high-dose pimobendan) compared with 3, 5,
and 4 deaths, respectively, in patients not receiving digoxin.
The climate at the time of the PICO study was not especially favorable for
positive inotropes, because in preceding years, several other clinical trials with
positive inotropes had reported increased mortality in patients receiving active
drug
. In particular, the PROMISE trial with the PDE III inhibitor
milrinone showed a 28% increase in mortality compared with placebo, despite
short-term hemodynamic improvements
. In this context, even a non-
significant tendency toward increased mortality was seen as sufficient grounds
for withdrawal of pimobendan from future clinical studies. Although the
mechanism of the increase in mortality with positive inotropes was not proven,
suspicion was cast at proarrhythmic effects resulting from increased cytosolic
calcium levels. Other studies have not had the same results, and a subsequent
study of 306 patients with stable chronic heart failure compared low-dose
pimobendan with placebo
. The incidence of adverse events (including
death from heart failure, sudden death, and hospitalization for worsening
heart failure) was 45% lower in the pimobendan group than in the placebo
group (hazard ratio 95% CI: 0.31–0.97).
Effects on cardiac rhythm
Pimobendan results in a dose-dependent increase in sinus rate in normal
dogs but has a less marked effect on heart rate in individuals with heart
failure. Several pimobendan studies in human patients have used 24-hour
Holter monitoring, without finding any evidence of proarrhythmia
This was true of the PICO study, even when patients with sudden cardiac
death were assumed to represent proarrhythmia.
The electrophysiologic effects of pimobendan include enhanced atrio-
ventricular conduction and a shortening of atrial, atrioventricular nodal,
and ventricular refractory periods
. It is not clear whether these effects
are indirect and result from a reflex adrenergic response to a lowering in
arterial pressure. Intravenous pimobendan increased the incidence of
ventricular fibrillation in a canine model of sudden cardiac death after
acute myocardial infarction
.
Neurohormonal effects
Pimobendan has been shown to have favorable effects on neurohormonal
factors in a number of studies. Plasma norepinephrine levels may be reduced
with pimobendan administration
, possibly by triggering a
reflex withdrawal of sympathetic tone. Pimobendan also has beneficial
effects on proinflammatory cytokines and has been shown to decrease levels
of tumor necrosis factor-a (TNFa) and interleukin (IL)-1b, an effect that
may be related to pimobendan’s inhibition of NF-kappa B
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V. Luis Fuentes / Vet Clin Small Anim 34 (2004) 1145–1155
Pimobendan seems to be a potent inhibitor of platelet aggregation, an
effect that may be mediated by inhibition of platelet thromboxane A
2
production
.
Veterinary pimobendan studies
Although there are still few published reports, there have been a number
of studies in dogs examining the use of pimobendan in dilated cardiomy-
opathy and chronic mitral valve disease.
Short-term studies
Early open-label trials included a dose-ranging study in 45 dogs with
chronic mitral valve disease or dilated cardiomyopathy. Pimobendan was
started at 0.2 mg/kg/d and was increased up to 0.4 or 0.6 mg/kg/d in two
divided doses until improvement was observed
. This dose was
maintained for a further 2 weeks until the final examination. The authors
concluded that 0.4 to 0.6 mg/kg/d seemed to be an effective dose in dogs
with heart failure. Another open-label study compared the effects of
pimobendan versus digoxin over 4 weeks in 109 dogs with congestive heart
failure
. The NYHA score was significantly better in the pimobendan
group than in the digoxin group after 4 weeks.
One of the most comprehensive randomized, blind, controlled studies to
date of pimobendan in canine congestive heart failure was the PiTCH study
. Dogs were recruited with NYHA class III or IV heart failure caused
by dilated cardiomyopathy (n = 81) or chronic mitral valve disease, with
105 dogs enrolled in total. Dogs were randomized to receive pimobendan
and placebo, pimobendan and benazepril, or placebo and benazepril for a
28-day period. A greater proportion of dogs failed to finish the initial study
period because of lack of efficacy or death in the benazepril group (34%)
compared with the pimobendan group (11%) or the combined group (9%).
The low numbers of mitral insufficiency cases in the PiTCH trial
prompted initiation of further trials in this subset of patients. One such
trial compared the use of pimobendan with the ACE inhibitor ramipril in
dogs with myxomatous mitral valve disease over a 6-month period
.
Dogs showing signs of modified NYHA class II to III heart failure were
randomized to pimobendan or ramipril in a single-blind fashion (owners
were aware of the drug identity). Of 44 dogs recruited, there were
significantly fewer adverse outcomes in the pimobendan group compared
with ramipril group (odds ratio = 5.03, 95% CI: 1.12–22.6).
Long-term studies
The PiTCH study also had a long-term arm, with an option to continue
with the medication after the 28-day initial study period. The pimobendan
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V. Luis Fuentes / Vet Clin Small Anim 34 (2004) 1145–1155
and combination groups continued with pimobendan and benazepril,
whereas the benazepril-only group continued with benazepril and placebo.
Additional medications could be added at the clinician’s discretion. Median
survival time in the placebo group was 42 days compared with 217 days in
the pimobendan group
It should be recognized that the above studies represent preliminary and
as yet unpublished data. A small, double-blind, randomized, placebo-
controlled study of dilated cardiomyopathy in Doberman Pinschers and
English Cocker Spaniels reported use of pimobendan as an add-on therapy
to background treatment with furosemide, enalapril, and digoxin
. An
improvement in NYHA heart failure classification was seen in 8 of 10 dogs
receiving pimobendan compared with 1 of 10 of the dogs in the placebo
group (P = 0.005). Median survival was improved in the Doberman
Pinschers in this study, from 50 days in the placebo group to 329 days in
the pimobendan-treated group (hazard ratio = 3.4, 95% CI: 1.4–39.8).
Similar benefits for Doberman Pinschers with dilated cardiomyopathy were
shown in another randomized placebo-controlled study
. Doberman
Pinschers with congestive heart failure caused by dilated cardiomyopathy
and receiving ACE inhibitors and diuretics (n = 15) were randomized to
placebo or pimobendan. Quality-of-life scores were significantly better in the
pimobendan group, and mean survival times were 128
29 days in the
pimobendan group compared with 63
14 days in the placebo group.
Recommendations for use of pimobendan
In Europe, pimobendan is available as 1.25-, 2.5-, and 5- g capsules. The
recommended dose rate in dogs is 0.1 to 0.3 mg/kg administered every 12
hours and given at least an hour before food. Dosing is usually started at the
low end of the dose range. Pimobendan can be combined with diuretics,
ACE inhibitors, or digoxin. The positive inotropic effects may be reduced
when given in conjunction with calcium channel antagonists or b-adrenergic
antagonists.
Future directions
Pimobendan is a highly interesting compound that is showing much
promise in the treatment of canine congestive heart failure. Its calcium-
sensitizing effect distinguishes it from other commercially available positive
inotropes and may be responsible for its comparative lack of adverse effects
compared with inotropic agents that rely on increasing cytosolic calcium
levels. An alternative viewpoint is that PDE III inhibition is not uniformly
harmful in all patient populations and that despite the findings of the
PROMISE trial
, it may be beneficial in dogs with nonischemic
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V. Luis Fuentes / Vet Clin Small Anim 34 (2004) 1145–1155
congestive heart failure. In fact, pimobendan has continued to be licensed
for human use in Japan since 1994, and US investigators have re-examined
pimobendan in recent times as a means of facilitating tolerance of
b-adrenergic antagonists in human patients with severe heart failure
.
The combination of carvedilol and pimobendan was safe and seemed to
result in favorable neurohormonal effects
. An additional possible use
for pimobendan is in treating pulmonary hypertension
Trials are currently underway to elucidate the role of pimobendan in the
treatment of chronic mitral valve disease. Early use of pimobendan tended to
be focused on cases with systolic dysfunction, because it was thought that
these patients would obtain the most benefit from a positive inotrope. New
evidence is suggesting that pimobendan may relieve clinical signs even when
systolic function is not impaired, and it is likely that the therapeutic
mechanisms are more complex than originally thought. The role of pimo-
bendan’s effects on neurohormones and cytokines also requires further study.
No work has been done on the effects of pimobendan in dogs with
naturally occurring acute heart failure, and there are only anecdotal reports
of its use in cats. Pimobendan’s antithrombotic effects may be particularly
helpful in the latter species.
Summary
Pimobendan is a new inodilator compound available in many countries
for use in canine heart failure. It combines calcium-sensitizing effects with
PDE III inhibition, resulting in positive inotropic effects and veno- and
arteriodilation. Because there is downregulation of the myocardial adren-
ergic signal transduction pathway in the failing heart, the calcium-sensitizing
effects may assume greater importance in patients with heart failure. Clinical
studies in human patients have shown sustained improvement in hemody-
namics and exercise tolerance, with favorable neurohormonal effects. One
study showed a nonsignificant trend toward increased mortality
, but
proarrhythmic effects have not been observed. Studies in naturally occurring
canine heart failure suggest that pimobendan’s effects are at least compa-
rable to those of ACE inhibitors, if not superior. Pimobendan is likely to
play an increasing role in the future in the treatment of canine heart disease.
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Beta-blockade in the management
of systolic dysfunction
Jonathan A. Abbott, DVM
Department of Small Animal Clinical Sciences, Virginia-Maryland Regional College of
Veterinary Medicine, Virginia Technical Institute, Phase II Duckpond Drive,
Blacksburg, VA 24061, USA
Heart failure is a clinical syndrome that results from systolic or diastolic
cardiac dysfunction. Management of systolic heart failure has traditionally
focused on the hemodynamic derangements associated with this disorder. In
this conceptual framework, b-adrenergic antagonists (BAAs) were thought
to be contraindicated, because acute negative effects on cardiac performance
result when the failing heart is deprived of adrenergic support. Current
evidence supports the view that chronic activation of the adrenergic nervous
system is maladaptive and partly responsible for the progression of
myocardial dysfunction. In fact, the efficacy of BAAs in the management
of people with heart failure caused by systolic dysfunction has been
convincingly demonstrated in a number of randomized clinical trials (RCTs).
Although there is reason to believe that this therapeutic avenue holds
promise for veterinary patients, evidence of clinical efficacy is currently
lacking. This review addresses the pathophysiologic basis for the use of
BAAs in heart failure and the potential role of BAAs in veterinary patients
with systolic dysfunction.
Physiology of the autonomic nervous system
Two functionally distinct divisions of the autonomic nervous system are
responsible for unconscious control of body functions. The two systems
differ with regard to neurotransmitters and receptors. The neurotransmitter
of the parasympathetic nervous system is acetylcholine. Catecholamines,
principally norepinephrine (NE) and epinephrine, are the neurotransmitters
of the sympathetic, or adrenergic, nervous system (ANS)
. The efferent
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Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.008
Vet Clin Small Anim
34 (2004) 1157–1170
receptors of the autonomic system have been classified on a biochemical
basis. Those of the parasympathetic system are chiefly cholinergic receptors
that bind to the fungal toxin muscarine; they are known as muscarinic
receptors and are blocked by atropine. The existence of functionally distinct
adrenergic receptors was originally postulated by Ahlquist
in 1948 based
on the variable effects of different amines in experimental preparations. The
a-adrenergic receptors are primarily located in the vasculature and are
responsible for vasoconstriction. The b-adrenergic receptors are present in
the heart, lung, and vasculature.
With respect to the cardiovascular system, parasympathetic discharge has
a restraining effect: inotropic state is diminished, conduction is slowed, and
heart rate is reduced. In general, activation of the ANS results in effects that
oppose parasympathetic influence; heart rate, conduction, contractility, and
vasomotor tone are increased. The effect of adrenergic activation is complex
because of the functional diversity of adrenergic receptors. Central and
presynaptic a
2
-receptors modulate adrenergic tone and decrease the release
of NE at effector junctions
, potentially resulting in vasodilation. The
b
2
-receptors distributed through the vasculature of skeletal muscle mediate
vasodilation. Stimulation of cardiac b
1
- and b
2
-receptors increases heart rate
and inotropic state. Recently, b
3
-receptors have been identified in canine and
human myocardium
. Interestingly, stimulation of cardiac b
3
-receptors
results in a negative inotropic effect
. The clinical and pharmacologic
relevance of these observations has yet to be clarified fully.
Binding of NE or epinephrine to b-receptors results in activation of
adenylate cyclase through the effect of a regulatory (G) protein. Adenylate
cyclase catalyzes the reaction that elaborates cyclic adenosine monophos-
phate (cAMP). cAMP is an intracellular messenger molecule that phosphor-
ylates a number of proteins favoring the adrenergic effects of increased heart
rate and contractility
Pathophysiology of heart failure and adrenergic dysregulation
In dogs, degenerative valvular disease causing mitral valve regurgitation
(MR) and dilated cardiomyopathy (DCM) are most often responsible for
heart failure. In cats, cardiac diseases that impair diastolic function (eg,
hypertrophic cardiomyopathy) are more common. This review emphasizes
the role of beta-blockade in the management of heart failure in dogs.
When cardiac performance declines, compensatory mechanisms are
activated that serve, at least temporarily, to maintain systemic perfusion
pressure and cardiac output. Vasoconstriction, the retention of salt and
water, and increases in heart rate and inotropic state are the principal means
by which cardiac output and blood pressure are maintained. These responses
are mediated partly through the actions of the ANS and the renin-
angiotensin-aldosterone system (RAAS)
. Other endocrine products,
including endothelin, and antidiuretic hormone (ADH) play a less clearly
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J.A. Abbott / Vet Clin Small Anim 34 (2004) 1157–1170
defined role. Additionally, elevated levels of proinflammatory cytokines,
including tumor necrosis factor and interleukins, are present in patients with
heart failure and may play a role in the pathogenesis of this syndrome
.
Heart failure is characterized by chronic adrenergic activation that is
unopposed by vagal restraint, and this is reflected in elevated plasma NE
concentrations in heart failure
. Further, plasma NE concentration has
a strong inverse relation to prognosis in people with heart failure
Raised plasma NE concentrations have also been documented in dogs with
spontaneous heart disease
, and NE concentrations correlate with
functional impairment
.
The development of this autonomic imbalance has a complex basis.
Arterial baroreceptors located in the aorta and carotid arteries play an
important role. In health, stimulation of baroreceptors by increases in
arterial pressure results in vagal discharge. Reduced baroreceptor sensitivity
has been demonstrated in people with heart failure and in animal models
. Baroreceptor dysfunction of this sort is responsible for perceived
arterial underfilling and chronic adrenergic activation despite adequate or
even excessive intravascular volume. Interestingly, increases in adrenergic
activity are not necessarily systemic; local factors, including elevated filling
pressures, likely contribute
. Additionally, heart failure is characterized
by reduced reuptake of NE from cardiac synapses
.
The pathologic consequences of chronically elevated ANS activity have
been extensively studied. These effects are interrelated but primarily involve
altered gene expression, decreased sensitivity of the adrenergic pathway, and
direct cytotoxicosis
. Necrosis is observed when cultured cardiocytes are
exposed to high concentrations of catecholamines, and this effect is mediated
through cAMP-dependent intracellular calcium overload
. More re-
cently, it has been shown that pathologic adrenergic activity results in
programmed cell death, or apoptosis, of cardiac myocytes
. Additionally,
NE induces myocardial hypertrophy and fibrosis, although the former is
mediated largely by a-receptors rather than b-receptors
The effect of increased adrenergic drive on cellular signaling and gene
expression is complex. Chronic catecholamine excess is associated with
activation of a group of enzymes, the b-adrenoreceptor kinases, which
renders b
1
-receptors insensitive to stimulation by adrenergic agonists
Internalization of b
1
-receptors and a decrease in receptor synthesis contribute
to a decrease in b
1
-receptor density known as b-receptor down regulation
The numbers of b
2
-receptors are generally unaffected, but they are uncoupled
from the G protein–adenylate cyclase complex
. Additionally, the
expression of an inhibitory G-protein becomes more prominent
Together these processes decrease the sensitivity of the adrenergic pathway so
that the myocardium is less responsive to increases in adrenergic tone.
Evaluation of myocardial and lymphocyte b-receptor concentrations in
healthy Great Danes and Great Danes with DCM has provided indirect
evidence of b-receptor downregulation in dogs with naturally occurring heart
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J.A. Abbott / Vet Clin Small Anim 34 (2004) 1157–1170
disease
. b
1
-receptor density is reduced, whereas the numbers of b
2
-
receptors are largely unaffected. As a result, the ratio of b
2
- to b
1
-receptors,
normally approximately 30:70, is increased in heart failure
. Down-
regulation of b-receptors may be partly responsible for exercise intolerance in
patients with heart failure, although it has also been suggested that this
process protects the myocardium from further consequences of adrenergic
toxicity.
Pharmacology of
b-adrenergic antagonists
The BAAs are classified based on receptor selectivity and ancillary
pharmacologic characteristics. The first-generation BAAs, of which pro-
pranolol is the prototype, are nonselective agents that block b
1
- and b
2
-
receptors. Beta-2–blockade causes a poorly tolerated increase in systemic
vascular resistance when first-generation agents are administered to human
patients with heart failure and has seen little use in the management of
this syndrome
. The second-generation BAAs include metoprolol,
atenolol, bisoprolol, and others. These drugs selectively block b
1
-receptors.
b
1
-Selectivity has an advantage when used in patients with reactive airway
disease, because BAAs do not impede sympathetically mediated bronchodi-
lation. The third-generation BAAs include carvedilol, bucindolol, and
labetolol. These drugs block b-receptors and also result in vasodilation.
In the case of carvedilol and labetolol, vasodilation results from alpha-
1–blockade, as is probably the case for bucindolol
. The importance of
b
2
-receptor antagonism is uncertain. Stimulation of presynaptic b
2
-receptors
results in cardiac NE release, and only nonselective agents decrease cardiac
or plasma NE concentrations
Evidence of efficacy
Based on the apparently sound premise that enhanced adrenergic drive is
necessary to support cardiac performance, the medical community was
initially resistant to the notion that beta-blockade might have favorable
effects in heart failure. In fact, two early studies of the effect of beta-blockade
in heart failure failed to show benefit
. It is noteworthy, however, that
the duration of these studies was less than 3 months. At about the same time,
a group of Swedish physicians evaluated the effect of chronic beta-blockade
in people with DCM
. Although this early work lacked appropriate
control groups, there was evidence of benefit, and it prompted further
investigation of the role of beta-blockade in heart failure. Somewhat later,
a small placebo-controlled trial provided evidence of benefit that was
apparent as a partial reversal of pathologic ventricular remodeling and
improvements in exercise tolerance
. This early work provided the
foundation for a series of large RCTs that have provided compelling
evidence of efficacy of BAAs for people in heart failure.
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Effects on ventricular remodeling and systolic performance
An increase in left ventricular ejection fraction (EF) resulting from long-
term beta-blockade has been documented in numerous clinical studies. The
increase in EF associated with carvedilol or bucindolol administration is dose
dependent
. There seems to be little difference between BAAs with
regard to observed improvement in EF. Although EF is an important
prognostic factor in people with heart failure, there are differences between
BAAs with regard to survival
. Based on this, other effects of beta-
blockade may partly explain the efficacy of these agents. Improved
myocardial function has not yet been demonstrated in dogs with heart failure
caused by spontaneous disease.
Effects on mortality
Separate clinical trials have demonstrated mortality reduction when
metoprolol (controlled release formulation), bisoprolol, and carvedilol were
compared with placebo in people with heart failure receiving background
therapy of angiotensin-converting enzyme (ACE) inhibitors and diuretics
with or without digoxin
. In fact, it has been argued that the magnitude
of benefit exceeded that evident from clinical trials of ACE inhibitors
Interestingly, the BAA bucindolol has been the exception to the otherwise
consistent results of the BAA clinical trials. The beta-blocker evaluation of
survival trial (BEST) study was halted ahead of schedule when interim
analysis failed to demonstrate a mortality benefit
. The reasons for the
BEST study results have been debated. There is some evidence to suggest that
bucindolol has intrinsic sympathomimetic activity
, and this pharmaco-
logic effect might accelerate the progression of myocardial dysfunction or at
least mitigate the favorable effect of beta-blockade. Additionally, the BEST
study enrolled many African Americans with severe heart failure. It has been
suggested that a genetic characteristic prevalent in the black population
might be responsible for a failure to respond favorably to b-adrenergic
antagonism
. Finally, the prevalence of severe heart failure in the drug
group suggests the possibility that some individuals are, in fact, dependent on
enhanced adrenergic drive to maintain cardiovascular stability. This latter
point is, however, partly refuted by the results of the carvedilol prospective
randomized cumulative survival (COPERNICUS) study, an RCT that
randomized people with severe heart failure to receive carvedilol or placebo
. In summary, there is compelling evidence that metoprolol, bisoprolol,
and carvedilol reduce mortality in people with mild, moderate, or severe heart
failure.
b-Adrenergic antagonists in dogs with heart failure
Unfortunately, there is, to date, no published evidence of efficacy of BAAs
in dogs with myocardial dysfunction. Rush et al
reported their experience
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with metoprolol in dogs with mitral valve disease and DCM. Metoprolol
dose was titrated based on patient tolerance; in some patients, metoprolol
was administered as an antiarrhythmic agent and in others, as adjunctive
therapy for heart failure. This retrospective study was not designed to
evaluate the efficacy of BAAs. The use of metoprolol seems to be safe in this
population, however. Adverse effects, including cardiovascular decompen-
sation attributed to metoprolol, were uncommon. A recent clinical trial
evaluated the effect of thyroid hormone supplementation in dogs with heart
failure caused by DCM
. Patients were randomized to receive thyroid
supplementation or placebo. All patients received propranolol in addition to
furosemide with or without digoxin. Propranolol was apparently tolerated,
although it is somewhat difficult to interpret the results of this investigation
as they relate to the topic of this review.
The effect of beta-blockade has been evaluated in dogs with experimen-
tally induced heart failure. Using a coronary microembolization cardiomy-
opathy model, one group of investigators showed that administration of
metoprolol for 3 months prevents progression of left ventricular dilation and
myocardial dysfunction
. Using the same model, they also demonstrated
favorable effects on ventricular remodeling
. Compared with a placebo
group, the dogs that received metoprolol had a higher EF associated with
a smaller end-systolic volume, less myocardial fibrosis, and a lesser degree of
hypertrophy. In another study, the same investigators observed a decrease in
cellular apoptosis (programmed cell death) in dogs treated with metoprolol
relative to controls
. BAAs have also been evaluated in dogs with
iatrogenic MR. Positive effects on myocardial function have been docu-
mented after administration of atenolol for 3 months
.
Mechanism of effect
The positive effect of BAAs in heart failure has been demonstrated in
clinical trials and in experimental studies of induced cardiac disease. Perhaps
surprisingly, the mechanism of this beneficial effect has not yet been
determined.
The effect of BAAs on receptor density and cellular density has been
suggested as an explanation for the beneficial effect of BAAs. Heart failure
is associated with a reduction in available b
1
-receptors and uncoupling of
b
2
-receptors from the G-regulatory protein complex. Together, these and
other factors may explain decreased adrenergic responsiveness and exercise
intolerance. In people with heart failure, chronic beta-blockade increases
b-receptor density, and in animal models, b-receptor downregulation is
prevented or reversed
. The clinical benefit of increased b-receptor
density is uncertain, however, because, presumably, the b-receptors are at
least partly blocked by drug. Of greater relevance, beneficial clinical effects
of carvedilol have been repeatedly shown; yet, this drug does not increase
b-receptor density but in fact contributes to b-receptor downregulation
.
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Renin concentrations have an inverse relation to prognosis in people with
heart failure. Further, ACE inhibitors, which antagonize some of the effects
of renin release, improve prognosis in people and dogs with heart failure
. Although the effect may only be temporary
, the administration
of BAAs decreases plasma renin concentrations in heart failure
, and
this might be partly responsible for the efficacy of these agents.
The effect of BAAs on heart rate is one of the most clinically prominent
manifestations of beta-blockade. Although heart rate is obviously an
important determinant of cardiac output, the reduction in myocardial
oxygen demand that accompanies a decrease in heart rate may be
responsible for the beneficial effect of BAAs. This notion is supported by
the results of a study in which the effect of heart rate was isolated from other
effects of BAAs by an experimental design that controlled heart rate through
the use of pacemakers
. In this model of induced MR, the chronotropic
effect of chronic atenolol administration was responsible for improved
indices of myocardial function. Effects on myocardial energetics associated
with a reduction in heart rate and protection from the cardiotoxic effect of
NE are perhaps the most compelling explanation for the beneficial effect of
BAAs in heart failure.
Differences between
b-adrenergic antagonists
There are distinct pharmacologic differences between the available BAAs,
and it is possible that some agents are superior to others for the
management of systolic dysfunction. Based on RCTs, clinical efficacy in
people has been demonstrated for metoprolol, carvedilol, and bisprolol
. Beneficial effects of metoprolol and atenolol have been evident in
studies of dogs with experimentally induced heart disease
. It is
probable that first-generation nonselective agents, such as propranolol
are inappropriate for the management of heart failure. Of the other agents,
the absolute superiority of a single agent has not been established, although
it has been suggested that the ancillary properties of carvedilol make it
particularly well suited to the management of systolic dysfunction.
Carvedilol is a nonselective BAA that also antagonizes a
1
-receptors,
resulting in vasodilation. This latter property may serve to reduce afterload,
which may preserve cardiac output and confer greater tolerability. Studies
of healthy dogs and of people chronically receiving carvedilol suggest that
carvedilol’s alpha-blocking property may be weak and not of great clinical
importance, however
. Carvedilol is also an antioxidant, and this
might contribute to the favorable effects of this drug
. The results of an
RCT that was designed as a head-to-head comparison of metoprolol and
carvedilol were recently published
. Although the findings have been
questioned based primarily on the dose of metoprolol used
carvedilol did confer a survival advantage.
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J.A. Abbott / Vet Clin Small Anim 34 (2004) 1157–1170
Use of
b-adrenergic antagonists in veterinary patients
The efficacy of BAAs in heart failure has been unequivocally demon-
strated in people with heart failure. Experimental evidence favors the use of
BAAs in dogs with systolic dysfunction. Based on this, the cautious use of
beta-blockers in veterinary patients can probably be justified. Nevertheless,
it is important to recognize that evidence of clinical efficacy in dogs with
spontaneous disease is lacking. Although clinical studies of people with heart
failure suggest that concerns regarding tolerability of beta-blockade are
largely unfounded, the assumption that these results can be extrapolated to
dogs with cardiomyopathy must be carefully evaluated. Dogs are most often
presented for veterinary evaluation when myocardial disease is relatively
advanced. In general, the prognosis is quite poor, and although the published
literature is not entirely consistent, mean survival after diagnosis is about 5
months
. In Doberman Pinschers with advanced myocardial disease,
the prognosis may be more dismal still; mean survival was reported to be 9.5
weeks
. This is relevant in that the positive effects of BAAs in people are
generally not manifest before 3 months of therapy. It is possible that
a substantial proportion of the veterinary population in whom BAAs might
be indicated is destined to die before these animals can benefit.
Although tolerability of BAAs in people with heart failure is high and
benefits of beta-blockade have been demonstrated n people with severe heart
failure, it has been noted that withdrawals from clinical trials that occur
before randomization during open-label run-in periods have been incom-
pletely reported
. There probably are some patients that are critically
dependent on adrenergic drive to maintain cardiac output and perfusion
pressure. In these cases, BAAs are bound to be poorly tolerated, and it is not
unreasonable to suggest that the prevalence of this phenomenon might be
high in dogs with advanced myocardial dysfunction.
Despite these cautions, there is reason to believe that beta-blockade holds
promise for veterinary patients with myocardial dysfunction. Moreover, as
noted, Rush et al
have reported on the use of metoprolol in dogs with
valvular disease and DCM; in this study, the drug was apparently safe and
well tolerated.
Published reports of clinical trials and anecdotal evidence suggest that the
key to patient tolerability is gradual dose titration. In the largest RCT
reported to date, beta-blockade was initiated at a low dose and gradually
increased over the course of 6 to 8 weeks to a target or maximum tolerated
dose. In experimental studies of induced disease in dogs, similar protocols
have been used. Anecdotally, even small doses of a BAA may be associated
with decompensation and worsening of congestive signs in dogs, although it is
important to recognize that DCM is a progressive disorder in which clinical
deterioration may occur independent of therapy. Regardless, it is probable
that patients with advanced myocardial dysfunction are most likely to
experience adverse effects of beta-blockade.
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Indications in veterinary patients
As discussed, beta-blockade is a nonstandard therapy for canine patients
with systolic dysfunction. However, based on published experimental
evidence and the inevitably tenuous extrapolation from medical reports,
BAAs are agents that may preserve myocardial function in dogs with cardiac
disease. DCM is the most obvious indication. This is the naturally occurring
disorder that most closely resembles the conditions that result in heart failure
in people, and it is probably similar to the most commonly used experimental
models of heart disease. Patients with clinically occult DCM might be
expected to tolerate beta-blockade and to live long enough to benefit.
Patients with clinically evident but compensated DCM are candidates for
beta-blockade, although the risk of clinical deterioration is likely higher.
MR resulting from myxomatous valvular degeneration is the most
common cardiac disease in the dog. Heart failure develops in patients with
this disease when systolic myocardial function is at least ostensibly normal
. Because the benefits of beta-blockade in heart failure relate primarily to
preservation or even restoration of myocardial function, the value of beta-
blockade in MR can be questioned. However, the use of invasive or in vitro
evaluation indices of contractility in dogs with induced MR discloses
myocardial dysfunction
. Indeed, a model of MR has been used to
demonstrate the positive effects of beta-blockade
. Further, the
development of myocardial dysfunction is sometimes echocardiographically
evident in patients with long-standing MR. Possibly, there is a particular role
for the use of third-generation BAAs, such as carvedilol, that have the
ancillary and presumably favorable effect of systemic vasodilation.
Practical considerations
The author considers the use of BAAs in dogs with clinically occult DCM,
in dogs with clinically evident but compensated DCM, and in dogs with MR
in which the echocardiographic study reveals confirmed or incipient
myocardial dysfunction. The latter group includes dogs in which the end-
systolic left ventricular dimension is close to the upper limit of the reference
range for this variable. Potential adverse effects, the need for gradual
titration, and the requirement for careful monitoring are thoroughly
discussed with the pet owner before BAAs are prescribed. For some patients,
an inability or unwillingness on the part of the pet owner to contend with the
inconvenience of frequent dosage adjustments represents a relative contra-
indication to BAAs.
When consultation with the pet owner suggests that the patient is
a candidate for beta-blockade, the agent is chosen based partly on cost.
The author prescribes carvedilol when financial considerations allow and
metoprolol for other cases, carvedilol is considerably more expensive than the
conventional formulation of metoprolol. Rush et al
reported an initial
dose of metoprolol of 0.2 to 0.4 mg/kg in a study group that consisted of dogs
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J.A. Abbott / Vet Clin Small Anim 34 (2004) 1157–1170
with causally diverse cardiac disease; an intial dose of 0.1–0.2 mg/kg might be
appropriate for dogs with myocardial dysfunction. Based on pharmacody-
namic studies of healthy dogs
, an initial carvedilol dose of about 0.1 mg/
kg seems reasonable and appears to be generally well tolerated by dogs with
myocardial dysfunction. When metoprolol is used, the dose is increased by
a factor of 25% to 100% every 7 to 14 days until a dose of approximately
1 mg/kg is attained or side effects become manifest. The conventional
formulation of metoprolol is available in 50- and 100-mg tablets. For many
dogs, it is more convenient to formulate a solution that is used until the dose
is a convenient fraction of the available tablets. Carvedilol is licensed for the
management of heart failure in people and is available as 3.125-, 6.25-, 12.5-,
25-mg tablets, all of which are identically priced. The dose is increased every 7
to 14 days, provided that adverse effects are not evident, until reaching a dose
of approximately 1 mg/kg. Generally, the dose is doubled for the first one or
two increments; thereafter, the dose is increased by 25% to 75% at each
interval. BAAs are used together with conventional agents, such as ACE
inhibitors and diuretics, as appropriate. Beta-blockade is not initiated until
standard therapy has resulted in resolution of congestive signs.
Monitoring of heart rate, blood pressure, and the patient’s demeanor is
important. Ideally, the patient is examined every 10 to 14 days, although this
is not always practical. Often, the pet owner can adequately monitor an
uncomplicated titration at home, particularly if he or she is provided with
instructions on how to record respiratory rate and heart rate.
Bradycardia, weakness associated with hypotension, and worsening of
congestive signs are potential adverse effects of beta-blockade, although they
seem to be uncommon using this approach. When these complications are
encountered in people receiving BAAs, a temporary decrease in dose or an
increase in diuretic dose is recommended
. Some favorable effects of beta-
blockade are dose related, although it likely that a low dose of a BAA is
superior to none at all
. Adherence to a rigid protocol during dose
titration is not likely to be advantageous; rather, the dosage schedule should
be tailored to the individual based on clinical response. It should be noted
that the optimal dose for BAA in the management of heart failure in dogs is
not known. The target doses provided here are partly based on assumptions
regarding the doses used in experimental studies. Whether or not these doses,
or any others, are efficacious in the treatment of dogs with spontaneous heart
disease is a questions that can be answered only by appropriately designed
clinical trials.
Summary
The concept that heart failure is simply the consequence of impaired pump
function is now outmoded. Congestive heart failure is a neuroendocrine
syndrome in which activation of the adrenergic nervous system and specific
endocrine pathways is integral to its pathogenesis. It is now clear that chronic
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J.A. Abbott / Vet Clin Small Anim 34 (2004) 1157–1170
increases in adrenergic drive associated with heart failure have detrimental
effects on myocardial function. The use of BAAs is now standard therapy for
people who develop heart failure caused by systolic dysfunction. Beta-
blockade may have a role in the management of dogs with heart failure.
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Interventional catheterization for
tachyarrhythmias
Kathy N. Wright, DVM
a,
*
a
The CARE Center, 6995 East Kemper Road, Cincinnati, OH 45249, USA
Interventional catheterization for the diagnosis and treatment of tachyar-
rhythmias has revolutionized our knowledge of the mechanisms underlying
various types of rhythm disturbances and provided the means to cure rather
than palliate many of these disorders. Supraventricular tachyarrhythmias
(SVTs) are rapid cardiac rhythms originating above the bifurcation of the
atrioventricular (AV) bundle or requiring the structures proximal to this
bifurcation for their maintenance. The QRS complex generally has a normal
or ‘‘narrow’’ configuration during SVTs, giving rise to the term narrow
complex tachyarrhythmias
. Examples of specific SVTs include the following:
AV reciprocating tachycardia: a large re-entrant circuit is produced with
an accessory pathway typically forming the retrograde limb of this
circuit, carrying the impulse from the ventricular to the atrial myocar-
dium, whereas the AV node forms the anterograde limb, carrying
the impulse from the atrial to the ventricular myocardium, thus pro-
ducing a normal QRS complex tachycardia. In rare cases, the circuit
can be reversed, producing a wide complex tachyarrhythmia.
Atrial re-entrant tachycardia: a re-entrant circuit is confined to the atrial
myocardium only. The PÕ wave morphology is typically different from
that of sinus rhythm, and the RPÕ interval during the tachycardia is
generally longer than the PÕR interval.
Automatic atrial tachycardia: a site within the atrial myocardium
develops abnormal (or abnormally rapid) depolarization at a rate faster
than sinus nodal depolarization. Again, distinct PÕ waves that have
a morphology different than that of sinus P waves can generally be seen.
The RPÕ interval during the tachycardia is generally longer than the PÕR
interval.
This work was supported by grant DO2CA-52 from the Morris Animal Foundation.
* The CARE Center, 6995 East Kemper Road, Cincinnati, OH 45249, USA.
E-mail address:
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.007
Vet Clin Small Anim
34 (2004) 1171–1185
AV nodal re-entrant tachycardia: the re-entrant circuit is confined to the
AV junction. Typically, there is a ‘‘slow’’ AV nodal pathway that forms
the anterograde limb of the circuit and a ‘‘fast’’ AV nodal pathway that
forms the retrograde limb of the circuit.
Automatic AV junctional tachycardia: tissue within the AV junction
depolarizes at a rate faster than the sinus node.
Sinoatrial nodal re-entry: a re-entrant circuit is confined to the sinus
node and area of adjacent atrial myocardium. The PÕ wave morphology
appears identical to (or virtually indistinguishable from) that of sinus
rhythm.
Atrial fibrillation: multiple micro–re-entrant circuits form within the
atrial myocardium, leading to the loss of distinct P waves and a generally
irregularly irregular ventricular response.
Interventional techniques are best suited to pathologic tachyarrhythmias
that arise from a single focus or have a small critical isthmus as part of
a macro–re-entrant circuit. A point or small linear radiofrequency (RF)
lesion would thereby be successful in terminating these tachyarrhythmias.
Catheter ablation of tachyarrhythmias versus antiarrhythmic
drug therapy
Why consider interventional techniques for treating a tachyarrhythmia
given the general anesthesia, cardiac catheterization, and cost involved? One
must consider several factors when addressing this question. First, how
significant is the tachyarrhythmia? To answer this requires several pieces of
information: the tachyarrhythmia rate, duration of a single run, frequency of
tachyarrhythmia runs, clinical signs demonstrated by the patient, and
myocardial function of the patient. As veterinarians, we depend greatly on
the owner’s observations to help us determine the significance of an
arrhythmia, for example, its frequency and the nature and severity of the
clinical signs demonstrated. We must understand, however, that some owners
are more observant than others. Also, their dog may have been demonstrat-
ing clinical signs for so long that it has become the new ‘‘normal.’’ They may
truly believe that this is the dog’s normal activity level and have no other
reference with which to compare it. In many cases, it was only after the
tachyarrhythmia was ablated that the owners had a true picture of how
compromised their dog was, with comments like ‘‘He acts like a puppy
again!’’ The standard of care in human medicine today dictates that even
asymptomatic patients exhibiting ventricular pre-excitation (ie, an anterog-
rade conducting accessory pathway) or a tachyarrhythmia presumed to be
AV reciprocating tachycardia undergo electrophysiologic testing to determine
the inducibility of AV reciprocating tachycardia or atrial fibrillation.
Interestingly, a recent study in asymptomatic human patients with the
Wolff-Parkinson-White syndrome and inducible arrhythmias at the time of
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electrophysiologic study clearly demonstrated that prophylactic accessory
pathway ablation markedly reduced the frequency of adverse events in these
patients compared with a control group not undergoing ablation
A Holter monitoring study is a useful test to determine the frequency and
rate of a given tachyarrhythmia and to uncover whether other tachyar-
rhythmias are present. The Holter recording can also provide valuable
information concerning the onset and termination of each tachyarrhythmic
run and the possible presence of intermittent ventricular pre-excitation
(allowing the clinician to know that an accessory pathway is present) that
was not seen on baseline electrocardiograms (ECGs). An echocardiogram
allows the clinician to assess overall myocardial function, chamber size, and
the presence or absence of underlying congenital or acquired heart defects
that could provide the substrate for a given tachyarrhythmia. Assessing
myocardial function during a tachyarrhythmia is not particularly useful,
because standard measures, such as fractional shortening, are always
decreased. This is secondary to poor diastolic filling during a rapid heart
rhythm, leading to decreased end-diastolic chamber measurements
Tachycardia-induced cardiomyopathy (TICM), conversely, is a form of
myocardial dysfunction caused by chronic SVTs or ventricular tachyar-
rhythmias
. What is most remarkable about TICM is its reversibility with
rigorous rate or rhythm control. TICM is indistinguishable from idiopathic
dilated cardiomyopathy (DCM), given currently available diagnostic techni-
ques, apart from the reversibility of TICM with arrhythmia control
. As
veterinarians, we recognize the numerous studies showing that normal dogs
can easily be paced into congestive heart failure, but we do not always
effectively translate that finding into our clinical practice. The tendency is to
assume that a dog has idiopathic DCM and secondary tachyarrhythmia
rather than a tachyarrhythmia with secondary myocardial dysfunction
(TICM). Antiarrhythmic drug therapy often does not produce rigid
tachycardia control, and because these dogs are assumed to have DCM
rather than TICM, interventional catheterization techniques are often not
considered. Thus, we do not know the true incidence of TICM in the canine
population. Interestingly, of the dogs referred for radiofrequency catheter
ablation (RFCA), more than one third had TICM with resolution after
ablation of their tachyarrhythmia. The importance of distinguishing TICM
from idiopathic DCM cannot be overemphasized. As shown in our case
series, TICM carries a favorable long-term prognosis for survival and
withdrawal of all cardiac medications once the inciting tachyarrhythmia
has been eliminated. This is in stark contrast to idiopathic DCM, which
carries a poor long-term prognosis for survival. Reports of human patients
going from the transplant list to participating in competitive sports within
6 months after tachyarrhythmia ablation further highlight the reversibility
of TICM
.
When calculating the cost of interventional versus drug therapy, one must
consider that interventional therapy is generally a one-time expense, whereas
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K.N. Wright / Vet Clin Small Anim 34 (2004) 1171–1185
antiarrhythmic drug therapy continues over the lifetime of the dog.
Typically, combination antiarrhythmic treatment is required, and if the
animal demonstrates TICM, other pharmacologic agents are needed to
improve myocardial function. With ablation of a tachyarrhythmia, no
further antiarrhythmic drug therapy is required. Furthermore, with the
resolution of TICM that typically occurs after ablation, other cardiac
support drugs can be withdrawn as well. When faced with a young or
middle-aged dog, therefore, RFCA becomes cost-effective as well as pro-
viding a potential cure for a tachyarrhythmia, something that antiarrhythmic
drugs cannot do. The cost-effectiveness of RFCA compared with long-term
antiarrhythmic drug therapy has also been demonstrated in people
.
The risks of an invasive procedure requiring general anesthesia should
also be considered. We have been able to develop an anesthetic protocol over
the years that is effective and tolerated well by dogs with rapid supraven-
tricular tachycardias and myocardial dysfunction. Continuous monitoring of
direct rather than indirect arterial pressure, oxygen saturation, end-tidal
carbon dioxide, and the 12-lead ECG provides added measures to detect
changes in the patient’s status quickly. Of 31 procedures performed, less than
10% of animals have had serious complications. Two suffered early
anesthetic death, and the third suffered neurologic damage from a resusci-
tated cardiac arrest. All these complications occurred early on in our
experience, before the institution of the rigorous monitoring and anesthetic
protocol used successfully today. Dogs are typically referred for RFCA late
in the disease process after TICM or other debilitating clinical signs have
already occurred. The risks are clearly greater in these animals than in those
referred earlier in the disease process before all drug therapies have proved
ineffective.
Antiarrhythmic drug treatment carries known risks to the patient as well.
Each antiarrhythmic agent has proarrhythmic potential. In addition,
supraventricular tachycardias are often treated with negative inotropes in
dogs with poor myocardial function. Six dogs with Wolff-Parkinson-White
syndrome and probable TICM have died suddenly while on drug therapy
before coming for ablation. Thus, the risks and benefits of catheter ablation
compare favorably with those of long-term drug therapy, which may be
associated with side effects, incomplete efficacy, and poor owner (or patient)
compliance
Principles of catheter ablation
The various techniques of catheter ablation all share a common basis in the
selective destruction of myocardial tissue responsible for initiating or
perpetuating a tachyarrhythmia. Direct current energy was the original
energy source used in catheter ablation procedures. An unacceptably high
percentage of serious complications occurred with direct current energy,
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K.N. Wright / Vet Clin Small Anim 34 (2004) 1171–1185
including cardiac tamponade, coronary sinus rupture, and ventricular
dysfunction, and sudden death occurred as a result of electrical arcing and
barotrauma
. The energy source now used in almost all clinical ablations is
RF energy. RF energy is an alternating current, with a frequency range
between 300 and 750 kHz when used for catheter ablation
. At these
frequencies, direct depolarization of excitable tissues is avoided (unlike the
situation with direct current energy). This feature, along with the ability to
control the size of the lesion by varying the duration and power delivered,
makes RF energy much safer for cardiac applications. The resistive properties
of RF energy lead to the generation of heat within the myocardium as energy
passes from the electrode into the tissue
. Direct resistive heating occurs
only in the regions of highest current density, an approximately 1-mm rim of
tissue contacting the tip electrode. Deeper tissues are heated by passive
conduction from this surface rim of tissue
. Temperature-controlled
electrode catheter systems are the best way to monitor and control RF
ablation. Electrode-surface interface temperature is the best predictor of RF
lesion volume
. Temperature-controlled ablation systems aid the electro-
physiologist in avoiding electrode-tissue interface temperatures greater than
100(C, the point at which plasma boils and coagulates on the catheter tip,
preventing further current flow to the tissue and potentially causing serious
tissue damage
. In addition, closed loop temperature control systems
regulate the power output to maintain the target temperature set by the
electrophysiologist (typically 60(C–70(C)
Currently available thermistor-tipped catheters used for RF ablation have
a radius of curvature that is effectively too large for the heart of a small dog
(\25–30 lb) or cat. The proximity of important structures, such as the AV
node or coronary arteries, to ablation targets also increases the risk in these
smaller sized patients. The relatively small lesion size produced by RF energy
is one of its safety features but has also limited its efficacy in the treatment of
certain ventricular tachyarrhythmias and atrial fibrillation. The exploration
of alternative energy sources that can safely produce deeper lesions has
included laser, microwave, ultrasound, cryoablation, and chemical (eg,
ethanol) sources. None, however, has replaced RF energy in terms of overall
efficacy and safety
.
Radiofrequency catheter ablation of accessory pathways
The greatest success of RF catheter ablation has been in curing narrow
complex supraventricular tachycardias, particularly those in which a focal
lesion can destroy the site of tachycardia initiation or a key location within
a re-entrant circuit. A success rate of greater than 95% has been achieved in
human patients with accessory pathways or AV nodal re-entry
. Of the
dogs that have been referred for electrophysiologic study and RFCA of
narrow complex tachyarrhythmias, most have been diagnosed with accessory
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pathways and less than 20% have been diagnosed with focal atrial
tachycardias. Multiple accessory pathways and the concurrent presence of
an accessory pathway and focal atrial tachycardia have been found in some
dogs. Studies in these and normal dogs demonstrate that the poor retrograde
conduction properties of the canine AV node would make support of AV
nodal re-entrant tachycardia, the most common paroxysmal supraventricu-
lar tachycardia in human adults, extremely difficult
. We have found that
canine accessory pathways are capable of significantly faster retrograde
conduction than those studied in a corresponding pediatric human pop-
ulation. These accessory pathways, when coupled with the rapid anterograde
conduction characteristics of the typical canine AV node, support a more
rapid orthodromic reciprocating tachycardia than is seen in people
. In
addition, the ventriculoatrial intervals used to exclude an accessory pathway
as the retrograde limb of a tachycardia (ie, exclusion orthodromic re-
ciprocating tachycardia as the tachycardia mechanism) are not applicable
in dogs
. The right-sided distribution of canine accessory pathways also
significantly differs from the preponderance of left-sided accessory pathways
seen in people
Orthodromic reciprocating tachycardia is a narrow complex tachyar-
rhythmia that results from a macro–re-entrant circuit established by
anterograde conduction of an impulse over the AV node–His-Purkinje
system to the ventricular myocardium and retrograde conduction of that
impulse over an accessory pathway to the atrial myocardium. This tachyar-
rhythmia can produce debilitating clinical signs, including congestive heart
failure and sudden death. It can be permanently cured by RF ablation of the
retrograde limb of the circuit (ie, the accessory pathway), leaving the normal
conduction system intact. Dogs with this rhythm disturbance have typically
been young to middle aged, ranging from 4 months to 7 years of age. Clinical
signs have most commonly included weakness, decreased exercise tolerance,
inappetence, vomiting, weight loss, pulsing of the ears or entire head, and
congestive heart failure signs (eg, dyspnea, peritoneal effusion). Anterograde
conduction over an accessory pathway, a capability not all have, produces
variable degrees of ventricular pre-excitation during sinus or atrial rhythms,
but this is not present during orthodromic reciprocating tachycardia.
Ventricular pre-excitation is the early activation of a portion or all the
ventricular myocardium by a supraventricular impulse conducting down an
accessory pathway and bypassing the normal specialized conduction tissue
. The accessory pathway acts as the retrograde limb during orthodromic
reciprocating tachycardia; thus, it is refractory in the anterograde direction
and cannot pre-excite the ventricular myocardium. Ventricular pre-excitation
is often intermittent in dogs, and Holter monitoring is often required to
discover it. Documenting the presence of ventricular pre-excitation before an
electrophysiologic study is helpful to the electrophysiologist because it
confirms the presence of an accessory pathway. Other accessory pathways
are incapable of conducting in a anterograde direction and thus never
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demonstrate ventricular pre-excitation. These are known as concealed
accessory pathways
Antiarrhythmic agents that influence accessory pathway conduction are
typically withdrawn for three to five half-lives before electrophysiologic
study. The animal is brought to the catheterization laboratory (
) in
a fasted state, and anesthesia is induced. Catheter introducer sheaths are
inserted percutaneously using the Seldinger technique in the femoral veins
and each external jugular vein. Multipolar electrode catheters are positioned
using fluoroscopic and electrogram guidance into the coronary sinus, high
right atrium or right atrial appendage, and right ventricular apex. A
deflectable-tip quadri- to decapolar catheter is positioned across the septal
tricuspid valve leaflet to record a His bundle potential. Ten bipolar
intracardiac electrograms and surface electrocardiographic leads I, II, V1,
and V6 are continuously displayed on a 32-channel physiologic recording
system and stored on optical disks (
The mechanism of each dog’s supraventricular tachycardia is determined
using established criteria and the response to specific incremental and
extrastimulus pacing maneuvers. In addition, the tachycardia cycle length
and anterograde and retrograde accessory pathways as well as the AV nodal
parameters are determined in each dog undergoing electrophysiologic study.
An accessory pathway capable of anterograde conduction is confirmed by
Fig. 1. The interventional electrophysiology laboratory is equipped with C-arm fluoroscopy
(A); a multichannel monitoring system to display surface electrocardiogram leads, intracardiac
electrograms, and blood pressure (B); an ablation unit; and standard anesthetic and emergency
equipment.
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K.N. Wright / Vet Clin Small Anim 34 (2004) 1171–1185
the presence of an abnormally short or negative His-to-ventricular (HV)
interval (ventricular pre-excitation)
. The earliest site of ventricular
activation during maximal pre-excitation is used to identify the ventricular
insertion of an accessory pathway, whereas the earliest site of atrial
activation during orthodromic reciprocating tachycardia (
) or ventric-
ular pacing is used to identify an accessory pathway’s atrial insertion
.
Given the oblique nature of many accessory pathways encountered in dogs,
the atrial and ventricular insertion sites could be at different locations along
the AV groove. Electrophysiologic testing is repeated after successful
ablation of one accessory pathway, because additional more slowly
conducting pathways may then become evident. We have found multiple
accessory pathways in several dogs, particularly brachycephalic breeds.
A thermistor-tipped, deflectable, quadripolar catheter is then used to
perform detailed mapping of the region in which the accessory pathway or
other supraventricular tachycardia mechanism lies. After a target site is
identified, the distal electrode of this catheter is connected to an RF
generator that delivers continuous unmodulated RF energy to the catheter
tip (
). Depending on the site targeted, a set temperature of 60(C to
70(C is programmed. Ablation catheter tip temperature, impedance, and
generator power are continuously displayed on a laptop computer coupled to
the RF generator. Time from the onset of RF delivery to successful
disappearance of the tachyarrhythmia is recorded. Successful ablation of
these accessory pathways has been achieved in more than 90% of the dogs we
have studied. No accessory pathway has been encountered that could not be
ablated, but the two early anesthetic deaths described previously occurred
before pathway ablation.
Fig. 2. A 30( left anterior oblique view of multielectrode catheters in standard positions within
the heart: coronary sinus (A), His bundle region (B), high right atrium (C), and right ventricle
(D).
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Use of radiofrequency catheter ablation for atrial tachycardias
Although mapping of accessory pathways involves the two-dimensional
structure of the AV annuli, mapping of atrial tachycardias involves mapping
in the complex three-dimensional structure of the atria
. Focal atrial
tachycardias may result from abnormal automaticity, triggered activity, or
micro–re-entry and can be ablated with a single RF lesion at the site of
tachycardia initiation
. Focal atrial tachycardias tend to cluster in certain
anatomic zones in people and dogs studied to date
. These cluster zones
include the region of the crista terminalis, the coronary sinus os, and within
the pulmonary veins. A deca- to duodecapolar catheter is deployed along the
crista terminalis to rule in or out this location as a site of origin. If a
pulmonary venous origin is suspected, a catheter must be passed retrograde
through the aorta into the left ventricle and retroflexed through the mitral
valve into the left atrium. Mobility of the catheter within the left atrium is
limited, making ablation of left atrial tachycardias more challenging.
Fig. 3. Surface electrocardiogram leads and intracardiac electrograms are displayed during
orthodromic reciprocating tachycardia using a midseptal accessory pathway. The ventricular
(V) and atrial (A) electrograms are labeled in the distal ablation catheter electrode pair (Abl ds).
Notice the short ventriculoatrial (VA) interval in this lead and in the middle pair of electrodes
on the His catheter (His md) compared with the other catheter electrodes. The His bundle
electrogram (H) is labeled in the distal His catheter electrode pair (His ds).
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Focal atrial tachycardia is most successfully ablated by targeting the site
of earliest atrial activation preceding the surface PÕ wave during tachycardia.
It can be difficult to discern the surface PÕ wave morphology during atrial
tachycardia; thus, using an intracardiac surrogate marker for the PÕ wave
onset is helpful. It is essential that the catheter electrodes being used as
a surrogate do not move during the study. A promising technique used in
some human catheterization laboratories is electroanatomic mapping using
a computer-based system to localize a mapping catheter in three-dimensional
space
. Intracardiac echocardiography is also useful to define the complex
anatomic relations between the right and left atria and to localize catheter
placement
. We have mapped focal atrial tachycardias in five dogs
(
). These have involved the pulmonary veins in the left atrium and the
high right atrium at the cranial-most extent of the crista terminalis.
Ablation of macro–re-entrant atrial tachycardias involves severing
a critical isthmus in the tachycardia circuit by making a continuous linear
Fig. 4. Site of successful ablation of a right posteroseptal accessory pathway. Surface
electrocardiogram leads and intracardiac catheters are displayed as in
. Ventricular (V)
and atrial (A) electrograms are labeled in the proximal pair of electrodes on the coronary sinus
catheter (CS 9, 10). Notice the short ventriculoatrial (VA) interval initially, which then
lengthens for two complexes. A ventricular electrogram (V) is seen, which is not followed by an
atrial (A) electrogram, indicating block within the accessory pathway through heating by
radiofrequency energy. Orthodromic reciprocating tachycardia terminates, because the
accessory pathway is no longer able to support conduction. After a pause, sinus rhythm
resumes. The first QRS is a ventricular fusion complex.
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RF lesion. The classic form of macro–re-entrant atrial tachycardia is atrial
flutter, which typically involves a circuit confined to the right atrium with its
unique endocardial anatomy
. We have identified similar macro–re-
entrant right atrial circuits within the right atrium in a dog with congenital
heart disease and right atrial dilation. Mapping of macro–re-entrant atrial
tachycardias is facilitated through the use of 20-pole catheters positioned
around the tricuspid annulus or crista terminalis. Entrainment mapping and
demonstration of split potentials are useful techniques to define the barriers
in a given macro–re-entrant tachycardia circuit
. Electroanatomic map-
ping of these rhythms has also been a breakthrough in the localization of
a critical zone of slow conduction and confirmation of bidirectional block
after ablation. Criteria for defining a successful ablation end point have had
to be modified for the linear lesions required for macro–re-entrant atrial
tachycardias compared with the focal lesions for accessory pathways, focal
atrial tachycardias, and AV nodal re-entry. Termination during RF energy
application and subsequent failure to reinduce the tachycardia, which is
useful for focal lesions, have proven inadequate for linear lesions, with
recurrence rates of 20% to 30%
Fig. 5. Supraventricular tachycardia is seen in the first four complexes of this tracing, which
could be confused with orthodromic reciprocating tachycardia using a slowly conducting
accessory pathway. The development of a 2:1 supra-His atrioventricular block, however,
excludes orthodromic reciprocating tachycardia. Focal atrial tachycardia originating from one
of the pulmonary veins was diagnosed. Labeling of electrograms is in accordance with that in
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K.N. Wright / Vet Clin Small Anim 34 (2004) 1171–1185
Use of radiofrequency catheter ablation for ventricular tachycardia
Certain forms of ventricular tachycardia are amenable to RF catheter
ablation. Re-entrant ventricular tachycardias (typically associated with
coronary artery disease in human beings) are difficult to ablate with this
technique because of (1) hemodynamic instability of ventricular tachycardia
in many patients, which precludes adequate mapping; (2) intramyocardial or
epicardial origin deeper than RF energy typically penetrates; (3) difficulty in
identifying an appropriate ablation site to eliminate the complex ventricular
tachycardia circuit; (4) difficulty in RF penetrating scarred endomyocar-
dium; (5) the existence of multiple ventricular tachycardia morphologies or
sites in a single patient; and (6) the progressive nature of the underlying
disease, leading to the emergence of new ventricular tachycardias over time
. Antiarrhythmic drugs and internal cardioverter defibrillators, if they
become more readily available to veterinary cardiologists, are more
appropriate for these patients. Other forms of energy, such as a laser or
microwave source, may prove useful in the future for these deeper
tachycardia circuits. Another modification that has helped in some cases
involves cooled saline irrigation of the catheter tip during RF energy delivery
. This permits a higher power to be delivered, resulting in increased lesion
size and avoiding a rise in impedance. In contrast, ventricular tachycardias in
patients without structural heart disease, otherwise known as idiopathic
ventricular tachycardias, can be successfully ablated in a high percentage of
patients. Idiopathic ventricular tachycardias are generally hemodynamically
stable, focal in origin, and have no associated cardiac structural pathologic
findings to interfere with RF energy delivery to the site of origin. In human
patients, idiopathic ventricular tachycardias typically arise from the right
ventricular outflow tract or left ventricular side of the interventricular
septum. Interestingly, one study found that human patients with idiopathic
left ventricular tachycardia had false tendons extending from the postero-
inferior left ventricle to the left ventricular septum
. The same false
tendons were found in only 5% of control patients. We and others have
identified false tendons echocardiographically in three young dogs with
monomorphic repetitive ventricular tachycardia (B. Bulmer, DVM, Man-
hattan, KS, personal communication, June 2003). Although electrophysio-
logic studies have not been performed in these animals, the possibility that
these dogs have idiopathic left ventricular tachycardia associated with these
false tendons must be considered. It would be reasonable to consider
electrophysiologic mapping and RF catheter ablation in young dogs like
these without structural heart disease other than perhaps the false tendons
mentioned previously. Whether the ventricular tachycardia in other dogs,
particularly Boxers, would be amenable to ablation is not known at this time.
The concern that the disease in Boxers resembles arrhythmogenic right
ventricular dysplasia makes one concerned that ablation may not be ulti-
mately effective. Catheter ablation in human patients with right ventricular
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K.N. Wright / Vet Clin Small Anim 34 (2004) 1171–1185
dysplasia is considered palliative rather than curative. These patients
typically have multiple ventricular tachycardia foci, and progressive myo-
cardial disease often permits the appearance of new ventricular tachycardia
foci in the future
. Hemodynamic stability is also a problem in Boxers
with symptomatic ventricular tachycardia, making mapping using standard
techniques quite difficult. More study is necessary before the utility of
ablation in this breed can be specifically determined.
The techniques used to map idiopathic ventricular tachycardia are similar
to those used for focal atrial tachycardias. Activation mapping involves
searching for the site of earliest local ventricular activation before the onset
of the QRS complex. Pace mapping, conversely, is pacing from various sites
on the ventricular endocardial surface to find a site at which the QRS
complexes on a 12-lead ECG exactly mimic those during the ventricular
tachycardia
. Long-term success rates of 83% have been achieved for RF
catheter ablation of idiopathic ventricular tachycardia in human patients
. Identification of this form of tachyarrhythmia in dogs requires
additional electrophysiologic study.
Summary
Catheter ablation of cardiac tachyarrhythmias is unique among our
therapeutic armamentarium because it offers the ability to cure certain
tachyarrhythmias permanently without implanted devices. TICM that is not
clinically distinguishable from idiopathic DCM can also resolve once the
underlying tachyarrhythmia is eliminated. Current techniques are best suited
to tachyarrhythmias in which a point lesion or small linear burn would result
in disruption of the tachyarrhythmia’s substrate. The equipment and expertise
required limit the availability of this treatment modality in veterinary
medicine. Its success with SVTs (particularly those secondary to accessory
pathways), however, make it a viable option for many owners, even if they
must travel some distance to reach a center performing these procedures.
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Dilated cardiomyopathy: an update
Michael R. O’Grady, DVM, MS*,
M. Lynne O’Sullivan, DVM, DVSc
Department of Clinical Studies, University of Guelph, Guelph, Ontario, Canada
This review focuses on areas of somewhat recent discovery that relate in
large part to the areas studied or under investigation by the authors over the
last 10 years. Readers are referred to reviews of areas of discussion that do
not fall within this domain. We believe that cardiomyopathy of Boxers is
substantially different from the dilated cardiomyopathy (DCM) observed in
the ‘‘typical’’ giant-breed dog or Doberman Pinscher, such that a discussion
of cardiomyopathy as it occurs in the Boxer is dealt with elsewhere
.
Definition
DCM is an important cause of cardiac morbidity and mortality in the
dog. Next to chronic mitral valve insufficiency (CMVI) and in some select
geographic regions where heartworm disease is common, DCM is the most
commonly acquired cardiac disorder in the dog.
The World Health Organization (WHO) and the International Society
and Federation of Cardiology (ISFC) have jointly championed the
classification of the cardiomyopathies. Dilated cardiomyopathy is the term
used to define the primary myocardial disorder characterized by reduced
contractility and ventricular dilation involving the left or both ventricles
of unknown or familial etiology. For cases with a specific cause for the
DCM, a modifier indicating this etiology precedes the term cardiomyopathy,
such as taurine deficiency cardiomyopathy.
This article was funded in part by Boehringer Ingelheim Animal Health Canada and
Novartis Animal Health Canada.
* Corresponding author.
E-mail address:
(M.R. O’Grady).
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.009
Vet Clin Small Anim
34 (2004) 1187–1207
Etiology
DCM, as already defined, is a morphologic diagnosis. The heart has
a limited number of responses to many potential myocardial insults. Thus,
the morphologic response called DCM provides no insight as to the
myocardial insult(s) that contributed to this outcome. Idiopathic DCM is
the most common form of DCM in the dog, but most of the potential
processes causing myocardial insult in dogs remain to be determined. In
people, the most common causes of DCM include familial/genetic, viral or
immunologic, and toxic factors
. Recognized causes of DCM in the dog
include genetic factors, tachycardia, taurine deficiency, toxic factors, and,
possibly, carnitine deficiency. The reader is referred to several excellent
reviews of these various etiologies
. We wish to address the potential for
an immunologic or viral etiology. There is substantial evidence to support
an immunologic or viral etiology in some cases of DCM in people
. In the
veterinary world, Cobb et al
could not demonstrate evidence of abnormal
antimyocardial antibodies in a sample of dogs with DCM. Day
did
observe antimitochondrial antibodies in 30% of a colony of English Cocker
Spaniels with DCM, however. This study also observed a relation between
DCM and reduced IgA as well as complement component C4, which are
markers of immune disease in human beings. Braz-Ruivo
failed to
identify parvoviral DNA in myocardial samples of Doberman Pinschers
with DCM. He also investigated the role of an immunologic etiology by
measuring levels of antimyosin and antilaminin antibodies and circulating
immunoglobulin (IgG and IgM) in serum of affected Doberman Pinschers.
He failed to observe abnormalities in either area of investigation. These
findings do not exclude the possibility of an immunologic reaction directed
against other myocardial proteins, including contractile, regulatory, and
cytoskeletal matrix as well as extracellular matrix or membrane.
Natural history and prognosis
The natural history of DCM has not been studied in most breeds. Most
of the natural history data available concerning DCM applies to the
Doberman Pinscher. One needs to ask whether the clinical features, natural
course, and response to therapy as described for the Doberman Pinscher are
typical for other dogs that acquire DCM. It is presumed that DCM in other
breeds is modeled on that of the Doberman Pinscher, except that the
progression of DCM in the final stage (overt stage) is more rapid in the
Doberman Pinscher. The rate of progression of the occult stage in other
breeds compared with the Doberman Pinscher is undetermined.
The natural progression of DCM can be described by three distinct
stages/phases (
). Stage I is characterized by a morphologically and
electrically normal heart and no evidence of clinical signs of heart disease.
Stage II is characterized by evidence of morphologic or electrical de-
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M.R. O’Grady, M.L. O’Sullivan / Vet Clin Small Anim 34 (2004) 1187–1207
rangement in the absence of clinical signs of heart disease. This stage has
also been called the occult stage of DCM. The term occult refers to the
owner’s perspective; that is, from the owner’s point of view, the dog appears
normal despite laboratory evidence of abnormality. The morphologic
abnormality consists of left ventricular (LV) enlargement in systole and/or
diastole. The electrical abnormality consists of the presence of premature
ventricular contractions (PVCs). These abnormalities, morphologic or
electrical, may coexist or may be of predominantly one form at any time
during this occult stage. In Doberman Pinschers, most occult dogs have
evidence of both abnormalities. Stage III is characterized by the presence of
clinical signs of heart failure. We also refer to this stage as the overt stage of
DCM. Because most dogs are nonworking, evidence of exercise intolerance
is usually lacking until the onset of pulmonary edema and congestive heart
failure (CHF). We did observe a fly ball racing Doberman Pinscher that
demonstrated a normal response time 2 weeks before the onset of pul-
monary edema, however. Similar observations have occurred among human
athletes demonstrating normal performance time intervals in the face of
substantive loss of systolic function. DCM is inevitably fatal unless the
etiology can be reversed.
Occult stage of dilated cardiomyopathy
There are few descriptions of the occult stage of DCM. Most of the
available data has been derived from the Doberman Pinscher. In the
Doberman Pinscher, the occult stage lasts 2 to 4 years if evidence of
the occult stage is detected early. The common clinical signs that herald
the onset of the final stage of DCM are evidence of respiratory distress,
syncope, and sudden death. In the Doberman Pinscher, multiple syncopal
events are rare; these dogs usually die with the first collapsing event. Sudden
death is the first clinical sign of DCM in approximately 30% of dogs
We presume that sudden death is the result of paroxysms of ventricular
tachycardia that progress to ventricular fibrillation
. Presumably in-
frequently, however, bradyarrhythmias may precede the onset of sudden
death in some Doberman Pinschers
Fig. 1. A timeline of the natural history of dilated cardiomyopathy (DCM). Three stages
describe the progression to clinical signs of congestive heart failure caused by DCM.
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In a small study of the natural history of DCM in Doberman Pinschers,
100% of the dogs that demonstrated at least 1 PVC on a 3-minute
electrocardiogram, 100% of the dogs with an M-mode long-axis echocar-
diographic left ventricular internal dimension (LVID) at end systole of
greater than 38 mm, and 85% of the dogs with an LVID at end diastole of
greater than 46 mm went on to develop clinical DCM
. These numbers
were based on a 28-month follow-up of 103 Doberman Pinschers free of
clinical signs, wherein 29 dogs went on to develop clinical signs of DCM
(stage III) and to die. We believe that these criteria for occult DCM may not
be ideal for either small (especially female) or extremely large (especially
male) Doberman Pinschers. Our continued work on the natural history of
DCM in Doberman Pinschers suggests that an LVID at end diastole of
greater than or equal to 49 mm or at end systole of greater than or equal to
42 mm has a high positive predictive value for identifying Doberman
Pinschers with occult DCM independent of the size of the dog
. With
respect to the presence of PVCs, we are using the criteria of greater than or
equal to 1 PVC per minute on a resting electrocardiogram as evidence of
occult DCM. Note that we have observed dogs with right-sided PVCs (left
bundle branch block morphology) from time to time. We suspect the finding
of these right-sided PVCs is not indicative of occult DCM, however, because
Doberman Pinschers usually have left-sided PVCs. A 24-hour Holter
examination has been recommended to identify Doberman Pinschers with
occult disease
. The finding of greater than 50 PVCs in 24 hours has
been suggested as indicative of occult DCM.
The use of echocardiographic fractional shortening (FS) in Doberman
Pinschers free of clinical signs as a discriminating marker for the presence or
absence of DCM is unreliable. Certainly, a FS of less than 15% is strong
evidence of occult DCM; however, we have observed normal Doberman
Pinschers with FS values in the range of 18% to 22%
. Note that FS
determined from a right parasternal short-axis view is greater than FS
determined from a long-axis view. Studies conducted at the University of
Guelph involve FS determined from a long-axis view.
In North America, atrial fibrillation is a frequent finding in Irish
Wolfhounds free of clinical signs and frequently does not herald impending
DCM
. In a European study, atrial fibrillation was rarely present in the
absence of DCM
. In this study of 500 Irish Wolfhounds, 49 were
diagnosed with occult DCM based on echocardiographic criteria. Atrial
fibrillation was detected in 73% of these occult dogs. Atrial fibrillation was
also detected in 11 dogs that did not meet the criteria for occult or overt
DCM. Of these, at least 3 dogs went on to develop occult or overt DCM.
Atrial fibrillation is a common finding in dogs that suddenly present with
clinical signs. We presume that compensated dogs, previously occult,
decompensate with the development of atrial fibrillation.
The identification of predictors of prognosis for dogs in the occult stage
of DCM has important implications for therapeutic interventions and
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decision making. There are few data in this area in the human or veterinary
literature. Sudden death is an important outcome in this stage of DCM.
Predictors of sudden death continue to be a controversy in human and
veterinary cardiology. The presence of sustained (>30 seconds) ventricular
tachycardia on a Holter monitoring study was associated with sudden death
in Doberman Pinschers with occult DCM
. In a recent investigation of
prognostic indicators in Doberman Pinschers with occult DCM, decelera-
tion time of the transmitral flow (TMF) early filling wave (DT
E
) was the
only variable (among a number of clinical, neurohormonal, and diastolic
and systolic echocardiographic parameters) predictive of the onset of CHF
or sudden death
. For each unit decrease in DT
E
, there was a 17%
increase in risk of CHF or sudden death. In a human study, a short DT
E
(an index of ventricular compliance) was identified as the most powerful
independent predictor of hospitalization for CHF and all-cause mortality in
asymptomatic LV systolic dysfunction patients, irrespective of TMF pattern
and systolic function indices
Owners of breeds like the Doberman Pinscher and Irish Wolfhound must
be advised that annual screening in the form of an echocardiogram or
a Holter examination is required, because the age of onset of occult DCM is
highly variable.
Overt stage of dilated cardiomyopathy
Unless an underlying cause for DCM can be identified and reversed
(eg, taurine deficiency), the prognosis after the onset of CHF is generally
poor but highly variable. Sudden death as a result of arrhythmias, death
caused by severe pulmonary edema, and euthanasia due to intractable CHF
are the typical modes of cardiovascular death in DCM patients. Depending
on the severity of disease, response to therapy, breed, age, and presence of
atrial fibrillation, to name only a few factors, survival times may range from
only a day to several years after diagnosis. Reported survival data have
arisen from two main sources: retrospective reviews and prospective clinical
trials. Comparing survival data between studies is further complicated
because of the variable therapies used, various breeds studied, and potential
geographic differences in frequency and timing of euthanasia. In addition,
survival is not determined by the date of death in most veterinary studies;
instead, time to adverse outcome is usually used. Adverse outcome is usually
defined as withdrawal from the study because of failure to improve or
getting worse; death caused by heart failure, including sudden death; and
euthanasia due to heart failure.
Unlike occult DCM, there are data concerning the overt stage of DCM in
breeds other than the Doberman Pinscher. In a retrospective analysis,
Monnet et al
observed a median survival time of 65 days in a group of
37 dogs of various breeds with DCM, including occult and overt disease.
The probability of survival at 1 year was 37.5%; at 2 years, it was 28%. In
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the largest retrospective study (189 dogs of various breeds with DCM and
CHF), Tidholm et al
reported mean and median survival times of 175
and 27 days, respectively, with a range of 0 to 1640 days. The survival rate at
1 year was 17.5% in this study; at 2 years, it was 7.5%. In the Long-Term
Investigation of Veterinary Enalapril (LIVE) trial, the effect of enalapril
versus placebo was examined in 43 dogs with DCM and CHF
. Average
time to adverse outcome was 143 days in the enalapril group and 57 days in
the placebo group (P = 0.06). Similarly, in the BENCH trial, the effect of
benazepril versus placebo on time to adverse outcome was examined in 37
dogs with DCM and CHF
. Longer ‘‘survival’’ times were found in this
study, with a mean of 394 days in the benazepril group and 164 days in
the placebo group (P = 0.66), potentially reflecting differences in stage of
disease at the time of diagnosis, breed distribution, or euthanasia practices.
We believe sudden death is much higher in Doberman Pinchers than in
other affected breeds
. Sudden death occurs in about 30% to 50% of
Doberman Pinschers in this stage. We have the impression that female dogs
may be slightly more prone to develop sudden death than male dogs;
however, this remains to be confirmed. In Newfoundlands, sudden death
occurred in 8% of a pool of 37 dogs with CHF as a result of DCM
. In
a mixed group of 189 dogs with DCM and CHF, 10% demonstrated sudden
death
. Clearly, sudden death is more likely to be observed if dogs are not
euthanized. As is the case with dogs with occult DCM, we believe sudden
death results from the development of paroxysms of ventricular tachycardia
that progress to ventricular fibrillation. The prevalence of ventricular ectopy
has been reported as 92% in Doberman Pinschers
, 16% in Newfound-
lands
, and 21% in a pool of various breeds with DCM
.
In human idiopathic DCM, approximately 25% of newly diagnosed
symptomatic patients die within 1 year and 50% die within 5 years
.
Given the potential for some patients to improve, whereas others with poor
short-term outcomes require cardiac transplantation, the identification of
predictors of prognosis is critical for therapeutic monitoring and decision
making. Furthermore, predictors of prognosis are often used as a stratifica-
tion tool in the design of clinical trials. Prognostic indicators in human
DCM have included New York Heart Association (NYHA) functional
class; hemodynamic variables, including pulmonary capillary wedge pres-
sure, LV end-diastolic pressure, and pulmonary artery pressures; and
electrocardiographic findings of frequent and complex ventricular arrhyth-
mias or atrial fibrillation
. Markers of neuroendocrine activation,
including low plasma sodium and increased plasma norepinephrine, atrial
natriuretic peptide (ANP), brain natriuretic peptide (BNP), and big
endothelin-1 (ET-1), are strong independent predictors of poor prognosis
. Certain echocardiographic indices, such as simple measures of size
(LV dimensions indexed to body size) and systolic function (ejection
fraction) have variably been predictive of outcome
, whereas
others have been more definitively linked with a poor prognosis, such as
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evidence of right ventricular (RV) dilation and tricuspid regurgitation
(indicative of RV dysfunction)
; increasing grade of mitral and tricuspid
regurgitation
; and evidence of advanced diastolic dysfunction, including
a TMF pattern (typically, E/A ratio
2 and/or short DT
E
) and blunted
systolic pulmonary venous flow (peak velocity and duration)
Few studies have been described in dogs with the purpose of determining
prognostic indicators for DCM, and predicting prognosis in any given single
patient continues to be a challenge. In the retrospective analysis of 37
symptomatic and asymptomatic dogs with DCM, of the 27 variables
assessed using bivariate Cox proportional hazard analysis, only pleural
effusion and pulmonary edema present radiographically were significant
predictors of poor prognosis
. Having examined a small group of dogs
with and without clinical signs, these findings mirror the timeline described
in
. In a larger study, Tidholm et al
concluded that of 27 variables
examined, 3 were independent predictors of survival: age (with young age at
onset of clinical signs being an indicator of poor prognosis), dyspnea, and
ascites (the latter two as identified on physical examination). The presence of
dyspnea and ascites suggests more advanced CHF. This finding agrees with
human studies demonstrating the effect of NYHA class score on outcome.
In Doberman Pinschers, the presence of bilateral CHF predicted a poorer
prognosis
. Vollmar
demonstrated that Irish Wolfhounds with more
advanced clinical signs had a worse outcome.
Atrial fibrillation is associated with an adverse outcome in people with
CHF
. The impact of atrial fibrillation has been assessed in Doberman
Pinschers
. In this study, the overall survival for Doberman Pinschers
with CHF was 6.5 weeks (median); with only left-sided CHF without atrial
fibrillation, it was 7.5 weeks; with bilateral CHF without atrial fibrillation, it
was 2.8 weeks; with atrial fibrillation, it was 2.9 weeks; and with bilateral
CHF and atrial fibrillation, it was 2.0 weeks. Tidholm et al
observed
that atrial fibrillation was not associated with increased mortality. They
noted, however, that the rate of euthanasia may be higher in Sweden than in
North America. Approximately 30% of Doberman Pinschers develop atrial
fibrillation
. Tidholm et al
demonstrated a 46% prevalence of atrial
fibrillation in 142 dogs with DCM, most of which were not Doberman
Pinschers. Liu and Tilley
state that atrial fibrillation occurs in 75% to
80% of giant-breed dogs with DCM. Vollmar
observed atrial
fibrillation in 97% of Irish Wolfhounds with DCM. A comparison of the
impact of atrial fibrillation in Doberman Pinschers versus other breeds has
yet to be reported.
Age has been reported to affect outcome such that younger dogs had
a worse outcome
. In a recent investigation of prognostic indicators in
Doberman Pinschers with DCM and CHF, age was likewise predictive of
survival time
. Calvert
suggested that younger Doberman Pinschers
(\2 years of age) have a worse outcome, and Vollmar
suggested that
young Irish Wolfhounds (\1.5 years of age) have a worse prognosis.
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Some investigators have found certain echocardiographic measures to be
predictors of prognosis, including end-systolic volume index, a restrictive
TMF pattern, and a short (\80 milliseconds) DT
E
, whereas FS, E-point–to-
septal separation, and left atrium/aortic root ratio were not of use
. In
Doberman Pinschers with DCM and CHF, LVID in diastole and LVID in
systole were predictive of survival time
. Monnet et al
, however,
found that echocardiographic measures of LV size indexed to body size and
measures of systolic function were not predictors of survival. We also
examined a number of clinical, echocardiographic (including systolic and
diastolic indices), and neurohormonal indices
. None of the diastolic
indices or neurohormones at enrollment was a significant univariate
predictor of survival. In contrast, absolute and percent change in norepi-
nephrine and big ET-1 from enrollment to the 1-month recheck were
significant predictors of survival
Thus, a number of variables may provide important prognostic in-
formation; however, the predictive reliability of any single variable on its
own is likely poor, and assessment of prognosis of an individual patient on
one initial screening examination continues to be difficult.
Prevalence
DCM is considerably less common than chronic mitral valve disease.
DCM is typically observed in large- and giant-breed dogs; however, it has
been recognized in medium-sized dogs, such as English and American
Cocker Spaniels and Dalmatians. On rare occasions, we have observed
DCM in small-breed dogs such as the West Highland White Terrier.
The prevalence of DCM is difficult to ascertain. In an Italian study
reported in 1988, 1.1% of 7148 dogs were diagnosed with DCM
. A
review of the findings of the Veterinary Medical Database of Purdue
University revealed a diagnosis of DCM (acquired, congestive, or right-
sided cardiomyopathy) in 0.5% of canine referrals
. A review of the
University of California Veterinary Database of cases referred between 1986
and 1996 revealed that 0.35% of cases were identified as DCM
. Note that
these data reflect the bias of a referral population. Thus, the ‘‘true’’
prevalence of DCM should be somewhat less. Note also that sudden death
is a common first clinical sign of DCM; unless owners of dogs with sudden
death seek a postmortem examination, DCM will likely go unrecognized
. Such cases cause the prevalence of DCM to be underrepresented.
The University of Purdue Veterinary Medical Database identified breeds
commonly affected with DCM (
. Other breeds known to be
affected with DCM or that we have observed with DCM that are not
represented in the Purdue database are German Shepherds, Salukis, Bull
Mastiffs, Bouvier des Flandres, Irish Setters, Bearded Collies, Bloodhounds,
Dogue de Bordeaux, Standard Poodles, Siberian Huskies, Staffordshire
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M.R. O’Grady, M.L. O’Sullivan / Vet Clin Small Anim 34 (2004) 1187–1207
Terriers, and Dalmatians. A recent Swedish study noted that Airedale
Terriers, English Cocker Spaniels, and Standard Poodles were at increased
risk for DCM as well as many of the breeds commonly observed in North
America (Boxers, Doberman Pinschers, Newfoundlands, and Saint Ber-
nards)
. This study also noted that Great Danes, Old English Sheepdogs,
and Irish Wolfhounds were not at an increased risk of acquiring DCM. In
another European study, 24% of 500 Irish Wolfhounds were diagnosed with
DCM
. These differences may reflect a genetic difference in some breeds
between regions.
There is a gender bias in dogs with DCM. The early descriptions of DCM
suggested that this was a disorder of primarily the male gender. More recent
work continues to demonstrate that male dogs are more frequently affected
than female dogs but that the disorder is much more prevalent in female
dogs than previously suspected. In Doberman Pinschers, approximately
50% of male dogs and 33% of female dogs develop DCM
. In the
University of Purdue Veterinary Medical Database, only the Springer
Spaniel had more female dogs diagnosed with DCM than male dogs
One study in Sweden observed no sex predilection in Newfoundlands
.
It is reported that female Doberman Pinschers manifest overt DCM at
a slightly older age than male Doberman Pinschers, with a median age for
female dogs of 9.5 years and a median age for male dogs of 7.5 years
Doberman Pinschers can manifest clinical DCM over a wide age range,
however, from 2 to 15 years of age. Our work suggests that approximately
25% of Doberman Pinschers older than 10 years of age manifest clinical
DCM. Thus, breeders can virtually never be assured that a dog is free of
Table 1
Breeds predisposed to dilated cardiomyopathy
Breed
No. with
DCM
Total referrals
% with
DCM
% of DCM
by breed
Scottish Deerhound
7
117
6.0
0.5
Doberman Pinscher
603
10,435
5.8
45.9
Irish Wolfhound
38
696
5.5
2.9
Great Dane
122
3157
3.9
9.3
Boxer
131
3800
3.4
10.0
Saint Bernard
29
1124
2.6
2.2
Afghan Hound
15
897
1.7
1.1
Newfoundland
22
1751
1.3
1.7
English Sheepdog
18
1894
1.0
1.4
English Cocker Spaniel
5
729
0.7
0.4
Springer Spaniel
25
4865
0.5
1.9
American Cocker Spaniel
53
15,373
0.3
4.0
Labrador Retriever
73
21,501
0.3
5.6
Golden Retriever
42
16,405
0.3
3.2
Mixed breeds
131
83,417
0.2
10.0
Abbreviation:
DCM, dilated cardiomyopathy.
Data from
the University of Purdue Veterinary Medical Database 1985 to 1991
.
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M.R. O’Grady, M.L. O’Sullivan / Vet Clin Small Anim 34 (2004) 1187–1207
developing DCM. In other breeds, the mean ages of onset of clinical signs
are 6.6 years in a mixed pool of dogs in Sweden
, 4.2 years in Irish
Wolfhounds
, and 8 years in a mixed pool of dogs in Europe
.
Diagnosis
The reader is referred to excellent reviews of the diagnosis of canine
DCM
. In terms of newer modalities for the diagnosis of
DCM, preliminary investigations suggest several technologies that may
prove useful in the future, potentially allowing earlier detection of disease,
and hence earlier intervention, as well as confirmation of equivocal results
from other routine diagnostic tests. Circulating markers of LV systolic
dysfunction, including BNP and cardiac troponins (cTn-I), may be useful in
this regard, potentially identifying dogs in the occult stage, even before
electrically or morphologically detectable abnormalities occur
.
Novel echocardiographic modalities, such as tissue Doppler imaging
(TDI), may identify occult disease earlier than with traditional echocardio-
graphic parameters. Mitral annular systolic motion has been proposed as
a sensitive measure of systolic function in human DCM patients because it is
less load dependent and much more sensitive to changes in contractility than
traditional echocardiographic indices
. TDI, specifically systolic myo-
cardial velocity gradient (MVG), was able to detect early myocardial
dysfunction despite normal LV dimensions and shortening in puppies with
the X-linked mutation of the dystrophin gene responsible for Golden
Retriever muscular dystrophy
. Other investigators are examining the
utility of TDI MVG and myocardial strain rate in the identification of occult
DCM in Doberman Pinschers
In a group of 10 Doberman Pinschers with occult DCM, select
echocardiographic parameters of diastolic function, namely DT
E
, systolic
pulmonary venous flow, and velocity of flow propagation by color M-mode,
were significantly different compared with the same parameters in a group of
normal Doberman Pinschers. Likewise, peak systolic mitral annular velocity
by TDI (S
m
) was decreased and plasma ANP was increased compared with
the normal group
. These indices may therefore have use in the diagnosis
of occult DCM.
Stress echocardiography is a valuable tool in human beings to identify
patients with asymptomatic myocardial dysfunction
. Dobutamine stress
echocardiography was assessed in Doberman Pinschers free of clinical signs
. Only an elevated LVID at end systole and reduced TMF E/A ratio
were independent predictors of occult DCM. Similarly, measures of heart
rate variability (HRV) can identify the autonomic nervous system imbalance
that characterizes heart disease
. HRV was assessed in this group of
Doberman Pinschers
. Time domain and frequency domain parameters
failed to identify dogs with occult DCM.
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Management
The management of DCM is addressed with respect to the stage of heart
failure on presentation. There are a number of excellent reviews of the
management of DCM
to which interested readers are directed
for discussion of the management of acute CHF and the use of diuretics and
digoxin in chronic CHF.
Management of occult dilated cardiomyopathy
Management of the occult stage of DCM is clearly of value, because this
stage of DCM inevitably progresses to the overt stage and death.
Management of the occult stage involves identifying the cause of DCM,
identifying factors that can precipitate the acute progression to CHF, and
instituting nonspecific measures to delay the progression of DCM from the
occult stage to the overt stage. The most common precipitating factor
involves the development of ventricular and/or supraventricular arrhyth-
mias. Because sudden death is common, especially in the Doberman
Pinscher, and the presence and complexity of PVCs suggest that these
individuals are at risk for sudden death, efforts to reduce the risk of sudden
death are indicated
. At present, no studies have been conducted to
address the potential to reduce the risk of sudden death in this cohort of
dogs. Even though antiarrhythmic agents are used to reduce the risk of
sudden death, the human experience in such cases suggests that most
antiarrhythmic agents are ineffective in this capacity. In fact, most
antiarrhythmic agents probably increase the risk of sudden death in people.
The most promising of the antiarrhythmic agents are amiodarone and
sotalol. Amiodarone is a drug with substantive clinical concerns, however,
including potentially severe toxicity and unusual pharmacokinetics and
pharmacodynamics, which make appropriate dosing uncertain at this time.
Although sotalol seems to be less problematic, convincing evidence of its
efficacy is lacking in the human arena and no work has been undertaken in
canine DCM. Although there is some evidence for the efficacy of mexiletine
plus atenolol or sotalol in the management of PVCs in Boxers
, no
controlled studies have been conducted with DCM.
Only angiotensin-converting enzyme (ACE) inhibitors have been in-
vestigated in the setting of occult DCM
. This retrospective study defined
the presence of occult DCM as having an LVID at end diastole of greater
than or equal to 49 mm or of greater than or equal to 42 mm at end systole.
The absence, presence, or severity of ventricular arrhythmias at the time of
enrollment was not considered. Sixty-one Doberman Pinschers with occult
DCM were identified, with 34 having received ACE inhibitor therapy and 27
having received no therapy during the occult stage. There was a significant
delay in the time to onset of the overt stage of DCM with the use of ACE
inhibitors (601 days) versus no therapy (314 days).
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The role of beta-blockers or aldosterone blockade remains to be
determined. In consideration of the role of the sympathetic nervous system
and the renin-angiotensin-aldosterone system (RAAS) in the development
and progression of heart failure, it may well be that these therapeutic efforts
are of merit. At present, although some studies are underway, there are no
reports evaluating the efficacy of these agents in the occult setting of DCM.
Management of overt dilated cardiomyopathy
Angiotensin-converting enzyme inhibitors
Two ACE inhibitors have been studied in canine DCM. The merit of
therapy must be considered with respect to quality of life and survival.
Enalapril was first evaluated in this context. Three studies were undertaken
to assess the utility of enalapril when used in conjunction with diuretics with
or without digoxin
. With respect to quality of life, there are
compelling data to suggest that enalapril improves quality of life when
compared with placebo
. With respect to survival, the reports of the
LIVE study promote confusion. The initial report indicated a significant
benefit in favor of enalapril compared with placebo
. The time to
adverse outcome was significantly longer for enalapril (158 days) versus
placebo (58 days). Adverse outcome was defined as died of heart failure,
died suddenly, or demonstrated inadequate improvement. The follow-up
publication provided rather different results
. Forty-three dogs were
studied: 21 dogs were allocated to the placebo treatment and 22 received
enalapril. The time to adverse outcome trended to significance (P = 0.06),
with a longer time for enalapril (143 days) versus placebo (57 days). It seems
that the earlier report involved a number of dogs that were subsequently
excluded from the final publication. Several important issues are worthy of
note. First, the number of dogs enrolled was small when compared with
human studies that frequently enroll thousands of subjects, limiting the
ability to find a significant difference. Excluded from the study were dogs
believed to have a life expectancy of less than 1 month. In clinical practice, it
is often difficult to predict which dogs will succumb in less than 1 month.
As clinicians, we endeavor to treat dogs with a poor life expectancy as well
as those with a better outcome. Thus, it is difficult to extrapolate from this
study as to the ‘‘real’’ impact of enalapril on all cases of CHF caused by
DCM.
The second ACE inhibitor investigated was benazepril in the BENCH
trial
. Thirty-seven dogs with CHF caused by DCM were enrolled: 17
dogs received benazepril and 20 received placebo. With respect to quality of
life, there was significant improvement in the pool of dogs with CMVI and
DCM. Data exclusive to the DCM pool are not provided in the report.
Because dogs with DCM constituted only 23% of the pool, we are unable to
infer benefit. The time to adverse outcome in the dogs with DCM was not
significantly different (P = 0.66), with a longer time for benazepril (394
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M.R. O’Grady, M.L. O’Sullivan / Vet Clin Small Anim 34 (2004) 1187–1207
days) versus placebo (164 days). In addition, the authors evaluated time to
worsening heart failure for dogs with mild to moderate heart failure at the
time of enrollment. Twelve dogs administered benazepril and 10 dogs
administered placebo were analyzed. The mean time for the dogs admin-
istered benazepril was 341 days, and for the dogs administered placebo, it
was 51 days (P = 0.95). Unlike the enalapril trial, there was no exclusion of
dogs with a projected short life expectancy. When comparing the LIVE and
BENCH trials, it is interesting that survival in the benazepril study is longer
than in the enalapril study even though the benazepril study presumably
included some dogs with a shorter life expectancy. As with the previous
study, the number of dogs enrolled in the BENCH trial is small, which
makes finding a significant difference unlikely. Finally, 16 dogs, 10
administered benazepril and 6 administered placebo (the report does not
specify whether these were dogs with DCM or CMVI), received no diuretics.
This suggests that these dogs were not in CHF at the time of enrollment, and
the inclusion of these dogs in the study complicates the answer to the
question, ‘‘What is the effect of benazepril on survival and clinical signs of
dogs with CHF?’’
In conclusion, ACE inhibitors improve the quality of life for dogs with
CHF caused by DCM. As for survival, there is a plethora of evidence in
people with CHF caused by DCM indicating the significant role these agents
play in reducing mortality
. It is our belief that ACE inhibitors would
have demonstrated a significant improvement in survival had greater
numbers of dogs been enrolled. Therefore, we continue to recommend the
use of ACE inhibitors for this stage of DCM.
Pimobendan
A detailed discussion of the use of pimobendan is found elsewhere in this
issue. Pimobendan is a new positive inotrope and vasodilator that has been
available in Europe for several years to treat CHF caused by DCM in the
dog. Pimobendan is a benzimidazole pyridazinone derivative. It mediates its
positive inotropic properties by two mechanisms. First, it belongs to a new
class of positive inotropes called calcium sensitizers. These agents induce an
increase in contractility by increasing the sensitivity of the regulatory
protein, troponin C, to the existing Ca
þþ
in the cell. All other positive
inotropes induce an increase in contractility by increasing Ca
þþ
entry into
the cell and have failed to increase survival in people with systolic
dysfunction as the cause of CHF. They mediate their deleterious long-term
response, in large part, by adversely affecting the balance of myocardial
oxygen consumption and supply. The calcium sensitizers may, however,
represent a new means of augmenting contractility without adversely
affecting this balance. In fact, myocardial oxygen kinetics seem to be
improved with pimobendan
. The second method whereby pimoben-
dan increases contractility is via phosphodiesterase III inhibition. This
method of increasing contractility is identical to that of milrinone and
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M.R. O’Grady, M.L. O’Sullivan / Vet Clin Small Anim 34 (2004) 1187–1207
amrinone. The vasodilation property of pimobendan is a result of the
peripheral action of phosphodiesterase III and V inhibition. This results in
venous and arterial vasodilation.
Several studies have evaluated the efficacy of pimobendan in dogs with
CHF caused by DCM. The first involved two populations of dogs:
Doberman Pinschers and English Cocker Spaniels
. It is noteworthy
that the authors did not mix these dogs but studied the effect of pimobendan
on the two populations independently. All dogs enrolled received concurrent
furosemide, enalapril, and digoxin. The dogs were randomized by breed to
receive pimobendan (5 dogs) or placebo (5 dogs). Quality of life was
improved in both pimobendan groups compared with the placebo group.
For the Doberman Pinscher group, the median survival was significantly
improved with pimobendan (329 days) versus placebo (50 days). Analysis of
the baseline criteria revealed that 3 of the dogs administered placebo and
only 1 of the dogs administered pimobendan had atrial fibrillation at
enrollment. Because atrial fibrillation has a marked adverse impact on
outcome
, the two treatment groups were severely imbalanced at
enrollment in favor of pimobendan. Nevertheless, the length of survival
observed in the dogs administered pimobendan markedly surpassed that
observed in Doberman Pinschers with CHF in North America, whereas the
length of survival observed in Doberman Pinschers administered placebo
was similar to that observed in North America. The Cocker Spaniel group
was followed for 4 years; at the end of this time, 9 of 10 dogs had not met the
primary end point criteria (6 were still alive, and 3 had died of noncardiac
disease). Thus, the impact of pimobendan on survival could not be assessed
in this group.
The next study that assessed the role of pimobendan in the management
of CHF involved a pooled canine population with DCM and CMVI
.
The authors did not evaluate the effect in DCM independent of CMVI.
Eighty-one dogs with DCM, 23 dogs with CMVI, and 1 dog with tricuspid
valve insufficiency were enrolled. The study had a two-phase design
involving a 4-week quality-of-life assessment and a subsequent optional
survival phase. Three treatment groups were studied: one randomized to
pimobendan alone, another to benazepril alone, and the third to the
combination of pimobendan and benazepril. All dogs received concurrent
furosemide. There was improved quality of life with benazepril and
pimobendan and pimobendan alone compared with benazepril alone. In
the long-term survival study, 73 dogs were assigned to pimobendan and 37
were assigned to placebo. Time to adverse outcome was assessed similar to
that described for the ACE inhibitor trials. The median time to adverse
outcome was significantly better with pimobendan (217 days) versus placebo
(42 days). Because the DCM population comprised 77% of the pool of dogs,
one would expect that the observed benefit was primarily a result of the
influence of pimobendan on the dogs with DCM. This remains to be
demonstrated, however.
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The final report studied Doberman Pinschers with CHF caused by DCM
. This was a single-blind (only the owners were blinded to the treatment
limb) randomized study comparing the efficacy of pimobendan versus
placebo in dogs receiving furosemide and benazepril. An interim report
involved seven dogs administered pimobendan and eight dogs administered
placebo. Dogs with atrial fibrillation at enrollment were excluded. The end
points were time to treatment failure and survival. Treatment failure was
defined as a failure of furosemide, 5 mg/kg administered orally every 8
hours, to resolve respiratory distress. If sudden death, death caused by heart
failure, or euthanasia as a result of heart failure occurred before achieving
this dose of furosemide, the death date was used as the treatment failure
date. Once the dogs reached treatment failure as a result of inadequate
diuresis, they were offered pimobendan; however, the owners continued to
remain blinded. An intention-to-treat analysis was performed. There was
significant improvement in quality-of-life indices at 1 and 2 months with
pimobendan. There was a significant improvement in time to treatment
failure with pimobendan (126 days) versus placebo (26 days) and in survival
with pimobendan (128 days) versus placebo (63 days). Together, these data
provide strong evidence of the ability of pimobendan to improve quality of
life and survival in dogs with DCM and CHF. This benefit was observed in
the face of ACE inhibition. Expect to see more studies assessing the role of
pimobendan in dogs with CHF in the near future.
Beta-blockers
There is a plethora of evidence in people with CHF caused by DCM
demonstrating the efficacy of beta-blockers when used with a background of
ACE inhibition
. Beta-blocker therapy counters the maladaptive neuro-
hormonal response that occurs when cardiac output is reduced. No clinical
trials have been reported in dogs evaluating the efficacy of beta-blocker
therapy in cases of CHF. Some general comments concerning beta-blocker
therapy are worthwhile. Because these are negative inotropes, dogs can
decompensate as beta-blocker therapy is initiated. The rule of thumb in
people is to start at a low dose and slowly increase the dose to the
maintenance level. The appropriate starting dose, rate of increase, and
maintenance dose have all yet to be determined for beta-blocker therapy.
Beta-blockers should be started once respiratory distress has been alleviated.
A number of investigators are beginning to collect data on the use of beta-
blockers in the veterinary cardiac patient
. Guidelines to their use should
be available in the near future.
Spironolactone
The recent study in people demonstrating the efficacy of spironolactone
in the management of CHF has stimulated an interest in the use of
spironolactone in dogs with CHF caused by DCM
. To date, no studies
have assessed the role of spironolactone in canine CHF. Because the RAAS,
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in general, and aldosterone, in particular, are elevated in dogs with CHF
caused by DCM, it is reasonable to expect that aldosterone blockade will be
as useful in the management of CHF caused by DCM as it is for people
similarly affected.
Antiarrhythmic therapy
PVCs are a common part of the clinical presentation of DCM in dogs,
particularly in the Doberman Pinscher
. It is probable that either the
frequency of PVCs or the complexity of premature beats identifies dogs at
risk for sudden death or reduced survival. If this is the case, intervening with
antiarrhythmic agents might be worthwhile. There have been no studies
conducted in the dog to address the efficacy of antiarrhythmic therapy in
this setting. The experience in people suggests that class I antiarrhythmic
agents are ineffective at preventing sudden death in patients with DCM and
are likely to promote arrhythmic sudden death. Of all antiarrhythmic
agents, only the class III agents are likely to be useful to prevent sudden
death in people. Although we have used class III agents in dogs with DCM,
with the absence of veterinary data in a controlled setting, we do not know if
these agents prevent sudden death. We recommend a therapeutic plan that
focuses on controlling pulmonary edema, use of ACE inhibitors at optimal
doses, use of pimobendan if available, and optimizing electrolyte balance to
hopefully reduce the frequency of ventricular ectopy and sudden death.
Other therapies
A great number of other therapies have been recommended. These include
a low-sodium diet; exercise restriction; and supplementation of taurine,
carnitine, fish oil, magnesium, coenzyme Q 10, and vitamin E. Interested
readers are referred elsewhere to address these issues
.
We wish to address the issue of resynchronization therapy briefly. In short,
substantial evidence exists for the favorable effect of resynchronization
therapy in the management of people with CHF caused by systolic
dysfunction
. Gordon
undertook a preliminary investigation of the
role of resynchronization therapy in a sample of Doberman Pinschers with
CHF caused by DCM. This study demonstrated that VDD pacing from the
left ventricle, right ventricle, or both ventricles simultaneously was feasible.
The preliminary evidence suggested that resynchronization therapy is
ineffective in Doberman Pinschers with DCM, however. Furthermore, these
dogs seemed to have features similar to those of the cohort of people who fail
to respond, including global myocardial disease and the absence of
significant intraventricular conduction delay.
Summary
Despite many advances in the diagnosis and treatment of DCM, it
continues to be an important cause of cardiovascular morbidity and
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mortality in large-breed dogs. In the coming years, it is hoped and
anticipated that further discoveries will be made in the areas of etiology,
therapy, and assessment of prognosis, ultimately with a view to having
a greater impact on the clinical management of these cases.
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New insights into degenerative
mitral valve disease in dogs
Jens Ha¨ggstro¨m, DVM, PhD
a,
*,
Henrik Duelund Pedersen, DVM, Dr Vet Sci
b
,
Clarence Kvart, DVM, PhD
c
a
Department of Small Animal Medicine and Surgery, Faculty of Veterinary
Medicine and Animal Science, Swedish University of Agricultural Sciences,
PO Box 7045, S-75007 Uppsala, Sweden
b
Department of Anatomy and Physiology, Royal Veterinary and Agricultural University,
PO 7 Gronnega˚rdsvej, DK 1870 Fredriksberg C, Denmark
c
Department of Anatomy and Physiology, Faculty of Veterinary Medicine
and Animal Science, Swedish University of Agricultural Sciences,
PO Box 7011, S075007 Uppsala, Sweden
Degenerative mitral valve disease (DMVD) is, by far, the most commonly
encountered acquired cardiac disease in adult dogs, and the condition is
caused by a progressive myxomatous degeneration (MD) of the atrioven-
tricular (AV) valves. DMVD has been given many names in the veterinary
literature, including endocardiosis and chronic valvular disease
. Similar
changes of the mitral valve are also seen in human beings, horses, and pigs
. In people, the condition with similarities to DMVD in dogs is called mitral
valve prolapse (MVP) syndrome
. Clinical signs of mitral regurgitation
(MR) caused by myxomatous lesions have long been recognized in veterinary
medicine
, and because of the high prevalence of DMVD in the canine
population, the disease is important for the veterinary small animal
practitioner. Indeed, a recent estimation of the mortality caused by cardiac
disease in the general canine population indicates that about 7% of all dogs
die or are euthanized because of heart failure (HF) before 10 years of age (eg,
the third most common cause of death in dogs in that age group)
. Because
many dogs develop decompensated HF because of DMVD after 10 years of
age, we can assume that this proportion is even greater in dogs of all ages.
MR caused by DMVD has been reported to account for 75% of the cases of
heart disease in dogs
and for a considerably higher proportion in
* Corresponding author.
E-mail address:
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.002
Vet Clin Small Anim
34 (2004) 1209–1226
affected breeds
. Many of the affected dogs eventually need therapy
for decompensated HF and die or are euthanized in the end because of
refractory cardiac failure. The presence of MR and ongoing medical
treatment for HF may negatively interact with other drugs, decisions for
surgical procedures, or anesthesia. Because DMVD is characterized by
chronic progression, the owner and veterinarian often have no other
alternative than to observe how the valvular lesions and MR progress
slowly, with little possibility of affecting the course of the disease, a fact that
many find frustrating. Finally, there is a need for breeding measures in
certain breeds with an exceptionally high prevalence of DMVD. This article
does not cover all possible aspects of DMVD, because this subject is simply
far too extensive to fit into this presentation. This presentation focuses on
new information about some specific aspects of DMVD that may be
controversial and of importance for the practicing veterinarian.
Mitral valve morphology
Because dogs that undergo postmortem examination are most commonly
those with severe DMVD and MR, it is common to describe the macroscopic
appearance of diseased leaflets as thickened and contracted with varying
frequency of ruptured chordae tendineae (
)
. The macroscopic
appearance of DMVD depends on at which stage of disease the valve is
examined, however. This classic description is a manifestation of severe
disease that has progressed over a long time, often several years. The
Fig. 1. Postmortem specimen from a dog showing classic severe degenerative mitral valve
disease. The mitral valve leaflets are thickened and contracted, with nodules rolling in the free
edges. Although changes are evident along the entire leaflet margin and its vicinity, they are
unevenly distributed and seem to be most pronounced in sections in which chordae tendineae
insert. Evidence of chordal involvement is present in the form of thickening, and some chordae
are missing, presumably ruptured. This stage of degenerative mitral valve disease is to be
regarded as end-stage disease. (Courtesy of Professor L. Jo¨nsson, Uppsala, Sweden.)
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macroscopic findings in cases of mild DMVD may not be apparent and may
be overlooked, especially in dogs without clinical evidence of MR. Findings
typical for early stages of DMVD include elongated chordae tendineae and
enlarged thickened leaflets with areas showing bulging/ballooning/prolapse
toward the atrial side
, which may be identified on a two-
dimensional (2D) echocardiogram in the living dog (
). The changes
begin in the area of apposition of the leaflets and are usually most
pronounced in sections where chordae tendineae insert. The bulging of such
areas toward the atrial side of the leaflets has been described as rolling of the
edges. With progression, the bulging becomes worse, the free edge becomes
thickened and irregular, and the lesions spread into other parts of the leaflets
. Within the same valve leaflet, one section may look relatively normal,
whereas another neighboring section is moderately or severely diseased. In
late stages, secondary fibrosis can cause marked thickening and contraction
of leaflets and chordae tendineae. The chordae tendineae may rupture
leading to an unattached free edge. Microscopically, there is myxomatous
proliferation of the valve, in which the spongiosa component of the valve is
unusually prominent and the quantity of acid-staining glucosaminoglycans is
increased
. The valvular interstitial cells in affected areas often have
morphologic changes of the nucleus, a localized concentration of abnormally
shaped mitochondria and rough endoplasmic reticulum, a disorganized
cytoskeleton, and lack of secretory vesicles
. There is haphazard
arrangement, disruption, and fragmentation of the collagen fibrils surround-
ing the interstitial cells
. The endothelial cells covering affected areas
become polymorphic, and some areas completely lose the endothelium,
exposing the underlying extracellular matrix
. Some large-breed dogs may
present with massive MR but comparably minor mitral valve abnormalities
on a 2D echocardiogram or at postmortem examination
. It is
currently not known if the MR in some of these large-breed dogs is the
manifestation of DMVD or another cardiac disease.
Fig. 2. Right parasternal long-axis four-chamber echocardiograms in which the mitral valve in
systole is apparent. A normal mitral valve (A), mild mitral valve prolapse (B), and severe mitral
valve prolapse (C). LV, left ventricle, LA, left atrium. The arrowheads indicate the mitral valve
leaflets. (From Pedersen HD, Lorentzen KA, Kristensen B, et al. Observer variation in the two-
dimensional echocardiographic evaluation of mitral valve prolapse in dogs. Vet Radiol
Ultrasound 1996;37:65–70; with permission.)
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Etiology and pathogenesis of degenerative mitral valve disease
Little is known with certainty about the underlying cause and pathogenesis
of the progressive thickening and degeneration of the leaflets. An old theory is
that the changes are a response to injury type lesions (ie, repeated impact to
the leaflets [especially in the areas of apposition] results in slowly progressive
changes)
. Because not all dogs develop DMVD, one or more primary
inciting factors probably increases the risk of disease in predisposed animals.
The nature of these primary initiating factors is not currently known,
although certain abnormalities of collagen and other extracellular matrix
components have been suggested to predispose to DMVD
. In people,
MVP occurs in association with a variety of connective tissue disorders
and craniofacial skeletal deformities
as well as in a variety of
congenital thoracic deformities, such as straight back, pectus excavatum, or
shallow chest
. Little is known about such associations in dogs.
Recently, a relation between MVP and a narrow chest in a population of
Dachshunds was reported
. It was hypothesized in this report and in one
on human patients
that a narrow chest may lead to entrapment of the
heart within the thorax, which could predispose to MVP and DMVD.
Regardless of the exact nature of the primary inciting factor(s), it has been
suggested that it leads to abnormal valve motion (ie, prolapse of the leaflets),
which, in turn, increases the shear stress imposed on them directly through
the abnormal leaflet apposition and indirectly through the increased
regurgitant flow
. It is likely that the endothelial damage or loss plays
an important role in the progression of the disease, because endothelial cells
are known to communicate extensively with subendothelial cells (eg, valvular
interstitial cells)
. Endothelial damage may lead to an imbalance in
local concentrations of growth-promoting and growth-inhibiting substances
produced by endothelial cells. Evidence for such imbalances in diseased
canine mitral valves includes the reported associations between disease
severity and the expression of endothelin receptors and nitric oxide synthase
. Furthermore, collagen and other matrix components become
exposed to the blood in areas of diseased valves in which the endothelium
seems to be missing, and this exposure is expected to promote thrombosis.
Although thrombosis may develop as a complication of DMVD in dogs,
thrombus formation on the mitral valve is uncommon. Its absence in the
presence of endothelial damage in DMVD is not currently understood.
Increased knowledge and understanding of the actions of these local
mechanisms may be of great importance for future treatment of DMVD
because they may suggest ways of treating the actual valve lesions rather than
only treating the resulting circulatory disturbances.
Because the underlying cause of DMVD remains uncertain, several
scientifically unsupported theories have been proposed. Examples of these
theories especially prevalent among breeders are that the valvular lesions
develop as a consequence of poor dental health, with hematogenic spread of
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bacteria from the oral cavity to the valves, or that DMVD may develop as an
unwanted side effect of vaccination. There is currently no scientific evidence
that any of these theories are well founded. Inflammation is not an apparent
part of DMVD
, and although low-degree DMVD may macroscop-
ically or echocardiographically not always be easy to differentiate from
bacterial endocarditis, these two diseases have completely different histo-
pathologic features. In dogs, endocarditis is rare, and when it does occur, it
typically affects large-breed dogs rather than the small-breed dogs that
typically have DMVD and MR
. With regard to species differences of
pathologic findings between dogs and people, a major difference seems to be
that human beings are more prone than dogs to develop endocarditis as
a complication of MD. In people, endocarditis is found in approximately
10% of operatively excised and severely affected mitral valves
Myxomatous degeneration and vascular changes
Myxomatous degeneration is not restricted to the mitral valve, and it may
be detected in any of the four intracardiac valves. The incidence of valve
involvement in dogs was reported as follows: 62% incidence of mitral valve
alone, 32.5% incidence of mitral and tricuspid valves, and 1.3% incidence of
tricuspid valve alone
. The pulmonary and aortic valves are less commonly
affected. Interestingly, lesions similar to MD of the AV valves have been
described in the main pulmonary artery in Cavalier King Charles Spaniels
. Other findings in dogs with advanced stages of DMVD include hyaline
or fibromuscular intramural arteriosclerosis and multiple small myocardial
infarcts
. Histologically, these vascular changes (which are common in
old dogs) resemble the changes seen in myxomatous valves, and the two
conditions often occur together
. Coexistence of these two abnormalities
is to be expected in old dogs, however, because of the high prevalence of both
conditions. Furthermore, intramural arteriosclerosis and multiple small
myocardial infarcts should predispose to sudden death. Sudden death is rare
in dogs with DMVD without decompensated HF, however, and it is
interesting that a recent retrospective study of 65 dogs with histologically
confirmed hyaline or fibromuscular arteriosclerosis of the intramural
coronary arteries showed that 16 (25%) had died suddenly
. Therefore,
a possible relation between DMVD and vascular changes in the intramural
coronary arteries and sudden death needs to be investigated further.
Inheritance and breeding
Heredity has long been suspected to play a major role in the transmission
of DMVD because of the strong association of this disease with certain
small- to medium-sized breeds. Two studies of families of Cavalier King
Charles spaniels and families of Dachshunds provide evidence that genetic
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factors play a large role in the etiology (
. The disease seems to
have a polygenic inheritance; multiple genes influence the trait, and a certain
threshold has to be reached before DMVD develops
. Male dogs have
a lower threshold than female dogs, which means that male dogs develop the
disease at younger age than female dogs within a family of dogs in which the
offspring, on average, have the same genotype. The polygenic mode of
inheritance means that a combination of a sire and a dam that both have
early onset of DMVD results in offspring that have, on average, early onset
of DMVD (and HF). A combination of dogs with late onset results in
offspring that manifest the disease at old age or never. The major role played
by genetic factors suggests that other factors (eg, level of exercise, degree of
obesity, diet) play a comparably small role in the etiology. Probably because
of this, little is known about the influence of such factors on the disease.
Breeding measures aimed at reducing the prevalence of DMVD have been
initiated in many countries in certain breeds, such as Cavalier King Charles
Spaniels and Dachshunds. These breeding programs use auscultation to
identify the presence of a heart murmur or echocardiography to detect and
quantify MVP or regurgitation. Dogs that are younger than a specific age
and have developed a heart murmur or echocardiographic findings consistent
with DMVD are not allowed to breed. Likewise, offspring from parents that
have developed a heart murmur or echocardiographic evidence of early
DMVD younger than a certain age limit are excluded from breeding in some
programs. These age limits are presumably different depending on whether
auscultation or echocardiography is used as the method of diagnosing
DMVD, because at a certain age, more dogs are likely to be diagnosed with
DMVD when echocardiographic evidence of MVP is used as a diagnostic
method than with auscultation
. Nevertheless, the age limits for
potential breeding dogs and parents are important. Because the prevalence of
DMVD is highly age dependent, the age limit should be set at an age at which
dogs with early onset of DMVD are excluded from breeding but not at too
high an age, because this may lead an unacceptable proportion of dogs being
excluded, which may leave the breeding population at unacceptably low
numbers
. It has been suggested that it is not advisable to exclude more
than 30% of the dogs from breeding because of a single disease
. With
improved DMVD status in the breed, the age limits may later be raised to
push the development and manifestation of DMVD toward a higher age.
Diagnosis of early degenerative mitral valve disease
The diagnosis of MR caused by DMVD is often not complicated, because
the clinical and echocardiographic findings are obvious and match. There
are, however, situations in which the diagnosis of DMVD may be less
obvious. Early stages of DMVD may be especially difficult. It may not be
clinically important for managing the patient to diagnose these early stages
correctly, because the effect of mild MR on the circulation is minimal and so
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Percentage dogs (%)
100
75
50
25
0
86%
88%
40%
35%
31%
1
1.5
2
2.5
3
Mean parental grading
Moderate intensity murmur
(Grade 3 and 4)
Low intensity murmur
(Grade 1 and 2)
No murmur
A
2
1,5
1
0,5
0
-0,5
-0,5
0
0,5
1
1,5
2
2,5
Parental MVP (mm) at 8 years
MVP (mm) in litters at 4 years
B
Fig. 3. Two studies have shown that genetic factors play a role in the etiology of degenerative
mitral valve disease (DMVD). (A) Relation between mean parental cardiac status and the
prevalence and intensity of cardiac murmur in offspring at 5 years of age in 30 different Cavalier
King Charles Spaniel litters. The parental cardiac status was graded 1 (late or no development
of DMVD) to 3 (DMVD present at a young age). Parents with a high mean cardiac status (ie,
developed DMVD at a young age) produced more offspring with heart murmurs than parents
with low mean parental grading (ie, late or no development of DMVD). Black, moderate-
intensity murmurs in offspring; shaded, low-intensity murmurs in offspring; white, no murmur
in offspring. (From Swenson L, Haggstrom J, Kvart C, Juneja RK. Relationship between
parental cardiac status in Cavalier King Charles Spaniels and prevalence and severity of chronic
valvular disease in offspring. J Am Vet Med Assoc 1996;208:2009–12; with permission.) (B) The
average mitral valve prolapse (MVP) severity in 18 different Dachshund litters at 4 years of age
shown as a function of mean MVP severity at 8 years of age. Parents with a high mean degree of
MVP produced offspring with a greater mean degree of MVP than parents with a low degree of
MVP. Boxes, family of long-haired Dachshunds; cross, family of short-haired Dachshunds.
(From Olsen LH, Fredholm M, Pedersen HD. Epidemiology and inheritance of mitral valve
prolapse in Dachshunds. J Vet Intern Med 1999;3:448–56; with permission.)
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J. Ha¨ggstro¨m et al / Vet Clin Small Anim 34 (2004) 1209–1226
is the likelihood that the disease will cause clinical signs of disease in the near
future
. Nevertheless, it is of great importance for breeding that these
dogs are correctly diagnosed, because the currently used breeding programs
are founded on the principle of excluding dogs with early onset of DMVD
and promoting the use of dogs with late or no onset. Because the age limits in
the breeding programs (especially in Cavalier King Charles Spaniels) are set
at an age at which many dogs start to develop DMVD
, a significant
number of dogs with mild disease are screened. There is currently no ‘‘gold
standard’’ for diagnosing cases of mild DMVD.
Auscultation
The early stages of DMVD are often characterized by the presence of a soft
heart murmur with maximal intensity over the mitral area. This murmur may
occur in every heartbeat, but it may also be intermittent
. A systolic
click may be present in some dogs, and this click may be the only abnormal
sound, but it may also be accompanied by an early, late, or holosystolic
murmur or by no murmur at all
. In the case of early systolic
murmur, potential differential diagnoses, such as physiologic flow murmurs
or low-degree aortic or pulmonic stenosis, should be ruled out. The presence
of these low-intensity murmurs is influenced by the degree of stress of the dog
at the time of examination. Stress or physical exercise may provoke murmurs
in dogs free of a murmur at rest or increase the intensity of the murmur in
dogs with a low-intensity murmur at rest
. Naturally, this variation may
cause confusion if the dog is examined at different times by different
auscultators and the results are in disagreement. Dogs with these ausculta-
tory findings indicative of early DMVD are not normal, even if progression
to more severe forms of DMVD does not occur in the near future.
Echocardiography often reveals changes consistent with DMVD (see below)
in the many of these dogs, but the findings may be inconclusive or normal in
others, with the latter being especially common in dogs with only a systolic
click. These early forms of DMVD may be classified as normal in some
breeding programs to ensure that only diseased dogs are classified as
diseased. This strategy has been chosen because the observer variation
among auscultators has been shown to be considerable in dogs with no or
mild DMVD but less in dogs with more progressive forms
Echocardiography
Echocardiography is a valuable tool to evaluate dogs with early DMVD
because it provides information about valve morphology and valve leakage
and it helps to rule out differential diagnoses. The technique has disadvan-
tages, however, because it is comparably time-consuming and expensive
compared with auscultation and it requires trained operators, which makes it
less convenient as a screening method of large populations. Ideally, diagnosis
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of early DMVD should be founded on the findings of abnormal mitral valve
morphology typical for DMVD and valve leakage. Abnormal mitral valve
morphology may be present without leakage and vice versa, however
. Although DMVD is the most common cause for mitral valve
leakage, the diagnosis of DMVD is less obvious in cases in which the only
abnormal finding is the presence of a small regurgitant jet. When examining
a mitral valve using 2D echocardiography, it is important to examine the
entire valve, because the lesions are often quite unevenly distributed
. A systolic bulging of one or both leaflets to the atrial side of the
mitral annulus is an early indication of affected valves, and it may be present
in dogs with or without MR (and a murmur) (see
. The presence
and degree of protrusion of the leaflets may be measured or subjectively
evaluated in the right parasternal long-axis view
. In dogs, the hinge
points of the two leaflets (imaged in the right parasternal long-axis view,
which consistently provides good images) have been used to define the
position of the mitral annulus in all recent studies assessing the presence and
severity of MVP
. In cases with insufficient valves, the degree of
displacement is reported to relate well to the severity of MR
. With
progression, the degenerative changes become more prominent and the
leaflets often have an irregular ‘‘club-like’’ appearance with greatest
thickening at the tip. The gross pathologic changes of the two leaflets
(anterior and posterior) are often equally severe at postmortem examination,
but the degenerative changes commonly appear more prominent on the
anterior leaflet in the right parasternal long-axis view on the echocardiogram.
It is rare, even in severe cases of DMVD and MR, to detect incomplete
closure of the leaflets as a means of confirming the presence of MR. Instead,
the MR may be detected and quantified by spectral or color-flow Doppler
ultrasonography
. Ideally, the regurgitant flow should be
aligned with the ultrasound beam, and this is most often achieved in the
left apical four-chamber view. Because the flow direction depends on the
orientation of the regurgitant orifice, which, in turn depends on the leaflet
morphology, other views may also give good alignment. Spectral Doppler
mapping may be used to identify the regurgitant jet when color-Doppler
mapping is not available. Furthermore, spectral Doppler mapping gives
information about the velocity of the regurgitant jet, and velocity time
tracings may help in estimating regurgitant volume (see below)
. Color-
flow echocardiography confirms the presence of a regurgitant jet, and the size
of the jet can be compared with the size of the left atrium. This measurement
is semiquantitative. A small jet rules out moderate to severe MR, but it is
difficult to discriminate between moderate and severe regurgitation from the
jet size. Nevertheless, the method has been reported to correlate reasonably
well with other echocardiographic measurements of regurgitant flow and
volume
. In case a more exact quantitative measurement of regurgitant
fraction is desired, the proximal isovelocity surface area (PISA) color-flow
method or spectral Doppler subtraction of forward aortic and regurgitant
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flows may be used
. Small jets in the vicinity of the mitral valve should
not be overinterpreted in dogs without any other valve abnormality, because
trivial regurgitation may often be detected in normal dogs
Consequences of mitral regurgitation on left ventricular function
A low degree of MR caused by DMVD does not lead to an apparent
change in any cardiac chamber or wall size or pump function. The forward
stroke volume is maintained, and the small regurgitant volume is easily
accepted by the left atrium. With progression of the valve lesions and
increasing MR, however, the potential loss of forward stroke volume is
compensated for by increased total stroke volume, increased force of
contraction, remodeling of the left atrium and left ventricle with myocardial
hypertrophy and dilatation, increased heart rate, and modulations of
systemic vascular tonus and extracellular fluid volume. The exact sequence
in which these compensatory mechanisms are recruited is currently not fully
understood. The cardiac compensatory mechanisms are presumably re-
cruited first, whereas the systemic mechanisms do not seem to be activated
until the cardiac mechanisms fail to compensate the MR (ie, decompensated
HF)
. To some extent, the MR is already compensated for by a slightly
increased heart rate during compensated phases, but this increase is usually
not obvious at a clinical examination because of the overall variability of
heart rate in dogs
. The heart rate is usually significantly increased in
advanced stages of MR, however, with evidence of decompensated HF
. MR creates unique hemodynamic stress by means of the
development of a low-pressure form of volume overload as a result of
ejection into the left atrium
. Myocardial systolic function is relatively
well preserved, because the ejection into the left atrium at low pressure
require little work by the left ventricle compared with other forms of heart
disease
. Dogs may tolerate even severe MR for years. Nevertheless,
because of chronic volume overload and the fact that the hypertrophy,
although necessary, is a pathologic remodeling, myocardial contractility
decreases slowly, even in clinically compensated dogs, but progressively and
inevitably
. Clinical overt myocardial failure in MR is referred to
as cardiomyopathy of volume overload, a condition that may also develop in
other types of heart disease, such as large patent ductus arteriosus
.
Reliable measurements of myocardial contractility are not readily obtained
in MR, and it is currently not known at which stage the depressed myocardial
contractility becomes of clinical significance. The reason for this is that the
volume overload causes an increase in preload (increased end-diastolic
filling), which, in turn, leads to an increased force of contraction according to
the Frank-Starling law
. When the ventricles contract, the resistance to
ventricular emptying is reduced in the first stages of ejection, because the
regurgitant volume is ejected into the left atrium at low pressure, leading to
exaggerated motion of the left ventricle (hyperkinesia)
, which is readily
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identified on the echocardiogram of a diseased dog. In moderate to severe
MR, values of ejection phase indices obtained from the echocardiogram
(eg, left ventricular fractional shortening, ejection fraction, mean velocity of
circumferential shortening) are often greater than normal. Therefore, in the
setting of moderate or severe MR, a normal fractional shortening represents
a significant reduction of myocardial contractility. End-systolic volume
indices (eg, left ventricular end-systolic short-axis dimension, end-systolic
volume index) more accurately estimate myocardial contractility in MR
. When decompensated HF is present and the sympathetic nervous
system is activated to increase apparent contractility, even these measure-
ments overestimate intrinsic myocardial contractility
. Our longitudinal
studies in Cavalier King Charles Spaniels indicate that although the end-
systolic dimension of the left ventricle does increase gradually before the
onset of signs of decompensated HF, the change is not great and may even be
within the normal reference range
. This increase in end-systolic
diameter usually becomes apparent after the onset of clinical signs of
decompensated HF
. This finding is in agreement with previously
published observations, but it does not provide information about overall
cardiac pump function
. Because the cardiac output is determined
by the forward stroke volume and the heart rate, evaluation of cardiac
output must take into account both heart rate and stroke volume. We
recently completed a study in which the pulmonary transit time (ie, the time it
takes for a blood cell to travel from the pulmonary trunk to the left atrium)
was studied using nuclear angiocardiography in dogs with varying severity of
MR caused by DMVD
. When the transit time was normalized for the
heart rate, we found that dogs with compensated MR but with evidence of
cardiomegaly had increased transit times. Dogs with signs of decompensated
HF had an even higher increase in transit times. Our interpretation of these
findings is that dogs with MR have reduced overall pump function (forward
stroke volume) even before signs of decompensated HF have developed. It is
currently not known if this finding is an indication that inotropic support is
indicated at this stage of the disease.
Diagnosis of mild decompensated heart failure
Dogs with DMVD attributable to DMVD usually develop clinical signs of
left-sided HF (cough, dyspnea, lethargy, reduced mobility, and increased
heart rate), although evidence of right-sided HF (ascites) may develop in
advanced cases
. Diagnosing moderate to severe HF is usually not
difficult, because the clinical signs of HF are usually obvious and match the
findings on the radiographs (ie, pulmonary edema, congestion). Likewise, it
is usually not difficult to diagnose the MR because it is invariably significant
. Mild decompensated HF may be difficult to diagnose, however,
because of the presence of vague clinical signs and the fact that the signs may
have gradually developed over a comparably long time. The stage when
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a patient starts to show clinical signs of DMVD and MR (ie, development of
decompensated HF) is the end of a process that started much earlier with the
onset of valve leakage. Over time, the valvular leakage was compensated
through a variety of mechanisms, a condition called ‘‘asymptomatic’’ or
compensated MR
. As the valve leakage increased, the valves
eventually became incapable of preventing pulmonary capillary pressures
from exceeding the threshold for pulmonary edema or of maintaining
forward cardiac output, a condition called ‘‘symptomatic’’ or decompen-
sated MR
. The distinction between these two stages is not clear,
however, and it is likely that minor signs of reduced activity and mobility are
present even before overt signs of decompensated HF have developed. It is
difficult to evaluate the presence of slight to moderately reduced exercise
capacity in most dogs with DMVD and MR objectively; many affected
animals are old and small companion dogs, which if obese, have little, if any,
demand on their exercise capacity. Furthermore, other concurrent diseases in
the locomotor system or elsewhere are common and restrict exercise.
Likewise, the hallmark of left-sided HF, coughing and dyspnea, may be
caused by several conditions, such as small airway disease, tracheal in-
stability, pulmonary fibrosis, neoplasia, heartworm disease, and pneumonia
. An increased heart rate and loss of respiratory sinus arrhythmia may
also be indicative of decompensated HF, but heart rate is variable and is
increased by many factors, such as stress and concurrent disease
.
Many of these differential diagnoses can be excluded by different clinical
tests, particularly radiography. Pulmonary findings on the radiographs may
also be inconclusive, because early radiographic changes of pulmonary
interstitial edema and bronchial pattern resemble the radiographic appear-
ance of chronic airway disease
. The tendency is to overdiagnose
pulmonary edema of HF
. Therefore, the most effective means to separate
dogs with early mild decompensated HF from those with other disease is
presumably to make the diagnosis based on the combined findings from the
clinical examination and the radiographs, an approach that has been used in
large clinical trials
. It is also useful to have series of radiographs and to
evaluate other evidence of left-sided HF that should be present by the time
pulmonary edema has developed, such as pulmonary venous distention. If
the findings are still inconculsive, re-examination within a week or a 48- to
72-hour trial of diuretic therapy with repeat radiographs may help to identify
the underlying cause. In the near future, ‘‘bedside’’ assays of different
endogenous markers of heart disease and HF, such as natriuretic peptides
(atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP]), should
be available to aid in diagnosing difficult cases.
When should therapy begin?
Ideally, DMVD therapy should halt the progression of the valvular
degeneration or improve valvular function by surgical repair or valve
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replacement. This therapy should preferably start before the onset of clinical
signs of disease. No medical therapy has been shown to change the course of
the disease by inhibiting or preventing the valvular degeneration, however,
and surgery is usually not technically, economically, or ethically possible in
dogs. Medical therapy of DMVD is therefore aimed at improving quality of
life by ameliorating the clinical signs and at improving survival. Mono-
therapy with angiotensin-converting enzyme (ACE) inhibitors has fre-
quently been prescribed for dogs with DMVD before the onset of
decompensated HF, most commonly in dogs with evidence of left atrial
and ventricular dilatation. Presumably, there are many reasons for this
strategy. Clinical trials in dogs with decompensated HF caused by DMVD
have shown that ACE inhibitor therapy improves quality of life and
increases survival when administered as adjunct therapy to other ongoing
HF therapy
. Furthermore, there is evidence from large clinical trials
in people that monotherapy with ACE inhibitors improves quality of life
and survival not only in asymptomatic patients with left ventricular
dysfunction
but in those without heart disease but belonging to a risk
group for developing it
. The local tissue renin-angiotensin-aldosterone
system (RAAS) has been suggested to be important for myocardial
remodeling in various animal models of HF
. An increased concen-
tration of plasma renin and aldosterone was reported in some asymptomatic
dogs with DMVD, indicating an early activation of the RAAS
. It is
therefore plausible that suppression of the RAAS could also be beneficial in
asymptomatic dogs with MR by counteracting systemic neuroendocrine
activation and left ventricular remodeling. Two large, placebo-controlled,
multicenter trials, the Scandinavian Veterinary Enalapril Prevention (SVEP)
and the VetProof trials
, were undertaken to study the effect of ACE
inhibitor monotherapy on the progression of clinical signs in asymptomatic
DMVD and MR in dogs. Both failed to show a significant difference
between the placebo and treatment groups in time from onset of therapy to
confirmed decompensated HF (
in dogs with or without
cardiomegaly. The two trials differed in the following features: the SVEP
trial included only dogs of one breed (Cavalier King Charles Spaniels),
whereas the VetProof trial included a variety of breeds; the dogs in the
VetProof trial more frequently had advanced DMVD than the dogs in the
SVEP trial; and the SVEP trial comprised more dogs than the VetProof trial
(229 versus 139 dogs). There are studies that may shed light on the results of
these two trials. The increased plasma concentration of renin and aldoste-
rone found in some asymptomatic dogs with MVD
was later found to be
associated with the presence of MVP rather than with the degree of MR per
se
. Furthermore, a longitudinal study involving Cavalier King Charles
Spaniels with moderate to severe MR attributable to DMVD showed no
signs of increased circulating RAAS activity during the progression from
compensated (ie, asymptomatic) to decompensated (ie, symptomatic) HF
. This finding has recently been corroborated in a study involving other
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J. Ha¨ggstro¨m et al / Vet Clin Small Anim 34 (2004) 1209–1226
breeds by Oyama and Sisson
. On the local tissue level, autoradiographic
studies indicate that in canine mitral valves, as opposed to rat valves,
angiotensin II receptors and ACE are scant
. This finding is at odds with
the theory that local RAAS systems in the valves contribute to progressive
valvular degeneration. In contrast, the canine myocardium has a comparably
high concentration of angiotensin II receptors and ACE
. Nevertheless,
experimental studies in dogs with MR showed no effect of an ACE inhibitor
on myocardial remodeling and progressive ventricular dilatation
.
Because angiotensin II production may be mediated through enzymes other
than ACE, in particular through chymase in dogs and people
, the same
authors investigated whether blocking of angiotensin II receptors could
prevent myocardial remodeling but found no effect
. Thus, it seems that
the remodeling process in MR may be more complicated than previously
thought; it has recently been suggested that this process is an example of
tissue activation that is difficult to stop or slow by current pharmacologic
means without changing the fundamental pathophysiology (ie, increased
heart rate and loading conditions)
. Finally, the large clinical trials in
asymptomatic heart disease in people have most commonly involved
patients with left ventricular dysfunction. Published clinical trials in primary
mitral valve disease and MR in people have been surprisingly few and have
reported conflicting results
. In conclusion, there is no evidence that any
therapy instituted before the onset of clinical signs of decompensated HF
prevents or delays the progression of DMVD.
Fig. 4. The SVEP study investigated the effect of enalapril on preventing decompensated heart
failure in dogs with asymptomatic DMVD. The graph shows the percentage of dogs included in
the enalapril and placebo groups, respectively, versus time. The difference in the number of days
in the study between placebo- and enalapril-treated dogs was not significant. (From Kvart C,
Ha¨ggstro¨m J, Pedersen HD, et al. Efficacy of enalapril for prevention of congestive heart failure
in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. J Vet Intern
Med 2002;16:80–8; with permission.)
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Feline hypertrophic cardiomyopathy: an
update
Catherine J. Baty, DVM, PhD
Department of Cell Biology and Physiology, BST South 221, University of Pittsburgh
School of Medicine, Pittsburgh, PA 15261, USA
As veterinarians, we find ourselves in a rather awkward position
regarding our knowledge about the most common feline heart disease,
hypertrophic cardiomyopathy (HCM)
. In the last decade, we have
made great progress in our understanding of the disease; yet, we now find
ourselves armed with reasonable evidence that there is a great deal we still
do not know. We have established that HCM is a heterogeneous disease
and have increasing evidence of a potentially large pool of asymptomatic
cats with HCM that are not routinely identified
. Although families
of cats with HCM seem to be more similar with regard to clinical
manifestations and disease progression, the disparities among unrelated
cats with HCM are dramatic. Important questions regarding the genetics of
the disease persist despite great efforts to collect, characterize, and even
breed families of cats found to be affected by the disease. More importantly,
we have not convincingly established many useful risk factors that should
help us to guide owners with regard to their pet’s prognosis. An important
step toward selecting appropriate therapy for cats with HCM that have been
presented with diastolic heart failure (HF) has been made with a blind,
multicenter, placebo-controlled, prospective clinical trial
Definition
The term hypertrophic cardiomyopathy refers to a primary myocardial
disease characterized by a hypertrophied nondilated left ventricle
Furthermore, HCM occurs in the absence of other cardiac diseases that
might be expected to cause left ventricular hypertrophy. Finally, because
Catherine J Baty, DVM, PhD, is a recipient of a Burroughs Wellcome Fund Hitchings-
Elion Fellowship.
E-mail address:
(C.J. Baty).
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.06.005
Vet Clin Small Anim
34 (2004) 1227–1234
HCM is classified as a primary myocardial disease, other noncardiac causes
of left ventricular hypertrophy must also be excluded.
Natural history
Early reports of cats with HCM were necropsy based and reflected
a dramatic disease manifesting congestive heart failure (CHF) and arterial
thromboembolism (ATE)
; however, with increasing accessibility to
echocardiography, asymptomatic cats are routinely identified with HCM
. Small families have been identified and clinically followed over
time and confirm the heterogeneity of the disease in terms of survival and
clinical manifestations
. Although it had been suspected that some
HCM cats with classic hypertrophic changes ultimately progress to end-
stage left ventricular remodeling with relative chamber and wall thinning,
this has now been echocardiographically documented in long-term follow-
up of a small family of domestic short-haired cats
.
Two large retrospective studies provide the basis for estimates of the
prognosis for cats diagnosed with HCM
. These studies share similar
limitations; they are essentially based on a referral population because they
were conducted at academic teaching institutions. Both studies break down
their study populations based on clinical signs at the time of presentation:
asymptomatic, CHF, or ATE. Survival was estimated based on those cats
that did not die within the first 24 hours of presentation. Median survival for
all HCM cats in the two studies was similar—just less than 2 years. In both
studies, cats with ATE do worst, cats with CHF fare somewhat better, and
asymptomatic cats survive the longest. The calculated mean survival times
for these subgroups differed substantially between the two studies, however,
and both showed pronounced variation among individual cats despite their
common condition. Median survival time reported from the two studies
ranged from 2 to 6 months for cats presenting with ATE, from 3 to 18
months for cats presenting with CHF, and from 3 to more than 5 years for
asymptomatic cats.
Statistical analyses of subgroups in these two retrospective studies and
two smaller series
have been used to try to identify specific character-
istics of diseased cats associated with a poor prognosis. Factors like age,
clinical signs at presentation, left atrial size, systolic anterior motion, heart
rate, outflow obstruction, and left ventricular thickness have been variously
identified as prognostic markers. The factors identified have not been
consistent among the studies, however, and the studies suffer from a variety
of problems, including lack of controls, relatively small numbers of cats, and
referral population bias.
Similar risk factors for poor prognosis, especially sudden death, have
been sought for human beings and have been found to be similarly
confounded by study limitations
. Recently, however, one large
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C.J. Baty / Vet Clin Small Anim 34 (2004) 1227–1234
multicenter study and another smaller nonreferral center study found that
outflow obstruction in people with HCM is a strong independent predictor
of disease progression to HCM-related death
. Whether outflow
obstruction is also an important risk factor in cats remains to be seen;
subaortic gradients have not been consistently available in the retrospective
clinical studies of feline HCM, one retrospective study suggested that
outflow tract obstruction due to systolic anterior motion was associated
with a more favorable prognosis
Pathogenesis
It is reasonable to consider whether the observed heterogeneity in this
disease might be explained by different etiologies. Although no disease-
causing mutation has yet been identified among families of cats with HCM,
there is evidence of Mendelian heritability in several pedigrees (Jo Arthur,
MA, VetMB, MRCVS, personal communication, January 1997)
. So,
some percentage of feline HCM is familial; what is not known is if there are
other important nongenetic etiologies of HCM. There have been few
investigations focusing on nongenetic causes of HCM, however, since the
thorough documentation of the genetic etiology of HCM in human beings.
The association between dietary taurine deficiency and dilated cardiomy-
opathy in the cat reminds us of the importance of nutritional etiologies
Infectious etiologies have not been enthusiastically investigated in HCM.
While admitting that nongenetic causes of HCM have not been aggressively
investigated to date, it should be noted that there is good precedence for the
heterogeneity in feline HCM in familial HCM in human beings
If at least some percentage of HCM is familial in the cat, why has not
a single disease-causing mutation been identified despite the efforts of several
investigators? The inability to identify a disease-causing mutation may be
a result of the historically limited amount of genetic reagents (eg, poly-
morphic markers) applicable to the cat; fortunately, this situation is rapidly
changing
. The lack of large well-documented feline pedigrees with
available DNA samples and genetic markers that work even in inbred
families has resulted in the use of a so-called ‘‘candidate gene’’ approach.
Using this approach, genes known to carry mutations in human HCM are
investigated as likely candidates to carry mutations in cats with HCM. In
people, the HCM-causing mutations tend to be private mutations (ie, shared
only among a family), and it may also be that way in cats. This situation
makes candidate gene screening more of a gamble; one must be lucky enough
to screen a particular gene in a particular family affected by a mutation in
that gene. Thus, this becomes a bit of a numbers game and, in fact, was
experienced early in human genetic investigations of HCM (Hugh Watkins,
MD, PhD, personal communication, August 1997), where a disease gene was
initially ‘‘ruled out’’ based on screening a number of small kindreds.
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C.J. Baty / Vet Clin Small Anim 34 (2004) 1227–1234
In human HCM, where many disease-causing mutations have been
identified and some have even been translated into transgenic mice, it is
evident that other factors modify the clinical, or phenotypic, manifestations
of the causal mutation. Some of these factors are genetic (ie, other genes),
and others seem to be environmental or nutritional
. These so-called
‘‘modifiers’’ add another layer of complexity to the effort of making
correlations between genotypes and phenotypes and identifying risk factors
for sudden death, rapid progression to HF, or arrhythmias. Certainly, these
factors are contributors to the heterogeneity observed in human HCM and
likely some portion of feline HCM.
Diagnosis
Antemortem diagnosis is usually made by echocardiography, with
laboratory tests to exclude other systemic diseases that might cause similar
cardiac changes (eg, primary hypertension, hyperthyroidism). By conven-
tion, left ventricular and interventricular septal thicknesses equal to or
exceeding 6 mm are used in the diagnosis of HCM
. The histologic gold
standard for HCM continues to be myocyte and myofiber disarray
.
Because HCM is believed to be predominantly a disease of diastolic
dysfunction, there has been an effort to assess diastolic function accurately
in a noninvasive manner
. Although recent publications have detailed
the successful application of Doppler imaging assessment of diastolic
function in cats, this technology is not widely available in nonreferral
settings
. Doppler tissue imaging seems to have particular promise in
identifying and characterizing diastolic dysfunction in HCM, but this
technology is even less available, even in tertiary care centers, and remains
to be validated against invasive diastolic measurements in cats with HCM
Recently, interest has focused on the use of biochemical markers to help
diagnose HCM and other forms of feline cardiac disease
. Cardiac
troponin I (cTnI) is a cardiac-specific protein that is expressed within
cardiac myocytes. Damage to cardiac myocytes results in the release of cTnI
and detectable levels in plasma and serum. Measurement of cTnI is used in
human beings to support the diagnosis of acute coronary syndromes,
including myocardial infarction
Two recent studies have investigated circulating cTnI levels in cats with
HCM compared with normal cats and found that most cats with HCM have
higher levels of cTnI
. The reported specificity and sensitivity of serum
and plasma levels of cTnI were high in these investigations. Although this
seems promising, it is still unclear how such testing would be used clinically.
Currently, there is no published study investigating circulating cTnI levels
in sick cats, especially cats with diseases that might be confused with HCM
initially, such as feline asthma, or important concurrent diseases, such as
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C.J. Baty / Vet Clin Small Anim 34 (2004) 1227–1234
chronic renal failure. Nevertheless, it is clear from the human literature that
even noncardiac disease can be associated with increased blood levels of
cTnI (eg, human patients with renal disease and pulmonary thromboem-
bolism have also shown elevated cTnI levels)
. There is evidence to
support the hypothesis that these elevations in cTnI are reflective of
subclinical myocardial damage
. If this test is to be used for screening
and diagnostic purposes in cats with HCM, additional studies are needed to
evaluate the utility of this test in a population of sick cats.
The test may be of use prognostically like it seems to be in human beings
. Much more work is required to show that cats with HCM with higher
cTnI levels tend to do worse clinically, however. For now, both studies have
shown a weak positive correlation between circulating cTnI concentrations
and diastolic thickness of the left ventricular free wall
Therapy
Until recently, there was no randomized, prospective, double-blind study
addressing therapy in cats with HCM. The Multicenter Feline Chronic
Heart Failure Study Group conducted a study on cats with HCM that had
suffered an episode of diastolic HF; however, some 20% of the cats included
in this study had restrictive cardiomyopathy or feline unclassified cardio-
myopathy
. Cats suffering concurrent thromboembolic complications
were specifically excluded from the study. There was a placebo control
group in this study, but these cats received a placebo in addition to
furosemide. The three other treatment groups received atenolol, Dilacor
(long-acting diltiazem), or enalapril in addition to the furosemide. Study end
points were recurrence of HF and death. After 3 years of study, 118 cats
with HF had been enrolled, although 180 cats were originally sought. There
was little evidence to suggest that any of the three drugs afforded benefit
over furosemide alone
. Interestingly, there was some evidence to suggest
that cats treated with atenolol in addition to furosemide did worse than
those in the other groups. The authors cautioned that the results should be
considered cautiously because the numbers were small and the study was
ongoing.
A small uncontrolled retrospective investigation assessed the use of
enalapril in 19 cats with HCM
. Based on their findings, the authors
suggested that enalapril might be well tolerated in cats with HCM and may
contribute to clinical improvement and narrowing of the left ventricular
outflow tract based on echocardiographic measurements over a 3- to 6-
month period. Although no larger blind placebo-controlled study has been
undertaken to confirm these findings, enalapril seems to be used fairly
commonly in cats with HCM
. Another small uncontrolled open-label
study using benazepril and standard therapy in HCM cats found similar
findings with regard to drug tolerance and potential clinical benefit
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Thromboembolic complications are obviously important to the success-
ful management of feline HCM. Although it was noted previously that cats
with HCM and ATE at the time of diagnosis do poorly, there are now more
therapeutic options for the management of these cases. Specifically, low-
molecular-weight heparins are being used by veterinarians to afford the
potential anticoagulant benefits of warfarin without the need for close
monitoring and risk of severe hemorrhage. New therapeutic options for the
management of ATE are discussed in detail in the article on feline aortic
thromboembolism in this issue.
Interestingly, as veterinarians managing asymptomatic cats with HCM,
we find ourselves in a similar place as physicians with asymptomatic
patients. Although it is our mutual goal to select prophylactic therapy that
prevents or delays progression of disease, we have virtually no data on
which to judge our current therapeutic selections
. The prospect of
conducting a prospective prophylactic study in asymptomatic cats is
daunting, given that some initially asymptomatic cats survive for years,
probably achieving near-normal life expectancies in some cases
. In
human beings, treatment to slow disease progression is generally limited to
patients judged to be at risk of sudden death. The efficacy of empiric
prophylactic treatments with calcium channel blockers or b-blockers to
delay the onset of symptoms or favorably modify the clinical course of
disease in asymptomatic young patients with marked left ventricular outflow
tract gradients is unresolved in people
, as it is in cats.
Summary
HCM continues to be a challenging disease for veterinarians. Acute cases
with ATE or CHF are difficult to manage, and we still lack the tools to
advise owners well with regard to their pet’s prognosis. Nevertheless, it
appears that the historical view of HCM as a serious disease with a poor
prognosis is now being adjusted to accommodate the apparently large
numbers of asymptomatic cats with much longer survival times. Although
there is evidence of a genetic cause of the disease in at least several families
of cats, no disease-associated mutation has been found to be causative of
feline HCM. Prophylactic treatment of asymptomatic or mildly affected
cats continues to be empiric, but a randomized, double-blind, placebo-
controlled, multicenter study on chronic therapy of symptomatic HCM cats
should provide new guidance for practitioners managing these cases.
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Boxer dog cardiomyopathy: an update
Kathryn M. Meurs, DVM, PhD
Department of Veterinary Clinical Sciences, The Ohio State University,
College of Veterinary Medicine, 601 Vernon Tharp, Columbus, OH 43210, USA
Dr. Neil Harpster first described myocardial disease in the Boxer dog in
the early 1980s. It was characterized as a degenerative myocardial disease
with unique right ventricular histologic findings that include myocyte
atrophy and fatty infiltration
. Affected dogs could be asymptomatic
or syncopal with ventricular arrhythmias, and they sometimes developed
congestive heart failure. The disease seemed to have a greater prevalence in
certain families of dogs. In the early 1990s, Dr. Bruce Keene described
a family of Boxers with myocardial dysfunction, tachyarrhythmias and
congestive heart failure, and decreased myocardial carnitine levels
.
Arrhythmogenic right ventricular cardiomyopathy
Careful evaluation of the disease by these investigators as well as others
has demonstrated that boxer dog cardiomyopathy has striking similarities
to a human myocardial disease called arrhythmogenic right ventricular
cardiomyopathy (ARVC)
. ARVC is an inherited disorder that is
characterized by fatty or fibrofatty replacement of right and, sometimes, left
ventricular myocardium. Ventricular tachycardia, which often exhibits an
upright or left bundle branch configuration, is a common clinical manifes-
tation. Affected individuals are at risk for sudden cardiac death. Similarities
in clinical presentation, pathologic findings, and presumed etiologic basis
have supported interest in reclassification of the disease as boxer arrhyth-
mogenic right ventricular cardiomyopathy.
This work was generously supported by the American Kennel Club–Canine Health
Foundation and the American Boxer Trust.
E-mail address:
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.003
Vet Clin Small Anim
34 (2004) 1235–1244
Cause
ARVC in the Boxer dog is a familial disease apparently inherited as an
autosomal dominant trait
. The presentation of the disease in affected
offspring is quite variable, however, suggesting that incomplete penetrance
of the disease may be involved. Affected dogs may experience lethal
ventricular arrhythmias and sudden cardiac death, may develop systolic
dysfunction and congestive heart failure, or may live an asymptomatic life
with frequent ventricular ectopy.
Clinical presentation
Boxer ARVC is an adult-onset myocardial disease and, as originally
proposed by Harpster, there seems to be three forms of the disease, now
referred to as concealed, overt, and myocardial dysfunction
. The
concealed form is characterized by an asymptomatic dog with occasional
ventricular premature complexes (VPCs). The overt form is characterized by
a dog with tachyarrhythmias and syncope or exercise intolerance. The third
group, diagnosed least frequently, is characterized by a dog that has
developed myocardial systolic dysfunction, sometimes with evidence of
congestive heart failure. Although it is likely that these three forms represent
a continuum of the disease (particularly the concealed and overt forms),
this has not been well documented.
Diagnosis
The diagnosis of canine ARVC can be challenging. Unfortunately,
a single diagnostic test for ARVC does not exist. The diagnosis is best
based on the presence of a combination of factors, including a family history
of disease, the presence of a ventricular tachyarrhythmia, a history of
syncope or exercise intolerance, and the postmortem finding of fibrofatty
infiltration into the myocardium.
Physical examination
Many affected dogs have a normal physical examination. In some cases,
an occasional ventricular premature beat may be detected. Heart murmurs
are infrequently heard, although the presence of a left apical systolic
murmur may suggest the myocardial dysfunction form of the disease.
Caution when evaluating heart murmurs in the Boxer is suggested, however,
because many adult Boxers have a left basilar systolic heart murmur that
may be physiologic or, in some cases, may be associated with subvalvular or
valvular aortic stenosis
. These murmurs should not be confused with
the left apical systolic murmur associated with the myocardial dysfunction
form of ARVC.
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K.M. Meurs / Vet Clin Small Anim 34 (2004) 1235–1244
Electrocardiography
Affected dogs should have increased ventricular ectopy, but it may be
intermittent. The presence of an upright VPC on a lead II (left bundle
branch block morphology) electrocardiogram is suggestive of the disease
(
). Some affected dogs have a different morphology to their VPCs or
may not have any VPCs detected on an electrocardiogram, however. A
normal electrocardiogram does not exclude a diagnosis of ARVC because
of the intermittent nature of the arrhythmia. If suspicion exists because of
auscultation of an arrhythmia, suggestive clinical signs (eg, syncope, exercise
intolerance), or a family history of disease, a 24-hour Holter monitoring
study is strongly suggested.
Holter monitoring
Holter monitoring is an important part of the diagnosis, screening, and
management of canine ARVC. Even if the diagnosis is suspected based on
the identification of occasional VPCs on an in-house electrocardiogram,
a Holter study can provide the best assessment of overall frequency and
complexity of the arrhythmia and serve as an important guide for
monitoring treatment. It is uncommon for normal healthy adult dogs to
have any VPCs. In one study, healthy adult large-breed dogs had a median
of 2 VPCs in 24 hours
. An evaluation of more than 300 asymptomatic
Fig. 1. Upright ventricular premature complexes (left bundle branch block morphology)
observed in electrocardiogram leads I, II, and III.
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K.M. Meurs / Vet Clin Small Anim 34 (2004) 1235–1244
adult Boxers in a study performed in our practice found that 75% of the
population had less than 75 VPCs in 24 hours. Therefore, the identification
of frequent ventricular ectopy (>100 VPCs over 24 hours) in an adult Boxer
is strongly suggestive of a diagnosis of ARVC, particularly if there is signi-
ficant complexity (couplets, triplets, bigeminy, or ventricular tachycardia) to
the arrhythmia.
Alternatively, a strong suspicion of ARVC sometimes exists but the
Holter monitor reading is not clearly abnormal. This may be because of the
significant day-to-day variability of VPC number in affected dogs. Consider-
able day-to-day variability in VPC number exists, and affected untreated
Boxers have been shown to have up to an 83% change in VPC number from
one day to the next
. Therefore, if a strong suspicion of ARVC exists but
the Holter reading was not diagnostic, a second Holter monitoring study
should be performed. If the dog is syncopal, an event monitor may be
considered. Additional testing may identify other possible causes of
syncope.
Echocardiography
Although ARVC is a myocardial disease, most of the myocardial changes
are abnormalities noted at histologic examination as opposed to abnormal-
ities obvious on gross examination of the ventricle. Therefore, most affected
dogs have normal echocardiograms, particularly with regard to evaluation
of the size and function of the left ventricle. In some cases, careful
echocardiographic evaluation of the right ventricle may detect right
ventricular enlargement and, possibly, right ventricular dysfunction. Thor-
ough evaluation of the right ventricle by echocardiography is difficult,
however, because of the complex anatomy of the right ventricle, and subtle
changes may be frequently overlooked. A small percentage of adult Boxers
with tachyarrhythmias are observed to have left ventricular dilation with
systolic dysfunction
. Because these cases are observed infrequently, it
should be remembered that most affected dogs do not have echocardio-
graphically apparent abnormalities.
Pathology
Postmortem findings can be helpful in the evaluation of sudden cardiac
death in the Boxer. Many affected dogs have a grossly normal appearance to
their heart at the time of death; however, some cases may show evidence of
right ventricular enlargement and, in some cases, left ventricular enlarge-
ment. Careful histologic evaluation should identify fatty, and sometimes
fibrofatty, segmental or diffuse replacement of the right ventricular free wall
from the epicardium toward the endocardium (
). Occasionally, the
interventricular septum and left ventricular free wall are also involved
.
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K.M. Meurs / Vet Clin Small Anim 34 (2004) 1235–1244
Screening
The familial nature of ARVC has led to increased interest by Boxer
breeders in the screening of breeding dogs for the disease. Unfortunately,
because of the absence of a perfect diagnostic test for ARVC, screening the
asymptomatic dog is challenging, and substantial efforts are being directed
toward the development of a genetic test. Careful consideration of multiple
criteria should be used to help determine the likelihood that an individual
asymptomatic dog is affected. Important factors might include a familial
history of ARVC in association with repeatable abnormal Holter monitor
readings. Holter monitoring results should be evaluated for the number of
VPCs as well as the complexity of arrhythmia (eg, single, couplets, triplets,
ventricular tachycardia). As mentioned previously, the identification of
frequent ventricular ectopy (>100 VPCs over 24 hours) in an adult Boxer
is strongly suggestive of a diagnosis of ARVC, particularly if there is sig-
nificant complexity (couplets, triplets, bigeminy, or ventricular tachycardia)
to the arrhythmia. Long-term studies that evaluate the predictive value of
these findings for identifying dogs at risk of dying from ARVC have not
been completed, however. Some affected dogs have an abnormal degree of
ectopy but never develop clinical signs, whereas some affected dogs with the
same degree of ectopy gradually progress and develop more severe
arrhythmias as they mature. Finally, some Boxers have thousands of VPCs
Fig. 2. Right ventricular myocardial sample from a Boxer with arrhythmogenic right
ventricular cardiomyopathy. Note the fibrofatty myocardial infiltration observed histologically.
The epicardium is located on the left aspect of the image.
1239
K.M. Meurs / Vet Clin Small Anim 34 (2004) 1235–1244
over 24 hours and a high grade of complexity and remain asymptomatic
. The factors that determine which dogs eventually progress to the
clinical form of the disease are not known and increase the frustration of
screening for this disease. Although breeders are concerned about passing
on this trait, they should be advised about the significant complexities of
performing screening and counseled not to remove dogs completely from
a breeding program because of a single abnormal Holter reading. Annual
Holter monitoring is strongly recommended, and significant emphasis on
a single Holter monitor reading is strongly discouraged. ARVC is an adult-
onset disease, and the degree of ventricular ectopy seems to increase with
age; thus, a single Holter monitoring study performed in a young adult dog
may not detect an affected dog that is not yet demonstrating the trait.
Additionally, in some cases, systemic disease or other forms of cardiac
disease may lead to the development of VPCs on a Holter monitoring study
that may not be apparent on subsequent ones. Inadvertently removing
a significant number of unaffected dogs from breeding programs may have
a detrimental effect on the overall gene pool of a purebred dog.
A possible system for screening asymptomatic dogs might include the
following Holter monitoring criteria:
1. None to 20 single VPCs over 24 hours: interpreted as within normal limits
2. Twenty to 100 VPCs over 24 hours: interpreted as indeterminate, suggest
repeating in 6 to 12 months
3. One hundred to 300 single VPCs over 24 hours: interpreted as suspicious,
consider keeping out of the breeding program for 1 year and repeating
the Holter study
4. One hundred to 300 VPCs over 24 hours with increased complexity (fre-
quent couplets, triplets, and ventricular tachycardia) or 300 to 1000 single
VPCs over 24 hours: interpreted as likely affected
5. More than 1000 VPCs over 24 hours: interpreted as affected, may con-
sider treatment as discussed below
The criteria listed are based on the appearance of the particular
prevalence of the arrhythmias in the asymptomatic population as opposed
to long-term outcome studies of dogs with the arrhythmias. They are given
as one possible screening method. It is strongly advised to consider all issues
for each dog, including family history, evidence of ongoing systemic disease,
and repeated Holter studies, before making strict recommendations.
Treatment
Treatment considerations for affected dogs are generally directed toward
the use of ventricular antiarrhythmics, because most affected dogs do not
have systolic dysfunction and do not seem to progress to heart failure. When
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K.M. Meurs / Vet Clin Small Anim 34 (2004) 1235–1244
prescribing antiarrhythmics for the affected dog, several considerations
should be taken into account. There are known benefits to the use of certain
antiarrhythmics in affected dogs, including the ability to decrease the number
of VPCs and the complexity of the arrhythmia. Additionally, syncopal
episodes have been shown to decrease with antiarrhythmic therapy
There is no evidence that the use of antiarrhythmics alters the risk of sudden
cardiac death in affected dogs, however. Additionally, there is a risk of
a proarrhythmic effect associated with the use of many antiarrhythmics, and
the arrhythmia could potentially be exacerbated. Finally, antiarrhythmic
therapy adds increased expense to the management of the case as well as
increased labor for the owner.
Therefore, the risks and benefits of treatment should be carefully
considered and discussed with owners before starting therapy. Ideally,
therapy should be managed by assessing a pretreatment and posttreatment
(2–3 weeks later) Holter monitoring study. Comparing the pretreatment and
posttreatment readings should help to detect a proarrhythmic effect as well
as help to evaluate the efficacy of treatment. Considerable day-to-day
variability in VPC number exists, and affected untreated Boxers have been
shown to have up to an 83% change in VPC number from one day to the
next
. Therefore, a positive treatment response is best attributed to
treatment when at least an 80% reduction in VPC number as well as
a reduction in the complexity of the arrhythmia on the posttreatment Holter
reading is observed. Additionally, an increase in symptoms after starting
treatment or a significant increase in the number of VPCs may suggest
a proarrhythmic effect. The significant day-to-day variability in VPC
number even in untreated affected Boxers underscores the inability to make
an accurate assessment of treatment on a brief in-house electrocardiogram.
Asymptomatic Boxers
The best indication to start therapy in an asymptomatic affected Boxer is
not well understood, and the risks and benefits of therapy should be
carefully evaluated. Certainly, some dogs die from their arrhythmia before
ever developing clinical signs; thus, the absence of clinical signs does not
mean that there is no risk of sudden death. If an arrhythmia is detected on
routine examination in an asymptomatic dog, a Holter monitoring study
should be performed to evaluate for the frequency and complexity of
the arrhythmia. Although a strict relation between the development
of symptoms and the number of VPCs does not exist, the development of
syncope is associated with higher numbers of VPCs and a greater degree
of complexity
. Sustained ventricular tachycardia (ie, ventricular
tachycardia run that lasts longer than 30 seconds) might be a risk factor
for sudden death in people with ARVC
. A VPC that occurs early in
diastole, the R on T phenomenon, is believed to be dangerous, because the
nadir of the ventricular fibrillation threshold occurs at about the time that
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K.M. Meurs / Vet Clin Small Anim 34 (2004) 1235–1244
the T wave is inscribed on the electrocardiogram. Based on this, treatment
may be reasonable if there are at least 1000 VPCs over 24 hours or if runs of
ventricular tachycardia or evidence of the R on T phenomenon exists.
Nevertheless, it should be recognized that risk factors for sudden death in
Boxer dogs with ARVC have been incompletely described; furthermore,
studies that evaluate the impact of antiarrhythmic therapy on long-term
survival have not been done.
Boxers with syncope/exercise intolerance
Boxers with syncope and ventricular arrhythmias are generally started on
treatment, ideally after a 24-hour Holter monitoring study. In some cases, if
the syncope is frequent or ventricular tachycardia is observed, a Holter
study may not be performed so as to start therapy as soon as possible. In
some cases, however, the absence of a pretreatment study may make it
difficult to assess the response to therapy fully. Therefore, when possible, a
Holter monitoring study is performed and the owner is advised to start
therapy immediately after removing the Holter monitor (before the results
are available) if great concern exists.
Treatment options
A reduction in VPC number and complexity of the arrhythmia in affected
Boxers with frequent ectopy has been demonstrated with two treatment
protocols
. The first is sotalol (1.5–2.0 mg/kg administered orally every
12 hours), and the second is a combination of mexiletine (5–8 mg/kg
administered orally every 8 hours) and atenolol (12.5 mg per dog
administered orally every 12 hours). In some cases, a loss of appetite or
mild gastrointestinal upset may be observed with mexiletine; however,
theoretically, the addition of atenolol allows the low end of the mexiletine
dose to be used to help reduce this side effect. Additionally, when mexiletine
is given with food, side effects may be less frequently observed. It is likely
that variations in drug response exist in individual dogs. Therefore, if a poor
response is observed with one drug, a different one may prove to be more
effective.
Boxers with left ventricular dilation and systolic dysfunction
A small percentage of Boxers with tachyarrhythmias present with systolic
dysfunction and, in many cases, left or biventricular heart failure
. If
echocardiography demonstrates systolic dysfunction and ventricular di-
lation, treatment for canine dilated cardiomyopathy is warranted. Addi-
tionally, supplementation with
L
-carnitine might be considered at a rate of
50 mg/kg administered orally every 8 to 12 hours, because a small number of
affected dogs have demonstrated improvement in systolic function and
prognosis after supplementation
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K.M. Meurs / Vet Clin Small Anim 34 (2004) 1235–1244
Prognosis
Dogs with ARVC are always at risk of sudden death. Many affected dogs
live for years even without treatment, however. Many dogs may be
managed, symptom free, for years on antiarrhythmics. A small percentage
of these dogs may eventually develop ventricular dilation and systolic
dysfunction.
L
-carnitine cardiomyopathy in Boxers
A deficiency in myocardial
L
-carnitine levels was observed in a family of
Boxers with left ventricular dilation and systolic dysfunction. The tachyar-
rhythmias included atrial fibrillation and VPCs. The dogs had normal to
high levels of plasma
L
-carnitine but low levels of myocardial carnitine.
Supplementation with
L
-carnitine as well as standard heart failure therapy
resulted in significant improvement in myocardial function and clinical
condition but did not result in total regression of the disease
. In general,
myocardial carnitine deficiency does not seem to be a common cause of
myocardial disease in the Boxer and is not likely to be directly associated
with boxer ARVC. Because it is difficult to assess myocardial carnitine levels
accurately without an endomyocardial biopsy and because plasma levels are
not an accurate assessment of myocardial levels, the true role of carnitine in
the boxer with systolic dysfunction and dilation is not known. Supplemen-
tation of these cases with
L
-carnitine, 50 mg/kg every 8 hours, may be
considered
.
References
[1] Harpster N. Boxer cardiomyopathy. In: Kirk R, editor. Current veterinary therapy VIII.
Philadelphia: WB Saunders; 1983. p. 329–37.
[2] Harpster N. Boxer cardiomyopathy. Vet Clin N Am Small Anim Pract 1991;21(5):
989–1004.
[3] Keene BW, Panciera DP, Atkins CE, Regizt V, Schmidt MJ, Shug AL. Myocardial
L
-carnitine deficiency in a family of dogs with dilated cardiomyopathy. J Am Vet Med
Assoc 1991;198:647–50.
[4] Basso C, Fox PR, Meurs KM, Towbin JA, Spier AW, Calabrese F, et al. Arrhythmogenic
right ventricular cardiomyopathy causing sudden cardiac death in Boxer dogs: a new
model of human disease. Circulation 2004;109:1180–5.
[5] Meurs KM, Spier AW, Miller MW, Lehmkuhl LB, Towbin JA. Familial ventricular
arrhythmias in Boxers. J Vet Intern Med 1999;13:437–9.
[6] Koplitz S, Meurs K, Spier A, Bonagura JB, Luis Fuentes V, Wight N. Aortic ejection
velocity in healthy boxers with soft murmurs and boxers without cardiac murmurs: 210
cases (1997–2001). J Am Vet Med Assoc 2003;222:770–4.
[7] Kvart C, French AT, Luis Fuentes V, Haggstrom J, McEwan J, Schober K. Analysis of
murmur intensity duration and frequency components in dogs with aortic stenosis. J Small
Anim Pract 1998;39:318–24.
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[8] Meurs KM, Spier AW, Hamlin RL, Wright NA. Use of ambulatory electrocardiography
for detection of ventricular premature complexes in healthy dogs. J Am Vet Med Assoc
2001;218:1291–2.
[9] Spier AW, Meurs KM, Lehmkuhl LB, Wright NA. Spontaneous variability in the
frequency of ventricular arrhythmias in Boxers with arrhythmogenic cardiomyopathy. J
Am Vet Med Assoc 2004;224:538–41.
[10] Meurs KM, Baumwart R, Atkins CE, Bonagura JB, DeFrancesco T, Keene BW, et al.
Myocardial dysfunction in boxer dogs with tachyarrhythmias [abstract]. J Vet Intern Med
2003;17:439.
[11] Meurs KM, Spier AW, Wright NA. Evaluation of the ambulatory electrocardiogram of
boxer dogs with ventricular tachyarrhythmias and syncope [abstract]. J Vet Intern Med
2002;16:338.
[12] Priori SG, Aliot E, Blomstrom-Lundqvist C, Bossaert L, Breithardt G, et al. Task Force
on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J 2001;
22:1374–450.
[13] Meurs KM, Spier AW, Wright NA, Atkins CE, DeFrancesco T, Gordon S, et al.
Comparison of the effects of four antiarrhythmic treatments for familial ventricular
arrhythmias in Boxers. J Am Vet Med Assoc 2002;221:522–7.
[14] Keene B.
L
-carnitine supplementation in the therapy of dilated cardiomyopathy. Vet Clin
N Am Small Anim Pract 1991;21(5):1005–9.
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K.M. Meurs / Vet Clin Small Anim 34 (2004) 1235–1244
Feline arterial thromboembolism: an
update
Stephanie A. Smith, DVM, MS
a,
*,
Anthony H. Tobias, BVSc, PhD
b
a
Department of Biochemistry, College of Medicine, 506 South Mathews,
MC-714, University of Illinois, Urbana, IL 61801, USA
b
Department of Small Animal Clinical Sciences, University of Minnesota, 1365,
Gortner Avenue, St. Paul, MN 55108, USA
Arterial thromboembolism (ATE) has been recognized in cats for almost
three quarters of a century. A case report published in 1930 described the
typical clinical and necropsy findings in a cat presented for posterior
paralysis with a distal aortic thromboembolus
. A series of nine cases of
ATE in cats was published 25 years later
. By the 1960s, ATE was well
recognized, with a prevalence rate of 1 in 142 new feline admissions to the
Teaching Hospital, University of Pennsylvania
. The prevalence of ATE
does not seem to have changed much in the last four decades. From 1992 to
2001, ATE was diagnosed in 1 in 175 new feline admissions to the University
of Minnesota Veterinary Medical Center (UMVMC)
The last seven decades have brought marked improvement in the
veterinary clinician’s ability to recognize ATE in cats and some improve-
ment in supportive measures for the acute episode but little improvement in
the prevention of ATE. Although options for anticoagulation therapy have
expanded to include a variety of new drugs, optimal thromboprophylaxis
for cats at risk for ATE has yet to be determined.
Pathophysiology
Thrombosis is the formation of a blood clot within the heart or blood
vessels. It is generally accepted that prior to development of ATE in cats, the
thrombus forms within the left side of the heart. Eventually, the thrombus
dislodges and is carried through the systemic vasculature until it becomes
lodged due to the diameter of the thrombus exceeding the diameter of the
* Corresponding author.
E-mail address:
(S.A. Smith).
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvsm.2004.05.006
Vet Clin Small Anim
34 (2004) 1245–1271
vessel lumen. The resulting embolus obstructs the affected artery; perhaps just
as importantly, its arrival initiates a cascade of events that lead to constriction
of collateral vessels. Interestingly, surgical ligation of the distal aorta fails to
reproduce the syndrome that is recognized clinically
. Nevertheless,
experimental induction of distal aortic thrombosis or injection of 5-hydroxy-
tryptamine (serotonin) but not saline or histamine into a surgically created
aortic cul-de-sac results in constriction of collateral vessels and an ischemic
neuromyopathy
. Administration of the serotonin antagonist cyprohep-
tadine before thrombus induction largely prevents the development of paresis
or paralysis
. Similarly, high-dose aspirin administered before surgical
induction of aortic thrombosis preserves collateral circulation
. These
findings provide indirect evidence that release of vasoactive mediators, such
as serotonin or thromboxane, from the thrombus is important in the
pathogenesis of ischemia associated with ATE
.
The assumption that the left heart is the source of emboli is supported by
the observation that 21% of cats with hypertrophic cardiomyopathy (HCM)
have left atrial thrombi identified at necropsy
, and intracardiac thrombi
are fairly commonly identified on echocardiography in cats with cardiac
disease
. The exact mechanism leading to the formation of in-
tracardiac thrombi is unclear, however. Thrombus formation may result from
alterations of the endocardial surface, blood flow, or composition of blood.
This concept, known as Virchow’s triad, provides the cornerstone for
understanding the pathophysiologic factors that predispose patients to
thrombosis. Alterations in any or all of these factors may play a role in
development of ATE in cats.
Alterations of the endocardial surface and blood flow
Disruption of the endocardial surface exposes collagen, von Willebrand’s
factor, and tissue factor, all of which may initiate thrombus formation. A
necropsy study of cats with cardiac disease described cases in which the
endocardium was damaged and cellular debris and fibrin had adhered to the
subendocardial tissues
It has been postulated that atrial enlargement associated with cardiomy-
opathy leads to blood stasis and turbulence and activation of coagulation. A
recent study reported that peak blood flow velocity in the left atrial
appendage was lower in cats with cardiomyopathy (0.31 m/sec) than in
normal cats (0.46 m/sec) and even lower in cats with left atrial thrombi or
concurrent ATE (0.14 m/sec), suggesting that stasis may indeed contribute to
the formation of left atrial thrombi
Most cats presented for ATE with concurrent cardiac disease have some
degree of left atrial enlargement
. Further, the propensity for left
atrial thrombus formation and ATE may be related to the severity of left atrial
enlargement. Specifically, it has been suggested that a left atrial dimension in
systole (LAD
s
) greater than 2.0 cm represents a significant risk for thrombus
1246
S.A. Smith, A.H. Tobias / Vet Clin Small Anim 34 (2004) 1245–1271
formation in cats with heart disease
. The available data on the relative
risk for ATE as a function of left atrial size are unclear, however. In the
UMVMC study, among cats with ATE with all types of cardiac disease, the
LAD
s
was less than 2.0 cm in just over half of the cases
. A study of cats with
HCM and ATE reported a LAD
s
of 1.99
0.49 cm. Thus, consistent with the
UMVMC data, the LADs was less than 2.0 cm in approximately half of the
cats with ATE in that study
. The implication of these data is that heart
disease in a cat of sufficient severity to result in any left atrial enlargement
represents a risk factor for ATE. The increased risk could be caused by
alterations of the endocardial surface, blood flow, or, more likely, both.
There are also some published data to support the notion that risk for ATE
increases as a function of left atrial size. In the study of feline HCM referred to
previously, the average LAD
s
in cats with ATE was significantly larger than
in cats with congestive heart failure (CHF) but without ATE. Further, the
average LAD
s
was significantly larger in cats that developed ATE after the
initial examination than in cats that did not subsequently develop ATE
Alterations of composition of blood
Alterations in blood composition may play a role in development of
intracardiac thrombi. A congenital or acquired coagulation protein or
platelet defect responsible for the thrombotic event is identified in more
than 50% of human patients with thrombosis
. Abnormalities in pro- and
anticoagulant proteins leading to hypercoagulability have not been exten-
sively investigated in cats, however. One study compared 11 cats with cardiac
disease (secondary to hyperthyroidism in nine cats) with normal cats and
reported higher antithrombin (AT) and lower plasminogen activity in those
with cardiac disease
. In another study, no difference was found in plasma
homocysteine concentration between normal cats, cats with cardiomyopa-
thy, and cats with cardiomyopathy and ATE. Plasma arginine and vitamin
B
12
concentrations were significantly lower in cats with cardiomyopathy and
ATE, however. It is unknown whether these abnormalities were the cause of
increased thrombogenicity or occurred as a consequence of ATE
Platelet hyperaggregability in cats with cardiomyopathy may play a role in
the development of ATE. In one study, platelets from cats with cardiomy-
opathy required less adenosine diphosphate (ADP) to induce aggregation
than platelets from normal cats
. In another study, cats with acquired
heart disease (primarily caused by hyperthyroidism) had decreased re-
sponsiveness to ADP and increased responsiveness to collagen
A genetic tendency for thrombogenicity might manifest as a breed pre-
disposition for ATE. Among 195 cats in three retrospective studies, most of
the affected cats were mixed breeds. Affected pure breeds included Abyssi-
nian, Himalayan, Persian, Siamese, Manx, and Maine Coon
. In the
UMVMC study of 127 cats in which breed representation was compared with
the hospital population, the latter three breeds were also reported but at rates
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comparable to the hospital population. Abyssinians, Birmans, and Ragdolls
were overrepresented compared with the hospital population, however
.
This could be the result of an increased genetic risk for cardiac disease or an
unrelated genetic risk for ATE in these breeds. A single family of cats with
HCM has been described in which 75% of cats developed ATE
. These cats
may have all developed ATE because they had a particular form of HCM that
predisposed them to ATE. Conversely, in human beings, families with a high
density of individuals affected by thrombosis usually have an identifiable
genetic risk for thrombosis that involves coagulation protein or platelet
defects
. Consequently, it is possible that this family of cats could also have
carried a genetic abnormality that predisposed them to hypercoagulability.
The notion that some cats may have an inherited or acquired hyperco-
agulability is additionally supported by occasional reports of feline ATE in
which thorough diagnostic evaluations fail to identify an underlying or
predisposing disease
. A genetic abnormality of coagulation could explain
this apparent ‘‘idiopathic’’ thrombosis. Finally, in human beings
and
cats
, a single episode of thrombosis markedly increases the risk of
developing a future thrombus, and in people, an inherited or acquired
coagulation protein or platelet defect can usually be identified.
Risk factors for development of arterial thromboembolism
from the UMVMC study, shows the distribution of associated
diseases in cats presented with ATE
. ATE is most commonly associated
with cardiac disease, and all forms of cardiomyopathy pose a risk for ATE.
No study has reported the relative risk of ATE with specific cardiac diseases
as compared to other diseases, but ATE has been reported to occur in
12%
, 13%
and 28%
of cats with HCM and in 41% of HCM cases
in a necropsy survey
. Several studies have shown that ATE is more
common in male cats than in female cats
, but this is primarily
a result of the greater predisposition of male cats to develop HCM
Neoplasia in cats
, particularly pulmonary carcinoma
, is a risk
factor for ATE, and some cats may have tumor embolism rather than
thromboembolism
. ATE in cats with thyroid disease has been reported in
conjunction with thyrotoxic cardiomyopathy
. Recently, ATE has been
reported in previously hyperthyroid cats that were euthyroid at the time of
the ATE episode and had echocardiographically normal hearts
. Thus,
thyroid disease seems to pose a risk for ATE that is independent of the
cardiac effects of hyperthyroidism.
Clinical presentation and initial evaluation
The clinical signs associated with ATE are referable to acute ischemia of
the tissue supplied by the occluded artery. The location of the occlusion is
dependent on the size of the embolus as well as on the anatomy of the
vascular tree. Because most thrombi that form in the atria reach a reasonably
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large size before embolizing, most thromboemboli lodge in the aorta or one
of its major branches and consequently have an impact on blood supply to
one or more of the limbs. If the embolus settles in the ‘‘saddle’’ location at the
aortic trifurcation, both rear limbs are affected. In the UMVMC study, this
was the most common presentation, occurring in 71% of cases. Smaller
emboli may travel into more distal arteries and affect arterial flow to only one
limb. Unilateral rear limb thromboembolism is much less common and may
affect either limb. Single forelimbs are occasionally affected because of
obstruction of a brachial artery, with right and left limbs affected with similar
frequency. In a few cases, forelimbs and rear limbs are both affected. Rarely,
nonappendicular sites are affected because of thromboembolism of cerebral,
renal, and mesenteric arteries
Because most patients with ATE present with appendicular artery oc-
clusion, the remainder of the discussion focuses primarily on this presentation.
Occlusion of limb perfusion
Most cats with ATE are presented for acute-onset lameness, plegia, or
paralysis of the affected limbs. Affected limbs are virtually always painful,
musculature is frequently firm, and pulses are weak or nonpalpable. Nail
Fig. 1. Disorders in 127 cats presenting with arterial thromboembolism (ATE) to the University
of Minnesota Veterinary Medical Center from 1992 to 2001. In 18 cats (labeled ‘‘unspecified
cardiac’’), necropsy indicated cardiac disease, but no specific diagnosis was made because
antemortem echocardiography was not performed. In 19 cats (labeled ‘‘undetermined’’), no
diagnostic tests were performed. In 3 cats (labeled ‘‘none’’), no disease was identified on
echocardiography or other diagnostic tests. The category ‘‘thyroid disease’’ includes 5 cats first
diagnosed with hyperthyroidism during evaluation for ATE and 7 cats previously diagnosed
with hyperthyroidism. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy;
HOCM, hypertrophic obstructive cardiomyopathy; UCM, unclassified cardiomyopathy. (From
Smith SA, Tobias AH, Jacob KA, Fine DM, Grumbles PL. Arterial thromboembolism in cats:
acute crisis in 127 cases (1992–2001) and long-term management with low-dose aspirin in 24
cases. J Vet Intern Med 2003;17(1):73–83; with permission.)
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beds and pads may appear pale to cyanotic depending on the degree of
ischemia, and affected limbs may feel cooler than nonaffected limbs. Among
episodes of appendicular ATE in which motor function was described by the
attending clinician in the UMVMC study, some motor ability was present in
34% of cases. Forelimb and unilateral rear limb episodes were more likely to
have motor function present
Manifestations of shock and pain
Most cats with ATE show signs of inadequate systemic perfusion and
shock. Shock may be maldistributive because of ischemia of the vascular bed
downstream from the occlusion and the associated release of vasoactive
substances, cardiogenic because of the underlying cardiac disease, or both.
Rectal hypothermia is common, affecting 35%
, 65%
, and 77%
of
cases. Rectal hypothermia occurs even when the distal aorta is not the
obstructed site
and is a manifestation of poor systemic perfusion and
shock. An additional indicator of inadequate systemic perfusion is azotemia.
Blood urea nitrogen (BUN) is increased in 41%
, 47%
, and 55%
of ATE cases. Creatinine elevations are less common at 26%
, 27%
,
and 57%
and also tend to be less severe. An elevated BUN/creatinine
ratio may be associated with prerenal azotemia and suggests inadequate
renal perfusion. Renal artery obstruction can not be excluded as the cause of
azotemia in these cats, however.
Virtually all cats with ATE are in obvious and considerable pain as
evidenced by excitement, frenzy, vocalization, rolling, and panting. In the
UMVMC study, 89% of cats with no radiographic evidence of CHF were
tachypneic or showed open-mouth breathing
. Thus, in many cases,
tachypnea or open-mouth breathing is a manifestation of pain rather than
respiratory distress. This interpretation is supported by the authors’
observation that tachypnea and open-mouth breathing often subside with
analgesic therapy. The frequently observed hyperglycemia (72%
, 85%
, and 93%
) probably results from cortisol and epinephrine release
caused by stress.
Congestive heart failure
Radiographic or necropsy evidence of CHF has been reported in 40%
, 44%
, 65%
, and 66%
of cats with ATE. Some cats without
evidence of CHF on presentation develop CHF while hospitalized
. In the
UMVMC study, cats with CHF had a slightly higher median respiratory rate
(64 beats per minute [bpm], range: 24–200 bpm) than cats without CHF (60
bpm; range: 20–160 bpm). Whereas this small difference attained statistical
significance, it is clearly not clinically relevant, and there was considerable
overlap between the CHF and non-CHF groups
. Thus, the presence of
concurrent CHF in cats with ATE cannot be determined from the respiratory
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rate or pattern alone. Thoracic radiographs are required to determine
whether cats with ATE have concurrent CHF.
Definitive diagnosis and diagnostic approach
A diagnosis of limb ischemia is straightforward in cats that present with the
classic ‘‘five P’s’’: pulselessness, pain, pallor, paresis, and poikilothermia.
Confirming that ATE is the cause of appendicular signs can be challenging in
some cats, however. Whereas the lack of a palpable pulse is suggestive in a cat
with acute loss of limb function, it is not diagnostic for ATE. Pulse
identification is often challenging in forelimbs in cats with normal arterial
flow. Femoral pulses may also not be easy to palpate in obese or un-
cooperative cats, regardless of the level of flow. Poor-quality or absent pulses
may also be caused by systemic hypotension rather than obstructed arterial
blood flow. Additionally, partially obstructed brachial or femoral arteries
result in more subtle signs. Differential diagnoses for acute loss of limb
function should include spinal cord disease (eg, intervertebral disk disease,
spinal neoplasia, embolism, trauma, foreign body), peripheral neuropathies
(eg, diabetic neuropathy), and acute intracranial disorders (eg, embolism,
trauma, shock, neuroglycopenic crisis, toxicity).
As shown in
, most cats with ATE have underlying cardiac disease
. Consequently, the presence of a heart murmur, gallop, or arrhythmia on
auscultation lends support to a diagnosis of ATE as the cause for acute
appendicular signs. Conversely, the absence of auscultable cardiac abnor-
malities does not exclude ATE. Several retrospective studies have reported
that many cats with ATE (30%
, 39%
, and 43%
) do not have
auscultable cardiac abnormalities. Further, in most cats with ATE (76%
77%
, 89%
), acute appendicular signs are the first indication of
underlying cardiac disease. Because of the frequent presence of occult cardiac
disease in cats with ATE and the strong association between ATE and cardiac
disease, a thorough cardiac evaluation is appropriate for any cat in which
ATE is suspected.
Simple diagnostic evaluations may lend additional support to a diagnosis
of appendicular ATE. In cats with plegia and nonpalpable pulses, evaluation
of arterial flow by Doppler is extremely useful. ATE is probable if arterial
flow cannot be detected by Doppler. Because appendicular arteries may be
partially occluded, however, the presence of arterial blood flow does not
exclude ATE as the cause of limb paresis.
As a result of muscle ischemia, cats with ATE almost invariably have
elevations of serum enzymes released from damaged muscle cells. Increased
serum aspartate aminotransferase has been reported in 83%
, 89%
and 99%
of cats with ATE. Serum creatine phosphokinase, although
reported in relatively few cases, is also usually elevated (80%
, 100%
often to a marked degree. Support for ATE may also be obtained by
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comparing a venous blood sample acquired from the affected limb with that
acquired from a central vein. In one study, local venous glucose (50
25 mg/
dL) was significantly lower than central venous glucose (182
89 mg/dL) in
cats with appendicular ATE and local venous glucose was markedly lower
than central venous glucose in every case. Local venous lactate (10.7
2.7
mmol/L) was significantly higher than central venous lactate (2.1
0.8 mmol/
L)
. The specificity of serum muscle enzyme elevations, decreased local
glucose concentration, and increased local lactate concentration as a di-
agnostic tool to distinguish ATE from other causes of appendicular signs in
cats has not been critically evaluated. Nevertheless, the high prevalence of
muscle enzyme elevations in cats with ATE suggests that these are sensitive
discriminatory tests. Consequently, ATE is not likely to be the cause of
appendicular signs if these serum muscle enzyme concentrations are within
the reference range.
Routine coagulation tests are generally unremarkable in cats with ATE
. In cats in which coagulation panels were performed before therapy,
75% were within the reference range
. Markers of active fibrinolysis (eg,
D-dimers, fibrin[ogen] degradation products) may be elevated
, especially
after administration of thrombolytic therapy
. Serum chemistry profiles
frequently disclose electrolyte abnormalities, acidosis, and azotemia. Com-
mon electrolyte abnormalities are hypocalcemia, hyperphosphatemia, hypo-
kalemia, hyperkalemia, and hyponatremia
More expensive and invasive diagnostic tests are occasionally necessary to
confirm a diagnosis of ATE. Radiography, ultrasonography, angiography,
and nuclear scintigraphy may all be used to evaluate the obstructed site
further. These imaging modalities may provide additional information,
particularly when other diagnostics have failed to identify an underlying
cause for loss of perfusion. These techniques may be useful for evaluation of
the vessel wall at the site of an obstruction, especially in cases in which the
cause of an obstruction is local rather than embolic (eg, neoplastic infiltration,
foreign body, vasculitis). Nuclear scintigraphic perfusion scans may also
provide prognostic information regarding the likelihood of recovery of limb
perfusion
Management of the acute arterial thromboembolism episode
The ultimate goal of management of the acute ATE episode is to
encourage survival of the affected limb(s) and the patient. The primary
therapeutic objectives during the initial crisis are to provide rest and
analgesia, improve systemic perfusion, provide additional support, and treat
CHF if present. Resolution of limb ischemia is of secondary importance,
especially because efforts aimed at thrombus dissolution may adversely affect
patient survival
. Therapy aimed at preventing further thrombus
formation and extension is probably indicated.
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Analgesia
The negative effects of pain on patient morbidity and mortality are well
documented. Clearly, analgesic therapy is essential for cats with ATE. The
particular analgesic that best addresses the pain of ATE in cats has not been
determined, and the use of a variety of analgesics, including torbutrol,
morphine, oxymorphone, and fentanyl, has been reported
. An extensive
discussion of analgesic therapy in cats is outside the scope of this article. For
an excellent review of analgesics for use in critically ill cats, the reader is
referred to the article by Glowaski
.
Systemic perfusion and additional support
Improving systemic perfusion is one of the most important goals in
managing the acute crisis in ATE patients. Because these patients are often
hypothermic, application of heat sources to increase body temperature has
been advocated
. Hypothermia is a manifestation of poor systemic
perfusion and shock, however. External warming causes peripheral vasodi-
lation, shunts blood away from vital core organs, and, consequently, worsens
core perfusion. External warming is thus not indicated unless hypothermia
persists after systemic perfusion has been addressed.
Correcting systemic perfusion is a significant challenge in these patients,
because the precise pathophysiology of shock is seldom clear. Fluid therapy
is indicated for the dehydrated patient and those that do not have CHF.
Conversely, administering fluids to any patient with cardiac disease must be
performed with the utmost caution. Positive inotropes may have a role in
these patients, especially in cases in which depressed systolic cardiac function
has been documented echocardiographically. Nutritional support is neces-
sary in those cases that show persistent anorexia. Clearly, more research is
needed to determine the ideal approach to managing systemic perfusion and
providing additional support to cats with ATE.
Administration of acepromazine to decrease anxiety and to improve
arterial flow to the ischemic area (by its vasodilatory effect) has occasionally
been recommended
. No study has evaluated the use of this drug in
cats with ATE. Further, this hypotensive drug has the potential to exacerbate
shock. On the other hand, in the authors’ opinion, the use of acepromazine is
inappropriate for cats with ATE.
Congestive heart failure management
In cats with ATE, tachypnea does not reliably predict the presence of
CHF, and this presents a therapeutic dilemma. Many veterinary clinicians
would initially prefer to manage a cat with ATE and showing tachypnea or
another abnormal respiratory pattern with a diuretic, such as furosemide,
based on the assumption that the cat has concurrent CHF. Cats with ATE
presenting with abnormal respiratory rates and patterns should not be
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treated for CHF before radiography, however, because the volume reduction
and vasodilation that result from routine CHF medications worsen systemic
perfusion. In the UMVMC study, slightly fewer than half (44%) of the cats
with ATE were suffering from concurrent CHF
. Consequently, thoracic
radiography should be performed before administration of furosemide to
any cat with ATE. If CHF is present, appropriate therapy is no different from
that administered to cats presenting with CHF without ATE. Cage rest,
oxygen supplementation, thoracocentesis in cats with clinically significant
pleural effusion, furosemide, and, possibly, venodilators should be used as
appropriate for the patient.
Cage rest in an oxygen-enriched environment is not detrimental to a cat
with ATE that has an abnormal respiratory rate and pattern caused by stress
and pain rather than by CHF. It is also beneficial for patients with
hypoxemia caused by pulmonary edema and pleural effusion. Consequently,
oxygen supplementation, preferably via an oxygen cage, is indicated for all
patients with ATE that present with respiratory signs.
Thrombolytic therapy
As mentioned in the introductory paragraph to this section, the authors
do not favor the use of thrombolytic therapy in the management of the acute
ATE episode. The following information is provided for completion and to
provide the basis for our opinion that the routine use of thrombolytic agents
in cats with ATE cannot be recommended based on currently available
information.
No controlled clinical trials have evaluated the use of thrombolytic agents
in cats with ATE, although several case series have been reported. A variety of
large clinical trials in human patients have compared the efficacy and safety of
tissue type plasminogen activator, streptokinase (SK), and urokinase for
treatment of coronary artery occlusion, and there are no clinically important
differences in efficacy between the three drugs
Tissue type plasminogen activator
Tissue type plasminogen activator is a naturally occurring glycoprotein
that catalyzes the conversion of plasminogen to plasmin in the presence of
fibrin (
). Human recombinant tissue type plasminogen activator is
available for clinical use. As a nonfeline protein, it has the potential to be
antigenic. The drug is supplied in a 50-mg vial, costing approximately $1100.
Information regarding the use of tissue type plasminogen activator for the
treatment of ATE in cats is limited to a single study involving six cases. In
that study, the drug was administered intravenously at a dosage of 3.0 to 8.0
mg/kg. Perfusion was restored in 64% of the affected limbs, and the rate of
survival to discharge was 50%. Reported complications were hyperkalemia,
acidosis, mild hemorrhage, and fever
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Streptokinase
SK is a bacterial protein isolated from Lancefield group C strains of b-
hemolytic streptococci, a human-specific pathogen
. When administered
systemically, it causes thrombolysis by accelerating activation of fibrin-
bound plasminogen to plasmin (see
. SK variants exhibit a limited
spectrum of function against mammalian plasminogens. Cleavage action is
potentially optimal for, or even restricted to, plasminogen from the species
normally infected by the bacterium that produces the SK
. Consequently,
SK from the human-specific pathogen may be a much less effective
thrombolytic agent in cats than in people. As a bacterial protein, it has the
potential to be antigenic. Administration to human beings has resulted in
antibody development and anaphylactic reactions
. The drug is supplied
in 250,000- and 750,000-U vials, costing approximately $100 per 250,000 U.
The 250,000-U vial is diluted in physiologic saline, 5 mL, and then further
Fig. 2. The fibrinolytic pathway. For simplicity, the pathway inhibitors have been omitted.
Products of the coagulation and contact pathways initiate production of the active enzymes: two-
chain urokinase plasminogen activator (tcu-PA) and two-chain tissue plasminogen activator (tct-
PA). These enzymes cleave plasminogen to its active enzyme, plasmin. Plasmin can then cleave
additional molecules of single-chain urokinase plasminogen activator (scu-PA) and single-chain
tissue plasminogen activator (sct-PA), producing a positive feedback loop. Plasmin’s primary
action is to degrade fibrin to its degradation products. Plasmin’s activity is not exclusive to cross-
linked fibrin (x-l-fibrin). It can also degrade non–cross-linked fibrin and fibrinogen.
Consequently, the presence of elevated fibrin and fibrinogen degradation products (FDPs) is
not specific for lysis of fibrin associated with stable clots. In contrast, D-dimers are only produced
from lysis of stable cross-linked fibrin. The site of action of streptokinase (SK) is included because
of the pharmacologic use of this enzyme, but it is not a naturally occurring part of the mammalian
fibrinolytic system. FIIa, thrombin or activated factor II; FXIIIa, activated factor XIII.
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diluted to 50 mL to create a 5000- U/mL solution that can be infused with
a syringe pump.
SK successfully lysed experimentally induced thrombi in normal cats. In
that study, no adverse effects during infusion were noted, but all cats were
euthanized shortly after the infusion was complete
. A prospective study of
thrombolysis with SK in eight cats with ATE (n = 6) and left atrial thrombi
(n = 2) evaluated a loading dose of 90,000 U administered intravenously over
30 minutes, followed by a constant rate infusion of 45,000 U/h for 3 to 6
hours. Adverse effects included neurologic signs, respiratory distress, and
electrolyte dyscrasias. All eight cats died during the constant rate infusion
.
A retrospective study reviewed 46 cats with ATE that had been treated with
SK, most of which received a 90,000-U loading dose followed by a constant
rate infusion of 45,000 U/h for 3 to 6 hours. In 54% of cases, arterial pulses
returned, and in 30% of cases, motor function returned within 24 hours. The
rate of survival to discharge from the hospital was 33%. Reported
complications were hemorrhage (24%) and hyperkalemia (35%), with
metabolic acidosis in all cats in which acid-base status was evaluated
.
In the UMVMC study, the rate of survival to discharge was 45% among
83 cats with ATE managed without thrombolytic therapy (all treated with
heparin and/or aspirin). Overt bleeding was not observed in any of these
patients, although 2 cats (2%) had other evidence of hemorrhage. There was
no significant difference in survival to discharge when the population of 46
cats treated with SK in the study cited previously was compared with the
UMVMC population treated without SK. Adverse effects in the SK-treated
cats were much more common, however
.
In cats with ATE, ischemia of tissues distal to the thrombus is usually severe
because of the massive amount of appendicular tissue affected by the arterial
occlusion and the potential delay in presentation of cats with ATE. The
frequency of hyperkalemia, acidosis, and death suggests that reperfusion
injury is a serious problem in cats treated with thrombolytic agents. In human
beings, thrombolytic therapy is recommended in acute appendicular arterial
occlusion when associated with profound limb ischemia, except when
revascularization of the ischemic limb could jeopardize patient survival
.
Clearly, the use of thrombolytics in cats with ATE has the potential to cause
fatal reperfusion injury. The frequency of hemorrhagic complications is also
quite high. Additionally, the use of these agents is associated with significant
cost. Given these factors as well as the lack of evidence for improved outcome
in cats treated with thrombolysis compared with cats managed without
thrombolysis, the routine use of thrombolytic drugs in cats with ATE is
difficult to justify.
Anticoagulant therapy
Anticoagulants are recommended during the acute crisis associated with
ATE. The aim of such therapy, at least in theory, is to prevent or reduce
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thrombus extension and the consequent further reduction in arterial flow as
well as to reduce the risk of additional intracardiac thrombus formation.
Unfractionated heparin
Unfractionated (UF) heparin is a heterogeneous mixture of sulfated
mucopolysaccharides. It catalyzes the binding of AT and heparin cofactor II
to various coagulation factors, preventing their participation in the co-
agulation cascade (
The authors recommend the use of intravenous or subcutaneous heparin
therapy during the acute phase of ATE because of the rapidity of onset of
anticoagulation but recognize that the efficacy of heparin in the treatment of
cats with ATE has not been established. In one study of cats treated with SK,
cats additionally receiving UF heparin were more likely to survive, although
the difference did not attain statistical significance
. Heparin is rapidly
absorbed from subcutaneous injection sites
. It should not be adminis-
tered intramuscularly because of the risk of injection site hemorrhage.
No outcome-based studies have evaluated any UF heparin dosage
regimen for cats with ATE, and recommendations are highly variable. In
the UMVMC study, some cats received initial intravenous therapy at doses
Fig. 3. Mechanism of action of heparin. For simplicity, only the activated forms of the
coagulation factors have been included and inhibitors other than antithrombin (AT) have been
omitted. Heparin (H) binds to AT, inducing a conformational change that allows AT to form
a stable inhibitory complex with various coagulation factors, removing them from further
participation in the coagulation cascade. Thrombin, or activated factor II (FIIa), and activated
factor X (FXa) are most significantly inhibited by unfractionated (UF) heparin. The mechanism
of action of low-molecular-weight heparin is similar to that of UF heparin, except that it is too
short to provide the necessary bridge to FIIa. FXIIa, activated factor XII; FXIa, activated
factor XI; FIXa, activated factor IX; FVIIIa, activated factor VIII; FVa, activated factor V;
FVIIa, activated factor VII; TF, tissue factor; FXIIIa, activated factor XIII.
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ranging from 75 to 500 U/kg
. In various studies, subcutaneous UF
heparin was administered at dosages ranging from 10 to 300 U/kg every 6 to
12 hours. Most cats received either 50 to 100 U/kg (‘‘low-dose’’) or 200 to 250
U/kg (‘‘high-dose’’) every 6 to 8 hours
Clinical trials in people indicate that a plasma heparin concentration
(measured by chromogenic factor Xa assay) of 0.35 to 0.70 U/mL is
associated with the greatest clinical efficacy and least hemorrhagic complica-
tions
. In normal cats, a UF heparin dosage of 300 U/kg administered
subcutaneously every 8 hours most consistently provides this plasma
concentration
. In cats with ATE, however, there is wide individual
variation in heparin pharmacokinetics, with some cats requiring much higher
dosages (up to 475 U/kg) to maintain plasma concentrations within the
therapeutic range recommended for human beings
The authors’ current UF heparin dosage recommendation is 250 to 300 U/
kg administered subcutaneously every 8 hours. The first dose is administered
intravenously in cats showing signs of shock. It has been suggested that UF
heparin therapy should be monitored and titrated using activated partial
thromboplastin time (aPTT) or activated clot time (ACT). The recommen-
ded target is a 1.5- to 2.5-fold aPTT prolongation when compared with
normal plasma control or prolongation of the ACT by 15 to 20 seconds
. These target aPTT and ACT prolongations with heparin therapy
should, at best, be regarded as rough guidelines. There are wide variations in
the sensitivity of aPTT reagents and in individual patient aPTT response to
a given heparin concentration, which results in inconsistencies in degree of
anticoagulation measured with this approach. The ACT is even less
predictive of plasma heparin concentration
. Further, in one report
of cats with ATE, a 1.5- to 2.5-fold prolongation in aPTT occurred at plasma
concentrations in most cases below the recommended therapeutic range for
human beings
. Consequently, the authors do not routinely monitor
aPTT or ACT in cats being treated with UF heparin. Plasma heparin
concentration measured by chromogenic factor Xa assay would be a more
accurate method to titrate the heparin dose, but the test is not widely
available at present. Additional information about the chromogenic factor
Xa assay is provided below.
Low molecular weight heparin
Small heparin polysaccharides are unable to bind thrombin (activated
factor II [FIIa]) and AT simultaneously. Consequently, low molecular weight
(LMW) heparin is unable to catalyze the inactivation of thrombin by AT but
retains the ability to enhance the inhibition of activated factor X (FXa) and
other coagulation factors by AT (see
). In human beings, for equivalent
antithrombotic effect, LMW heparin is associated with less bleeding than UF
heparin and also requires less frequent administration
. Because frequency
of administration is not generally an issue in hospitalized patients, LMW
heparin offers no practical advantage over UF heparin for short-term
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anticoagulation in cats with ATE. The reader is referred to the section on
long-term management for more information on LMW heparin.
Aspirin
Aspirin (acetylsalicylic acid) is a cyclooxygenase inhibitor that irreversibly
inhibits the production of thromboxane A
2
(TXA
2
) in platelets. Because
TXA
2
is a potent platelet aggregator and vasoconstrictor, aspirin decreases
platelet aggregability and vasoconstriction in response to injury. Aspirin
administered during or immediately after acute myocardial infarction is
associated with improved outcomes in people
. The pathogenesis of the
obstruction is different, however, because human coronary arteries are
occluded by thrombi that form locally at the site on an atherosclerotic
plaque, whereas cats with ATE present with thrombi that have embolized
from the heart to an arterial site. No controlled trials have evaluated the
efficacy of aspirin for acute management of ATE in cats, but in an
experimental model, cats given aspirin, 650 mg, administered orally 1 hour
before thrombus occlusion of the aorta had better collateral circulation than
non–aspirin-treated controls
. The authors usually initiate aspirin
therapy as soon as oral drug administration becomes possible, and preferably
once the cat has begun eating so as to minimize gastrointestinal irritation.
Further information about the dose and frequency of administration of
aspirin is provided below. Heparin therapy is discontinued 2 to 3 days after
the patient is stable and receiving aspirin.
Short-term outcome
Arterial thromboembolism in cats virtually always occurs as a devastating
complication of significant underlying disease. It usually results in severe
hemodynamic compromise that is difficult to manage as well as severe serum
electrolyte and acid-base abnormalities. Arterial thromboembolism is thus
inevitably associated with a poor prognosis. Reported rates of survival to
discharge are 33%
, 35%
, 37%
, and 39%
. Euthanasia is
common at 24%
, 29%
, and 35%
Most reports do not distinguish between euthanasia with no attempt to
treat versus euthanasia as a result of deterioration or lack of response to
treatment. Clearly, this is an important distinction because it introduces the
influence of clinician bias and owner commitment in the face of a disease with
a poor prognosis. In the UMVMC study, survival to discharge was 45%
when cats that were euthanized with no attempt to treat were excluded from
the analysis
. Further, survival in that study gradually improved over the
10 years reviewed, with 73% of cats treated for acute appendicular ATE in
the year 2001 surviving to discharge.
Significant differences between survivors and nonsurvivors have been
reported for rectal temperature
and heart rate
, with both being
higher among survivors. Having only one limb affected
and the presence
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S.A. Smith, A.H. Tobias / Vet Clin Small Anim 34 (2004) 1245–1271
of motor function
were significantly more frequent among survivors.
Serum phosphorus concentration was slightly but significantly higher among
nonsurvivors
. Data from the 127 cats with acute ATE that comprised the
UMVMC retrospective study were used to develop a logistic regression model
to predict the probability of survival to discharge. Once rectal temperature
was included in the model, no other variable improved the accuracy of
prediction. The model, presented in
, predicts a 50% probability of
survival at a rectal temperature on admission of 98.9(F. It correctly classified
67% of survivors and 79% of nonsurvivors in the UMVMC study
. Rectal
temperature is easily measured and provides important prognostic informa-
tion. Its prognostic value probably stems from the fact that a low rectal
temperature, as well as other variables (eg, azotemia), reflects compromised
overall hemodynamic status.
Long-term management
Underlying disease
Because most cats with ATE have underlying cardiac disease, appropriate
therapy for manifestations of the cardiac disease is necessary. Similarly,
therapy for cats with neoplasia and any other concurrent and underlying
Fig. 4. Logistic regression model predicting survival probability to discharge based on rectal
temperature at admission. The equation for the predictive model is:
P
¼
1
1
þ e
47:58593þ0:4811605
T
where P is survival probability and T is rectal temperature. (From Smith SA, Tobias AH, Jacob
KA, Fine DM, Grumbles PL. Arterial thromboembolism in cats: acute crisis in 127 cases (1992–
2001) and long-term management with low-dose aspirin in 24 cases. J Vet Intern Med
2003;17(1):73–83; with permission.)
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S.A. Smith, A.H. Tobias / Vet Clin Small Anim 34 (2004) 1245–1271
diseases should be provided. A discussion of these therapies is beyond the
scope of this article, however.
Thromboprophylaxis
Aspirin
Thromboprophylaxis with aspirin is commonly recommended for cats at
risk for ATE at a dose of 81 mg per cat administered orally every 48 to 72
hours
. Aspirin has been prescribed at this dose for decades, but
clinical evidence suggests that its efficacy for preventing ATE is questionable
. In human beings, a low aspirin dosage (1 mg/kg every 24 hours)
effectively prevents recurrent thrombosis in a variety of disorders
. This
low dose may be effective, in part, because it is sufficient to inhibit platelet
cyclooxygenase irreversibly (thereby limiting platelet aggregation) although
it spares endothelial prostaglandin I
2
synthesis. Endothelial prostaglandin I
2
is a vasodilator, and it inhibits platelet aggregation outside the area of injury,
thereby limiting thrombus growth. It remains to be determined whether or
not a lower dosage of aspirin benefits cats at risk for ATE. Nevertheless,
a recent report of long-term therapy in 24 cats with previous ATE showed
that aspirin at a dose of 5 mg per cat administered every 72 hours
was associated with similar or lower rates of ATE recurrence when com-
pared with other thromboprophylactic therapies, and adverse effects were
minimal
.
The use of aspirin requires no specific monitoring but it has the potential
to cause gastrointestinal side effects, including anorexia, nausea, vomiting,
hematemesis, and ulceration at any dosage. Aspirin has the distinct
advantages of being inexpensive and orally administered. It is readily
available, although the low aspirin dose requires compounding.
Warfarin
The vitamin K–dependent coagulation proteins (II, VII, IX, and X) and
regulatory proteins (protein C and protein S) are synthesized as inactive
prozymogens. These prozymogens are converted to their active forms by the
enzyme vitamin K epoxide reductase. Warfarin exerts its anticoagulant effect
by inhibiting this enzyme
Anecdotal reports of the use of warfarin in cats at risk for ATE suggest
a starting dose of 0.5 mg per cat per day
. The pharmacokinetics and
pharmacodynamics of warfarin in normal cats indicate an appropriate initial
dose of 0.06 to 0.09 mg/kg/d, although there is marked individual variation
and the drug has a narrow therapeutic index
. The pharmacodynamics
in sick cats at risk for ATE have not been evaluated. Warfarin is highly
protein bound (primarily to albumin) in cats
, and minor shifts in
albumin status or concomitant use of other protein-bound drugs may result
in massive changes in the degree of anticoagulation.
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Warfarin (Coumadin) is supplied as a 1-mg tablet, but the drug is
unequally distributed within the tablet. Tablets should not be broken for
administration but crushed and mixed well
. The powder can be weighed
out by a compounding pharmacist and used to fill gelatin capsules.
Prothrombin time (PT) is the laboratory test recommended for monitor-
ing warfarin therapy, and it must be adjusted for variations in thrombo-
plastin reagent and laboratory technique. The laboratory should provide
a method-specific index of responsiveness of the thromboplastin reagent,
called an international sensitivity index (ISI). An international normaliza-
tion ratio (INR) is then calculated as follows: INR = (Patient PT/Control
PT)
ISI
.
In human beings, the recommended therapeutic range for the INR
depends on the condition predisposing to thrombosis. No studies have
prospectively evaluated the effectiveness of any warfarin regimen in animals.
In cats, an INR of 2.0 to 3.0 is generally recommended
, because this level
of anticoagulation is associated with minimal hemorrhage and reasonable
efficacy in people. Limited experience with the use of warfarin in cats suggests
that although an INR of 2.0 to 3.0 is an ideal goal, a wider INR range may
have to be acceptable to the veterinary clinician. Further, although
monitoring warfarin by means of the INR is well established in human
beings, its validity in feline medicine has not been critically evaluated.
Because the ISI is determined using samples from human beings, this measure
of thromboplastin response may not apply to cats.
Warfarin should only be administered once anticoagulation has been
achieved with heparin, because hypercoagulability may develop when
warfarin therapy is initiated as a result of decreased protein C and protein
S levels
. Warfarin and heparin therapy should overlap for at least 4 to 5
days. No validated recommendations for monitoring warfarin therapy in
cats are available, but anticoagulation monitoring should be performed
frequently, especially when warfarin therapy is initiated. When warfarin
therapy is initiated in human patients, an INR is determined daily while the
warfarin dose is being titrated until the INR is in the therapeutic range for 2
consecutive days. The testing intervals are then gradually extended to weekly
and then to monthly in those patients on long-term therapy in whom test
results have been stable
. The timing of blood sample collection in
relation to the administration of the drug is unimportant, because the PT is
dependent on coagulation factor concentrations at the time of sampling
rather than on plasma warfarin concentration. Anticoagulation status
should be re-evaluated with any change in concurrent drug therapy, because
many drugs affect warfarin-protein binding.
Potential adverse effects of warfarin include hemorrhage, which may be
severe and possibly fatal, skin necrosis (not reported to date in cats), and
teratogenicity. Warfarin is relatively inexpensive, but the costs associated
with its use in cats are much higher than aspirin because of the requirement
for drug reformulation and frequent INR monitoring.
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Heparin
Because UF heparin requires frequent parenteral administration to
achieve consistent anticoagulation, it is generally not suitable for long-term
therapy. In human beings, LMW heparin requires less frequent parenteral
administration, but there is little published information about the use of
LMW heparin in cats. A small study of dalteparin (Fragmin) in normal cats
given at a rate of 100 or 200 U/kg every 24 hours for 5 days showed that the
lower dosage resulted in plasma heparin concentrations in the therapeutic
range. This conclusion was based on chromogenic factor Xa assays
performed on plasma collected 4 hours after the fifth injection. In one cat
in which the plasma heparin concentration was measured at 2, 8, 12, and 24
hours after injection, the concentration fell below the therapeutic range by 8
hours
. A separate study of the pharmacokinetics of enoxaparin (Love-
nox) in normal cats suggested an initial dose of 100 U/kg administered
subcutaneously every 24 hours (D.L. Kellerman, DVM, Manhattan, KS,
personal communication, 1997). One of the authors has attempted long-term
therapy with enoxaparin starting at 100 U/kg administered subcutaneously
every 24 hours in three clinical feline patients. Chromogenic factor Xa assays
disclosed that the dosage was appropriate but that the administration
interval was not. Two cats required enoxaparin administration every 12
hours, and one required administration every 8 hours to maintain plasma
heparin concentrations within the therapeutic range (S.A. Smith, DVM, MS,
unpublished data). Thus, although there is little information available on the
use of LMW heparin in cats, current evidence suggests that dalteparin and
enoxaparin require more frequent parenteral administration than every 24
hours. Further, the pharmacokinetics may be variable in cats at risk for ATE,
as has been recognized for UF heparin
Because LMW heparin does not bind to thrombin, it has little impact
on the aPTT. Consequently, the chromogenic factor Xa assay is required
to measure plasma heparin concentrations when LMW heparin is used.
This assay is available commercially through the Cornell University
Coagulation Laboratory. Submission information may be obtained at:
http://web.vet.cornell.edu/public/coaglab/heparin.htm
. Based on studies
in human beings and experimental animals as well as on personal
experience with several cats (S.A. Smith, DVM, MS, unpublished data),
it seems that once an appropriate dosage regimen has been determined for
an individual, the plasma heparin concentration remains fairly constant
over time.
Potential adverse effects of heparin therapy include hemorrhage,
thrombocytopenia (not reported in cats to date), and osteoporosis (seen
in one case treated with UF heparin for 18 months by one of the authors).
In human beings, all the adverse effects seem to be less frequent with LMW
heparin
. UF heparin is relatively inexpensive. Markedly higher costs
associated with the use of LMW heparin may limit its use in veterinary
patients.
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Other platelet antagonists
Ticlopidine and clopidogrel are thienopyridine derivatives. Ticlopidine
has no direct platelet effects, but extensive hepatic biotransformation results
in active metabolites in human beings. Clopidogrel and the active metabolite
of ticlopidine irreversibly antagonize ADP receptors on platelet membranes,
interfering with primary and secondary platelet aggregation. Ticlopidine at
dosages of up to 100 mg per cat per day failed to alter feline platelet function,
possibly because of lack of hepatic biotransformation to the active
metabolite
. Clopidogrel administered orally to normal cats at 18.75 to
75 mg per cat per day significantly decreased in vitro platelet aggregation in
response to ADP and collagen and significantly increased oral mucosal
bleeding time. The maximal effect was reached within 3 days of initiating the
drug and resolved within 7 days of discontinuing the drug. No adverse effects
were noted
. The use of clopidogrel for thromboprophylaxis in cats at risk
for ATE has not been reported.
Eptifibatide is a glycoprotein IIb/IIIa receptor antagonist that inhibits
feline platelet aggregation in vitro
. At doses required to maintain platelet
inhibition in normal cats, however, the drug was associated with idiosyn-
cratic and unpredictable circulatory failure and sudden death. Use of
eptifibatide is consequently not recommended in cats
. A drug with
a similar mechanism of action, abciximab, was evaluated in a model of
arterial injury in cats. Cats received aspirin alone or aspirin and abciximab.
Cats in the aspirin and abciximab group showed significantly greater
inhibition of platelet function and less thrombus formation than those
receiving aspirin alone
Choosing an anticoagulant
No prospective studies have been conducted to determine the safest and
most effective anticoagulant for thromboprophylaxis in cats.
summarizes some of the results from several retrospective studies of ATE in
cats in which a variety of anticoagulants were prescribed. A few cases (n = 5)
are included from one study that reported long-term survival, without ATE
recurrence in some cases, despite the lack of any anticoagulation
. The case
numbers reported in these studies are small, making interpretation of the
survival data difficult. Inclusion criteria vary between studies, and survival
times are thus not readily comparable. Nevertheless, it is apparent that the
currently available survival data do not clearly support the use of a particular
anticoagulant over any of the others. Consequently, the choice of anticoag-
ulant for thromboprophylaxis in cats must be based on factors other than
survival, such as ease of administration and monitoring, incidence of adverse
side effects, and cost.
Given the lack of a demonstrable survival benefit, the need for repeated
examinations, the cost of anticoagulation monitoring, and the risk of fatal
hemorrhage, the use of warfarin in cats at risk for ATE is difficult to justify.
UF and LMW heparin both require parenteral administration at least once
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S.A. Smith, A.H. Tobias / Vet Clin Small Anim 34 (2004) 1245–1271
Table 1
Results of several thromboprophylactic protocols prescribed in various studies of arterial thromboembolism in cats
Drug
n
MST
Recurrence
rate (%)
If
recurrence,
% fatal
Adverse
effects
Reference
Notes
Standard-dose
aspirin
8
61
NR
NR
NR
Population composed of cats with
hypertrophic cardiomyopathy that
survived [24 hours after presentation
18
149
28
83
22%
gastrointestinal signs
Population composed of cats that
survived to discharge from the hospital
10
184
30
67
NR
Includes 3 cats that died \7 days
after presentation
Low-dose
aspirin
24
105
25
40
4%
gastrointestinal signs
Population composed of cats that survived
to discharge from the hospital
Warfarin
12
51
45
NR
17%
fatal hemorrhage
Population composed of cats that survived
to discharge from the hospital; all cases
initially treated with streptokinase
17
69
24
100
18% hemorrhage
18
44
63
11% fatal hemorrhage
Dalteparin
14
255
43
24
NR
None
5
450
40
50
Abbreviations:
MST, median survival time; n = number of cases; NR, not reported.
a
Standard dose was 81 mg per cat administered every 2 to 3 days.
b
Low dose was 5 mg per cat administered every 3 days.
c
Not different when survival curves were compared by log-rank test.
d
Not different when survival curves for standard-dose aspirin and low-dose aspirin were combined and compared by log-rank test with survival curve for
warfarin.
e
Not different when survival curves were compared by log-rank test.
f
The population only included those cases for which follow-up information was available. Cases that were lost to follow-up were excluded rather than
censored. Consequently, MST is not reported, because survival analysis could not be performed correctly.
1265
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Smith,
A.H.
Tobias
/
Vet
Clin
Small
Anim
34
(2004)
1245–12
71
a day, and usually more frequently than that. Further, the cost of LMW
heparin is likely to limit its use for long-term thromboprophylaxis in cats.
Among the various platelet antagonists, aspirin is associated with gastroin-
testinal side effects, but this is more common at a dose of 81 mg per cat
administered every 48 to 72 hours than at the low dose of 5 mg per cat
administered every 72 hours. Further, low-dose aspirin is inexpensive and
requires no monitoring. At present, other platelet antagonists are too
investigational to recommend for routine use. Consequently, the authors’
current preference for thromboprophylaxis in cats is aspirin at a dose of 5 mg
per cat administered every 72 hours. The authors also recognize that it
remains to be established whether low-dose aspirin or any other anticoag-
ulant provides a significant morbidity and mortality benefit over not
prescribing thromboprophylaxis at all in cats at risk for ATE.
Long-term prognosis
Return of limb function
Affected limbs have the potential for complete return of function.
Nevertheless, neurologic function may not return, tendon contracture may
occur, or ischemia may result in tissue necrosis, necessitating wound
management, skin grafting, or amputation. Fortunately, permanent limb
damage is the exception rather than the rule, although time to complete
recovery may be days, weeks, or even months
. In the UMVMC study,
among 44 cats that were discharged after recovering from their acute ATE
episode, 2 (5%) developed limb necrosis requiring that the limb be amputated,
2 (5%) had minor tissue necrosis requiring wound management, and 1 (2%)
developed limb contracture
Recurrence of arterial thromboembolism
lists the recurrence rates of ATE in cats treated with a variety of
anticoagulants. Recurrent ATE occurred in 24% to 45% of cats in the
various studies, with some cats experiencing multiple episodes. Recurrent
episodes are often fatal or prompt euthanasia
Survival predictions
In the UMVMC study, the presence or absence of concurrent CHF during
an acute ATE episode had no significant effect on survival to discharge. The
presence of concurrent CHF did have a significant deleterious effect on long-
term survival after discharge, however. Cats with CHF during the initial
ATE episode had a median survival time of 77 days, whereas cats without
concurrent CHF had a median survival time of 223 days. No cat with CHF
and ATE survived longer than 254 days. These findings suggest that most
cats with ATE have a poor long-term prognosis primarily because they are
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S.A. Smith, A.H. Tobias / Vet Clin Small Anim 34 (2004) 1245–1271
Box 1. Recommendations for cats presented acutely with
arterial thromboembolism
Physical examination, including rectal temperature for
prognostic information
Emergency management
Placement in oxygen-enriched environment if respiratory rate
or pattern is abnormal
Administration of analgesic therapy (eg, morphine,
oxymorphone, torbutrol, fentanyl)
Initial diagnostics
Thoracic radiographs to determine if pulmonary edema or
pleural effusion is present
Serum chemistry to assess electrolyte status and check for
azotemia
Urine specific gravity before any furosemide or fluid therapy
Follow-up diagnostics
Complete cardiac workup, including echocardiography and
electrocardiography
Thyroid status if age appropriate
If no evidence of cardiac disease, additional diagnostics to
assess for occult neoplasia
In-hospital short-term management
Congestive heart failure management if indicated by results of
thoracic radiographs
Heparin (unfractionated), 250 to 300 U/kg, administered
subcutaneously every 8 hours (first dose administered
intravenously if evidence of shock). Because of the lack of
predictive value of the activated clot time or activated partial
thromboplastin time, we do not routinely monitor heparin
therapy at the University of Minnesota Veterinary Medical
Center. Ideally, the chromogenic activated factor X assay
should be performed.
Intravenous fluid therapy if clinically indicated and patient not
in congestive heart failure
Nutritional support (generally by nasoesophageal tube
feeding) if clinically indicated
Long-term management
Aspirin, 5 mg per cat, administered orally every 3 days initiated
as soon as the patient is eating.
Discontinue heparin gradually over 2 to 3 days after patient is
stable and receiving aspirin
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S.A. Smith, A.H. Tobias / Vet Clin Small Anim 34 (2004) 1245–1271
suffering from serious and frequently advanced underlying (usually cardiac)
disease rather than specifically because of the difficulty in preventing
recurrent ATE. This is further illustrated by the fact that recurrent ATE
was the ultimate cause of death or euthanasia in only 20% of the cats in the
UMVMC study. Progressive CHF is a much more common cause for death
or euthanasia among cats that were discharged after recovering from an
acute episode of ATE
. Nevertheless, recurrence of ATE remains
a significant and frequently devastating problem. Further research is
necessary to establish a safe, effective, and practical method for thrombo-
prophylaxis in at-risk cats.
Summary
ATE remains a devastating complication of cardiac disease. Despite some
improvements in our understanding of the underlying causes and clinical
features of this disease, short-term management remains a challenge, and
mortality is high. Long-term mortality is primarily attributable to the severe
underlying cardiac disease. Many questions remain to be answered regarding
the ideal management approach for feline ATE. The authors’ preferred
diagnostic and therapeutic approaches for these difficult patients are detailed
in
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dosing considerations, monitoring, efficacy, and safety. Chest 1992;102(4 Suppl):337S–51S.
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[52] Fox PR. Evidence for or against efficacy of beta-blockers and aspirin for management of
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1271
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Index
Note: Page numbers of articles are in boldface type.
A
Acute renal failure
causes of, 909–922
antibiotics, 912–913
babesiosis, 916–917
borreliosis, 917–918
cyclooxgenase 2 inhibitors,
913–916
grapes, 911
infectious diseases
emerging and re-emerging,
916–920
leptospirosis, 918–919
NSAIDs, 913–916
plants, 909–910
raisins, 911
vitamin D toxicosis,
911–912
Agar disk diffusion technique
in UTI diagnosis, 931
Aluminum toxicosis
in chronic hemodialysis, 954–955
Analgesia
in FIC management, 1053
Anesthesia/anesthetics
during renal biopsy specimen
procurement, 890
Antibiotic(s)
acute renal failure due to, 912–913
Anti-inflammatory drugs
nonsteroidal (NSAIDs)
acute renal failure due to,
913–916
Antimicrobial dilution technique
in UTI diagnosis, 931–932
Antimicrobial susceptibility testing
in UTI diagnosis, 930
B
Babesiosis
acute renal failure due to, 916–917
Bacterial catheter infection
in chronic hemodialysis, 957–959
Bacteriuria
defined, 924
Biopsy
laparoscopic
in renal biopsy specimen
procurement, 895–897
percutaneous
with ultrasound guidance
in renal biopsy specimen
procurement,
895–897
renal, 887–908. See also Renal biopsy.
surgical
in renal biopsy specimen
procurement, 897–898
Blood testing
in renal disease diagnosis, 878–882
Bone disease
metabolic
in chronic hemodialysis, 955
Borreliosis
acute renal failure due to, 917–918
C
Calcium oxadate uroliths
management of, 969–987. See also
Urolith(s), calcium oxalate,
management of.
Calcium oxalate crystal formation
altered inhibitors and promoters of
uroliths due to, 974
Canine nephroliths
ESWL for
complications of, 1062–1064
effectiveness of, 1062
Carnitine deficiency
in chronic hemodialysis, 956
Cat(s)
ESWL in, 1066
Vet Clin Small Anim
34 (2004) 1273–1279
0195-5616/04/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S0195-5616(04)00108-1
Catheter(s)
in vascular access for hemodialysis
advances in, 940–943
infections due to
bacterial
in chronic hemodialysis,
957–959
Chronic kidney disease
described, 867
diagnosis of
early, 867–885. See also Renal
disease; Renal failure.
Colposuspension
for urethral sphincter mechanism
incompetence, 1060–1061
Computed tomography (CT)
in ectopic ureter evaluation, 1067
Conflict
FIC management and, 1048–1052
CT. See Computed tomography (CT).
Cyclooxgenase 2 inhibitors
acute renal failure due to, 913–916
Cystitis
feline idiopathic, 1043–1055. See also
Feline idiopathic cystitis (FIC).
Cystoscopy
transurethral
of ectopic ureters, 1066–1067
Cystourolith(s)
ESWL for, 1067–1068
D
Dialysate
in vascular access for hemodialysis
advances in, 947
Dialysis
complications of
chronic hemodialysis and,
956–959
Dialysis catheter dysfunction
in chronic hemodialysis, 956–957
Dialysis delivery systems
in vascular access for hemodialysis
advances in, 946–947
Dialysis prescription formulation,
949–952
single-needle techniques in, 951–952
sodium profiling in, 949–950
staged azotemia reduction in, 951
standard prescription variables in, 949
ultrafiltration in, 950–951
Dialyzer(s)
in vascular access for hemodialysis
advances in, 947
E
Ectopic ureters, 1063–1070
clinical features of, 1063–1064
complications of, 1070
diagnosis of, 1064–1067
CT in, 1067
minimum database in, 1064
radiography in, 1064–1065
transurethral cystoscopy in,
1066–1067
ultrasonography in, 1065
urethral pressure profilometry in,
1067
differential diagnosis of, 1067
pathophysiology of, 1063
prognosis of, 1070
treatment of, 1067–1070
neoureterostomy in, 1068–1069
nephroureterectomy in,
1069–1070
ureteroneocystostomy in,
1067–1068
Electron microscopy
renal biopsy specimen evaluation by,
905
Environmental enrichment
in FIC management, 1045–1052
Erythropoietin resistance
in chronic hemodialysis, 954
Extracorporeal shock wave lithotripsy
(ESWL)
‘‘dry"
method for, 1060–1062
for canine nephroliths
complications of, 1062–1064
effectiveness of, 1062
for cystouroliths, 1067–1068
for ureteroliths, 1064–1066
in feline patients, 1066
limitations of, 1066–1067
technology of, 1057–1059
F
Feline idiopathic cystitis (FIC), 1043–1055
management of
analgesia in, 1053
conflict and, 1048–1052
environmental enrichment in,
1045–1052
food in, 1045–1047
litter boxes in, 1047
1274
Index / Vet Clin Small Anim 34 (2004) 1273–1279
pheromones in, 1052–1053
play in, 1047–1048
space in, 1047
treating owner in, 1053–1054
water in, 1047
pathophysiology of, 1043–1045
Feline lower urinary tract disease
(FLUTD), 1043. See also Feline
idiopathic cystitis (FIC).
Feline urologic syndrome (FUS), 1043. See
also Feline idiopathic cystitis (FIC).
FIC. See Feline idiopathic cystitis (FIC).
Fistula(ae)
in vascular access for hemodialysis
advances in, 943–944
FLUTD. See Feline lower urinary tract
disease (FLUTD).
Food
in FIC management, 1045–1047
Funguria
defined, 924
FUS. See Feline urologic syndrome (FUS).
G
GFR. See Glomerular filtration rate (GFR).
Glomerular filtration rate (GFR)
clearance-based estimates of
in renal disease diagnosis,
878–881
Grape(s)
acute renal failure due to, 911
H
Hematuria
described, 849
diagnosis of, 849–866
cytologic/histologic tissue
evaluation in, 859–861
imaging in, 856–857
indications for, 849, 852
initial evaluation in, 852
laboratory tests in, 854–856
physical examination in, 852–853
surgery in, 861
urinalysis in, 853–854
urinary bladder antigen test in,
855
urine culture in, 855
uroendoscopy in, 858
diseases associated with, 850–851
timing of, 852
Hemodialysis, 935–967
applications for, 938–940
chronic
aluminum toxicosis and,
954–955
bacterial catheter infection and,
957–959
carnitine deficiency and, 956
dialysis catheter dysfunction and,
956–957
dialysis-related complications in,
956–959
erythropoietin resistance and,
954
hormonal derangement
associated with, 953–955
insulin resistance and, 953–954
malnutrition associated with,
952–953
management problems in,
952–959
metabolic bone disease and, 955
services providing
in North America, 961
taurine deficienicy and, 956
uremia-related complications of,
952–953
described, 935
dialysis prescription formulation,
949–952. See also Dialysis
prescription formulation.
for acute uremia
causes of
changes in, 959
outcomes of, 959–960
principles of, 936–938
prognosis of, 959–960
referral guidelines for practitioners,
961–962
vascular access for
advances in, 940–949
catheters, 940–943
dialysate, 947
dialysis delivery systems,
946–947
dialyzers, 947
fistulae, 943–944
locking solutions, 946
monitoring modalities,
947–949
subcutaneous vascular
ports, 944–945
Hormonal derangements
in chronic hemodialysis, 953–955
Hypercalciuria
uroliths due to, 972–973
Hyperoxaluria
uroliths due to, 973–974
1275
Index / Vet Clin Small Anim 34 (2004) 1273–1279
I
Immunofluorescent microscopy
renal biopsy specimen evaluation by,
906
Incontinence
urinary. See Urinary incontinence.
Infection(s)
inflammation vs.
described, 924–925
Infectious diseases
emerging and re-emerging
acute renal failure due to,
916–920
Inflammation
infection vs.
described, 924–925
Insulin resistance
in chronic hemodialysis, 953–954
Intracorporeal lithotripsy, 1068–1069
L
Laparoscopic biopsy
in renal biopsy specimen procurement,
895–897
Leptospirosis
acute renal failure due to, 918–919
LifeSite Hemodialysis Access System
in vascular access for hemodialysis,
944–945
Light microscopy
renal biopsy specimen evaluation by,
901–904
Lithotripsy. See also Extracorporeal shock
wave lithotripsy (ESWL).
ESWL
‘‘dry"
method for, 1060–1062
technology of, 1057–1059
for nephroliths, 983
for ureteroliths, 983
intracorporeal, 1068–1069
sites for, 1069–1070
update on, 1057–1071
Litter boxes
in FIC management, 1047
Locking solutions
in vascular access for hemodialysis
advances in, 946
M
Malnutrition
in chronic hemodialysis, 952–953
Metabolic bone disease
in chronic hemodialysis, 955
Microburia
defined, 924
Microscopy
electron
renal biopsy specimen
evaluation by, 905
immunofluorescent
renal biopsy specimen
evaluation by, 906
light
renal biopsy specimen
evaluation by, 901–904
Monitoring modalities
in vascular access for hemodialysis
advances in, 947–949
N
Neoureterostomy
in ectopic ureter management,
1068–1069
Nephrolith(s)
canine
ESWL for
complications of,
1062–1064
effectiveness of, 1062
management of, 982–983
Nephroureterectomy
in ectopic ureter management,
1069–1070
NSAIDs. See Anti-inflammatory drugs,
nonsteroidal (NSAIDs).
P
Percutaneous biopsy
with ultrasound guidance
in renal biopsy specimen
procurement, 892–893
Pheromone(s)
in FIC management, 1052–1053
Plant(s)
toxic
acute renal failure due to,
909–910
Plasma creatinine concentration
in renal disease diagnosis, 878–881
Play
in FIC management, 1047–1048
Pressure profilometry
in urinary sphincter mechanism
incompetence evaluation, 1058
1276
Index / Vet Clin Small Anim 34 (2004) 1273–1279
Proteinuria
in renal disease diagnosis, 873–877
Pyuria
defined, 924
R
Radiography
in urinary sphincter mechanism
incompetence evaluation, 1058
of ectopic ureters, 1064–1065
Raisin(s)
acute renal failure due to, 911
Renal biopsy, 887–908
complications associated with,
899–900
evaluation prior to, 888–890
patient selection for, 887–888
specimen evaluation in, 901–906
electron microscopy in, 905
immunofluorescent microscopy
in, 906
light microscopy in, 901–904
specimen processing in, 900–901
specimen procurement in, 890–898
blind technique in, 895
keyhole technique in, 893–895
laparoscopic biopsy, 895–897
needle selection for, 890–892
palpation technique in, 895
patient care following, 898–899
percutaneous biopsy using
ultrasound guidance in,
892–893
sedation during, 890
surgical biopsy, 897–898
Renal disease
diagnosis of
early, 867–885
general concepts in,
868–870
inherent dilemmas in,
870–873
test in
clearance-based
estimates of
glomerular
filtration rate,
878–881
tests in
blood tests, 878–882
plasma creatinine
concentration,
878–881
sensitivity vs.
specificity of,
870–871
urine specific gravity,
878
urine tests, 873–878
progressive vs. nonprogressive
diagnosis of
early, 872–873
Renal failure
acute
causes of, 909–922. See also
Acute renal failure, causes
of.
diagnosis of
early, 867–885
general concepts in,
868–870
inherent dilemmas in,
870–873
Retrograde urohydropropulsion
in calcium oxalate urolith
management, 979–981
S
Sedation
during renal biopsy specimen
procurement, 890
Single-needle techniques
in dialysis prescription formulation,
951–952
Sodium profiling
in dialysis prescription formulation,
949–950
Space
in FIC management, 1047
Staged azotemia reduction
in dialysis prescription formulation,
951
Standard prescription variables
in dialysis prescription formulation,
949
Subcutaneous vascular ports
in vascular access for hemodialysis
advances in, 944–945
Surgical biopsy
in renal biopsy specimen procurement,
897–898
T
Taurine deficienicy
in chronic hemodialysis, 956
Tension reduction
for ureteral obstruction,
1004–1006
1277
Index / Vet Clin Small Anim 34 (2004) 1273–1279
Transurethral cystoscopy
of ectopic ureters, 1066–1067
U
Ultrafiltration
in dialysis prescription formulation,
950–951
Ultrasonography
of ectopic ureters, 1065
percutaneous biopsy with
in renal biopsy specimen
procurement, 892–893
Uremia
acute
severe
causes of
changes in, 959
complications associated with
in chronic hemodialysis,
952–953
Ureter(s)
anatomy of, 989–991
ectopic, 1063–1070. See also Ectopic
ureters.
Ureteral obstruction
causes of, 991–993
clinical findings in, 993–994
imaging of, 994–999
management of, 989–1110
medical, 999
minimally invasive, 999
surgical, 999–1007
ureteroneocystostomy in,
1001–1004
ureterotomy in, 1000–1001
ureteroureterostomy in,
1004
tension reduction in
techniques for, 1004–1006
urine diversion in, 1006–1007
physiology of, 991
prognosis of, 1007
Ureterolith(s)
ESWL for, 1064–1066
management of, 982–983
Ureteroneocystostomy
for ureteral obstruction, 1001–1004
in ectopic ureter management,
1067–1068
Ureterotomy
for ureteral obstruction, 1000–1001
Ureteroureterostomy
for ureteral obstruction, 1004
Urethral pressure profilometry
in ectopic ureter evaluation, 1067
Urethral sphincter mechanism
incompetence, 1057–1063
clinical features of, 1058
diagnosis of, 1058–1059
pressure profilometry in, 1059
radiography in, 1058
urinalysis in, 1058
differential diagnosis of, 1059
pathophysiology of, 1057–1058
prognosis of, 1062–1063
treatment of, 1059–1062
colposuspension in, 1060–1061
medical, 1059–1060
surgical, 1060–1062
urethropexy in, 1061
Urethropexy
for urethral sphincter mechanism
incompetence, 1061
Urinalysis
in hematuria diagnosis, 853–854
in urinary sphincter mechanism
incompetence evaluation, 1058
in UTI diagnosis, 927–928
Urinary bladder antigen test
in hematuria diagnosis, 855
Urinary incontinence. See also specific
types, e.g., Urethral sphincter
mechanism incompetence.
ectopic ureters and, 1063–1070
surgical management of, 1057–1073
urethral sphincter mechanism
incompetence, 1057–1063
Urinary tract infections (UTIs)
cause of, 923
clinical findings in, 925–927
defined, 924
diagnosis of, 923–933
agar disk diffusion technique in,
931
antimicrobial dilution technique
in, 931–932
antimicrobial susceptibility
testing in, 930
historical information in, 925
imaging studies in
results of, 925–927
laboratory results in, 925
physical examination findings in,
925
urinalysis in, 927–928
urine collection in, 928
urine culture in, 928–930
incidence of, 923
1278
Index / Vet Clin Small Anim 34 (2004) 1273–1279
Urine collection
in UTI diagnosis, 928
Urine culture
as test for cure, 1027–1041
case scenario, 1027–1028
bacterial
urine samples for
collection methods for,
1031–1032
preservation of, 1032
collection of, 1031–1032
diagnostic
described, 1029
in hematuria diagnosis, 855
in renal disease diagnosis, 873–878
in UTI diagnosis, 928–930
interpretation of
in recurrent infections diagnosis
and management,
1038–1040
preservation of, 1032
therapeutic
benefits of, 1030
considerations for use, 1029–1031
described, 1029
in detection and management of
antimicrobic failures,
1032–1038
Urine diversion
for ureteral obstruction, 1006–1007
Urine specific gravity
in renal disease diagnosis, 878
Uroendoscopy
in hematuria diagnosis, 858
Urolith(s)
altered inhibitors and promoters of
calcium oxalate crystal formation
and, 974
calcium oxalate, 969–987
diagnosis of, 974–978
historical information in,
974–975
imaging studies in, 976
laboratory studies in,
975–976
physical examination in,
975
urine saturation studies in,
976–977
urolith analysis in,
977–978
management of, 969–987
combination therapy in,
983
retrograde
urohydropropulsion
in, 979–981
voiding
urohydropropulsion
in, 981–982
prevention of, 983–986
etiopathogenesis of, 969–974
overview of, 969
hypercalciuria and, 972–973
hyperoxaluria and, 973–974
incidence of, 969
risk factors for, 972–974
types of, 969
urine saturation and, 970–972
Urolithiasis
incidence of, 969
V
Vascular ports
subcutaneous
in vascular access for
hemodialysis
advances in, 944–945
Vitamin D toxicosis
acute renal failure due to, 911–912
Voiding urohydropropulsion
in calcium oxalate urolith
management, 981–982
W
Water
in FIC management, 1047
1279
Index / Vet Clin Small Anim 34 (2004) 1273–1279
Document Outline
- 00 Table of contents
- 01 Forthcoming
- 02 Preface
- 03 Dedication
- 04 Advances in echocardiography
- 05 Neuroendocrine evaluation of cardiac disease
- 06 Management of Atrial Fibrillation
- 07 Use of pimobendan in the management of heart failure
- Use of pimobendan in the management of heart failure
- 08 Beta-blockade in the management of systolic dysfunction
- Beta-blockade in the management of systolic dysfunction
- 09 Interventional catheterization for tachyarrhythmias
- Interventional catheterization for tachyarrhythmias
- Catheter ablation of tachyarrhythmias versus antiarrhythmic drug therapy
- Principles of catheter ablation
- Radiofrequency catheter ablation of accessory pathways
- Use of radiofrequency catheter ablation for atrial tachycardias
- Use of radiofrequency catheter ablation for ventricular tachycardia
- Summary
- References
- Interventional catheterization for tachyarrhythmias
- 10 Dilated cardiomyopathy_an update
- 11 New insights into degenerative mitral valve disease in dogs
- New insights into degenerative mitral valve disease in dogs
- Mitral valve morphology
- Etiology and pathogenesis of degenerative mitral valve disease
- Myxomatous degeneration and vascular changes
- Inheritance and breeding
- Diagnosis of early degenerative mitral valve disease
- Consequences of mitral regurgitation on left ventricular function
- Diagnosis of mild decompensated heart failure
- When should therapy begin?
- References
- New insights into degenerative mitral valve disease in dogs
- 12 Feline Hypertrophic Cardiomyopathy_ An Update
- 13 Boxer dog cardiomyopathy_an update
- 14 Feline Arterial Thromboembolism_An Update
- 15 Index
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