The Blood Vessels and Heart 18
ROGER W. BYHARDT
BLOOD VESSELS Effects of Irradiation on the Coronary
Arteries
Anatomy
Irradiation for Esophageal Cancer
Small Blood Vessels
Irradiation for Breast Cancer
Large Blood Vessels
Irradiation for Hodgkin Disease
HEART
Irradiation for Seminoma
Anatomy
Summary of Studies Concerning the
Methods of Assessing Radiation-Induced
Cardiac Effects of Irradiation
Cardiac Effects
Coronary Irradiation to Prevent Restenosis
Radiation Factors Related to Cardiac Injury
Prevention of Radiation-Induced Heart
Effects of Irradiation on the Pericardium
Damage
Effects of Irradiation on the Myocardium
Management Strategies for Patients at Risk
Effects of Irradiation on the Conduction
for Radiation-Induced Heart Damage
System and Heart Valves
a total dose of 50 Gy, or about 40 Gy for damage to capil-
BLOOD VESSELS
laries. The radiation tolerance of veins is somewhat higher.
Understanding the effects of radiation on blood vessels Although some of the cardiac effects of radiation are
is key to understanding many of its normal tissue effects. similar to the vascular effects, especially the effects on the
Many of the late effects and, to a lesser extent, the acute coronary arteries, the results are more complex and multi-
effects of radiation on different tissues and organs are me- factorial. Several decades ago, many thought the heart was
diated by a continuum of vascular effects. Throughout the relatively resistant to radiation injury; however, the emer-
body, cellular viability and organ function depend on blood gence of more effective imaging and functional assessments
vessel integrity. Probably the most critical component of has provided credence to the old adage that  the more one
the blood vessel structure, especially that of capillaries looks, the more one finds.
and small arterioles, is the monolayer of endothelium lin-
Anatomy
ing the interior. Because endothelial cells proliferate rela-
tively slowly, cell loss and the often-abnormal proliferative Walls of blood vessels consist of three concentric layers
response of surviving cells begin months after radiation (tunicae). The inner layer (intima) consists of endothelium;
therapy has been completed. In smaller-caliber vessels, the the outer layer (adventitia) is made up of connective tis-
aberrant endothelial cell proliferative response or the de- sue, bracketing a middle layer (media) consisting of smooth
velopment of thromboses in the affected area can partially muscle.
or completely obstruct blood flow, leading to downstream
tissue necrosis. In larger vessels with smooth muscle walls,
Small Blood Vessels
radiation damage to the muscle cells leading to fibrosis and
Acute Vascular Changes
diminished blood flow occurs years later. Endothelial cell
proliferation is less likely to restrict blood flow in these Erythema. The first and most noticeable gross vascular
larger-caliber vessels but can still provide sites for the for- change after irradiation is cutaneous or mucosal erythema.
mation of thrombi. The intensity of the erythema increases in direct propor-
Although the acute effect of radiation on blood vessels tion to the radiation dose and the area irradiated. Erythema
is an important trigger, it is the late effect of radiation on of the skin appears in waves that occur at predictable times
small vessels leading to impairment of circulation that has during the course of radiation therapy on the first day,
the greatest clinical significance. An impaired blood sup- during the second or third week, and at the end of the first
ply leads to local tissue changes in nutrition, electrolyte month.
concentrations, and oxygenation. These changes impair the The mechanism of radiation-induced erythema is not
ability of tissues to respond to other types of injury. known, but the first period of erythema is thought to be a
The early and late vascular effects of radiation depend vascular response to local extracapillary cell injury, whereas
on vessel size and location, the presence of vascular dis- the later periods of erythema are presumed to be caused
ease, the dose of radiation, the time over which radiation is by direct capillary damage.1 Radiation-induced erythema
delivered, the volume irradiated, and the stresses to which is not a result of nerve injury. It has been suggested that a
the irradiated volume is subjected. With conventional daily histamine-like substance is produced by the radiation injury
doses of 1.8 to 2.0 Gy, the risk of arterial damage rises after and that this substance diffuses through tissues to produce
411
412 PART 5 Thorax
erythema within and slightly beyond the margins of the ir-
radiated volume. However, this mechanism is questionable
because radiation-induced erythema is not decreased by
administration of antihistamines. Moreover, during the first
period of erythema, the vessels maintain their ability to
constrict in response to a scratch test, and histamine does
not produce wheal formation.
Skin temperature rises several degrees with the onset of
radiation-induced erythema, suggesting that vasodilation,
not merely vasocongestion, occurs. Local administration of
epinephrine or acetylcholine reduces but does not elimi-
nate vasoconstrictive and vasocongestive responses. Direct
observation of radiation-induced changes in arterioles and
capillaries in bats wings, in the webs of frogs feet, in hu-
man nail folds, and through experimentally placed trans-
parent  windows confirms that acute radiation-induced
damage to small blood vessels is nonspecific. FIGURE 18-1. Arteries from a 34-year-old woman irradiated
During the acute phase of erythema, damage of the ves- 5 months earlier with 65 Gy for carcinoma of the cervix. Fatty
deposits in the intima have caused extensive narrowing of the
sel endothelium is not striking. With the radiation doses
lumina. Notice the edema surrounding the blood vessels.
used clinically, however, some endothelial cells are killed,
and thrombi form and narrow or obliterate the vessel
lumen.
Increased Vessel Permeability and Vessel Dilation. resembles an inflammatory response.4 As is true for an in-
The functions of small blood vessels are to deliver oxygen flammatory response, these effects subside as the chronic
and nutrients to cells and to carry waste products away from vascular changes manifest.
cells. These functions depend on blood flow rates and on
Chronic Vascular Changes
the transmission and transport of nutrients and waste prod-
ucts through the capillary wall. The relative contributions After the acute reaction to radiation subsides and before
of the two layers of the capillary wall the endothelium major narrowing of the vessel lumen develops, diffusion of
and the basement membrane to capillary permeability material through capillary walls decreases. The vessel wall
remain uncertain. A few hours to a few weeks after treat- may not appear to be seriously damaged; however, the ul-
ment with moderate doses of radiation, the permeability trafiltration ability of the endothelial lining is decreased.4
of the capillary wall increases, as manifested by associated The basement membrane of the capillary wall is thickened,
edema. As expected, the rapidly proliferating endothelial and this thickening is presumed to contribute to decreased
cells of newly developing capillaries are more sensitive to capillary permeability. The connective tissue barrier be-
radiation than are endothelial cells in older capillaries.2,3 tween the capillaries and the dependent tissues becomes
This fact explains some of the inhibitory effects of irradia- thicker as a result of extracapillary fibrosis. The cause of
tion on wound healing. this extracapillary fibrosis is unknown, although Rubin and
One of the most consistent early effects seen in the cap- Casarett5 related it to a connective tissue reaction after
illaries and prearterioles after irradiation is vessel dilation,  leakage of plasma constituents from capillaries.
which can be accompanied by endothelial cell swelling, Still later, the number of small vessels is decreased
degeneration, and necrosis and the presence of a cellular through the process of vessel occlusion (Fig. 18-2). Arte-
inflammatory infiltrate. Increased vascular permeability riolar capillary intimal hyalinosis proceeds as a discontinu-
with resulting tissue edema is a common early manifesta- ous process. Tumoricidal doses of radiation inhibit capillary
tion (Fig. 18-1). sprouting and vascular remodeling,6 which probably con-
The pathogenesis of radiation-induced vascular dilation tributes to delays in wound healing after irradiation. How-
and increased capillary permeability is not clear. Endothe- ever, vascular endothelium seems to recover rapidly, and
lial cell damage can be minimal or absent even in the case it is possible that migrating unirradiated endothelial cells
of severe edema. It is possible that irradiation interferes, at account for this apparently rapid recovery.
least temporarily, with vasomotor regulatory mechanisms The most common chronic radiation-induced changes
and results in hemodynamic alterations conducive to tissue seen in vessels of small and medium caliber are swelling
edema. and vacuolation of the endothelial cells of the tunica intima
Increased capillary permeability manifested as local vasorum. Later, proliferation of endothelial cells and lipid
edema can be seen after doses of 5 Gy or more. Various deposits may occur. These lesions resemble atheromatous
substances, including labeled plasma, erythrocytes, Evans plaques but differ in their location because atheromatous
blue dye, and colloidal gold, permeate the capillary walls plaques rarely occur spontaneously in small arteries. These
more rapidly after irradiation. The peak change develops lesions are not specific for radiation damage; any physical
2 weeks after a single exposure. The contribution of or chemical damage to the vessel, especially the tunica
thrombi and vasodilation to the increased permeability is adventitia vasorum, results in similar lesions. This is par-
unknown. The capillaries exhibit increased fragility. Bleed- ticularly true in experimental situations in which animals
ing occurs more readily even though the clotting mecha- are rendered hyperlipemic by dietary means. In humans,
nism is normal. The combination of thrombus formation, no evidence has been found of any relationship between
vasodilation, and increased capillary fragility and bleeding serum cholesterol levels and development of the foamy
18 The Blood Vessels and Heart 413
reactions, sclerotic changes in aged patients, hypertension,
associated trauma such as surgery, and fractionation sched-
ule. The recognition of these factors and the exploitation of
the advantages of increased fractionation are the basis for
individualization of radiation therapy techniques.
Large Blood Vessels
In large blood vessels, high doses of radiation produce few
recognizable acute changes. Veins are little affected, and
the changes affecting large, elastic arteries usually occur as
late manifestations.
Mechanisms of Radiation-Induced Injury
The mechanisms of chronic radiation injury to large blood
vessels are not known. Although a direct effect of radiation
on the cellular elements of the tunica media cannot be ex-
cluded, the changes seen are similar to those observed after
damage of the adventitial vessels nourishing most of the vas-
cular wall-changes that also can be produced experimentally
by burning or freezing the adventitia. Extensive dissection
around the vessels with destruction of their blood supply
is likely to be a predisposing factor but is by no means a
FIGURE 18-2. Small blood vessels 5 months after irradiation
with 65 Gy in 7 weeks. The vessels have strikingly thickened prerequisite for such radiation-induced changes.
walls and narrowed lumina.
The changes themselves basically consist of degeneration
of muscle cells of the tunica media. The muscle cell degen-
eration can be a patchy, localized process or can manifest as
lesions in the intima after irradiation. These lesions can be a wide zone of cystic medionecrosis. Weakening of the ves-
seen a few days after radiation therapy and can persist for sel wall may lead to rupture, but more often, fibrosis of the
many years. tunica media is observed. The intima overlying the areas
Concomitant with these changes in the intima, vacuola- of medial degeneration usually develops changes indistin-
tion and degeneration of the smooth muscle cells of the tu- guishable from those of ordinary atherosclerosis.8 Similar
nica media vasorum may occur. Repair with fibrosis of the changes can be produced experimentally by damaging the
tunica media is seen in chronic lesions. Narrowing of the adventitia by chemical or physical means.
lumen occurs mainly as a result of concentric fibrosis and The pathogenesis of these experimental lesions seems to
loss of vascular elasticity, but thrombosis and intimal pro- be interference with nutrition of the arterial wall through
liferation also play important roles. In the superficial part damage of the adventitial vasa vasorum. It seems likely that
of the cutis, extensive dilation of capillaries, recognized as a similar mechanism operates in radiation-induced damage
telangiectasia, is usually seen after radiation therapy. The to large arteries; damage is mediated through narrowing
telangiectatic vessels arise from existing capillaries and are and occlusion of the vasa vasorum caused by irradiation.
presumed to be a result of greater blood flow through the In clinical situations, the presence of tumor cells and the
few remaining damaged small blood vessels. The sequelae tissue reactions they elicit also may contribute to the de-
of small blood vessel obliteration vary with the organ in creased blood supply of the vessels.
question. The vasculoconnective tissue of the skin can tol- The decreased strength of the vessel walls after irradia-
erate extensive damage before necrosis occurs. However, tion is particularly important when radical neck dissection
rather minor defects in the vasculature of the brain, myo- is performed after high radiation doses have been given to
cardium, kidney, or lungs may result in seriously limited the carotid arteries. In this situation, rupture of the carotid
function. arteries may occur.9
In addition to the changes in small blood vessels that Arteriosclerosis and Atherosclerosis. After irradia-
directly result from irradiation, changes caused by tumor tion, changes within the vessel lumen are more obvious
shrinkage also can be seen. Quantitative studies show im- than changes in the vessel walls. Single, large doses of 15
proved vascular filling after irradiation. After irradiation, to 20 Gy produce arteriosclerosis and atherosclerosis
the appearance of vessels in large tumors reverts to the within 30 to 40 weeks. This sclerosis is confined to the
appearance of vessels in small tumors.7,8 These vascular irradiated zone.8 Fractionated doses of 30 to 50 Gy produce
changes are fundamental to the process of radiation- less severe changes than large single doses.
induced reoxygenation of the tumor. Hypertensive Vascular Damage. Asscher10 found that
The popularity of radiation doses of about 60 Gy in radiation sensitizes blood vessels to hypertension. Hyper-
6 weeks is a recognition of the tolerance of most normal tension from any cause produces early profound hyperten-
vasculoconnective tissues. The incidence of necrosis of sive vascular damage in irradiated blood vessels, whereas
normal tissues increases rapidly with increasing dose when unirradiated blood vessels subjected to the same hyper-
doses higher than 60 Gy administered in 6 weeks (or the tension may appear relatively normal for months.10 When
equivalent) are delivered to large volumes. A variety of fac- hypertension develops years after high-dose irradiation, the
tors modify the response of small vessels to radiation, includ- patient can develop a localized vascular insufficiency lead-
ing tissue oxygen concentration, associated inflammatory ing to necrosis of the irradiated volume.
414 PART 5 Thorax
Radiation-Induced Carotid Artery Disease. Silver- more rigorous dosimetric information coupled with im-
berg and colleagues11 compared a variety of variables in provements in cardiac functional assessment has provided
9 patients with atherosclerotic carotid artery disease as- a clearer picture of radiation dose-effect relationships.
sociated with neck irradiation and 40 unirradiated control Pericarditis is often reported as being the most com-
patients. The 9 irradiated patients with occlusive carotid ar- mon radiation-induced heart injury, but subtle functional
tery disease were younger than the controls, were less likely changes may be present that are detectable only by spe-
to have peripheral vascular disease and coronary artery cialized testing. Acute pericarditis usually appears during
disease, and were less likely to have hyperlipemia or hyper- the first year after treatment and has a benign, self-limited
cholesterolemia.11 These findings support the recognition course; it tends to manifest as acute chest pain, dyspnea,
of radiation-induced carotid artery disease as a clinical en- and low-grade fever, with or without progression to fibrosis
tity. Reconstructive carotid surgery in patients with carotid and tamponade.
artery damage resulting from radiation therapy should be The heart does not function in isolation. Inclusion of
approached as if radiation were not a factor, even though heart and lung in the irradiated volume results in a com-
there may be some periarterial fibrosis and increased dif- plex interplay of cardiac and pulmonary effects. In addition
ficulty in separating the plaques from the tunica media.11 to the total radiation dose and fraction size and the volume
Arrest of Growth of Vessel Diameter. During child- of heart incidentally irradiated, the extent of radiation-
hood, the aorta and other large vessels grow in proportion induced cardiotoxicity may be affected by adjacent tumor
to increasing body surface area, not in relation to chrono- affecting the lymphatic drainage from the heart. Heart
logic age.12 In children, doses of 25 to 28 Gy given to large structure and function are also intimately linked to the
vessels over 2 to 3 weeks arrest growth in vessel diameter.13 integrity of the coronary arteries. Numerous clinical stud-
The inhibitory effect of irradiation on the growth of vessel ies have shown a relationship between cardiac irradiation,
diameter is greatest when irradiation is delivered during accelerated coronary vessel atherosclerosis, and increased
infancy and decreases with increasing age at irradiation. risk of ischemic coronary artery disease, which increase the
risk of myocardial infarction.8,16-26 These effects are not
inevitable; they depend on dose and volume and on the
HEART
individual s genetic and lifestyle-associated risks for coro-
Despite dosimetric efforts to exclude the heart from the nary artery disease. The available clinical findings should be
radiation field, it often receives radiation during the course interpreted with care, because some studies did not include
of treatment for several malignancies. For example, treat- a control group with which to distinguish the risk of
ment of the chest wall in patients with left-sided breast radiation-induced coronary injury from the expected inci-
cancer often involves some exposure of the heart, includ- dence of coronary disease in appropriately age- and risk-
ing the coronary vessels. Larger heart volumes are included matched populations.
during treatment of the mediastinum in patients with lung
Anatomy
cancer, esophageal cancer, lymphoma, or seminoma.
The variety of radiation doses and dose distributions The wall of the heart is composed of three layers: the epicar-
used to treat each tumor type have provided useful clini- dium (visceral layer of the pericardium), the myocardium,
cal data regarding dose-effect relationships for cardiac ir- and the endocardium. The epicardium and pericardium are
radiation, including fraction-size effects. The most useful thin, relatively avascular layers that function to minimize
data on the late effects of cardiac irradiation have come friction and provide damping of cardiac contractions. These
from studies of patients with breast cancer, Hodgkin dis- layers are particularly susceptible to radiation damage, and
ease, and seminoma, because many of these patients sur- the response is not unlike that produced by an infection.
vive for long periods after the treatment, long enough for The myocardium varies in thickness according to the site
late effects to become manifest. Conversely, the relatively within the heart wall. The endocardium is continuous with
short survival times after definitive irradiation for inoper- the intima of the blood vessels, and the two layers seem to
able lung or esophageal cancer have resulted in much less respond to irradiation in similar ways.
information on late cardiac effects. The radiation treatment Radiation-induced injuries of the heart trigger a dose-
plans for these types of cancer usually result in a gradient related thickening of one or more layers of the heart wall.
of dose through the heart, making it a challenge to relate The heart valves and conduction system also may show
subclinical and clinical cardiac effects to a specific dose dose-related radiation effects. The microvasculature and
of radiation. A clear understanding of the relationship of the larger blood vessels of the heart (e.g., coronary arteries)
radiation-related heart injury to partial-volume cardiac may undergo radiation dose related changes. The effects of
doses has been limited by a scarcity of dose-volume do- radiation on the microvasculature of the heart often form
simetric information until the middle to late 1990s. The the basis for radiation injury of the cardiac components.
widespread use of computed tomography (CT) based Irradiation of the coronary arteries may lead to the most
treatment planning systems has provided more detailed in- serious side effects.
formation on cardiac dose-volume relationships.
Methods of Assessing Radiation-Induced
By using animal models and multifraction techniques
Cardiac Effects
similar to those used in clinical practice, investigators have
shown that late cardiac injury from radiation is multifacto- A spectrum of tests are now available to evaluate potential
rial. Although damage to the cardiac microvasculature is a radiation-induced heart damage, including cardiac magnetic
significant risk,14,15 all of the components of the heart are resonance imaging (MRI), fast-scan cardiac CT, ventricu-
affected by radiation, including the pericardium, myocar- lography, gated single photon emission CT, and multigated
dium, endocardium, valves, and coronary vessels. Clinically, acquisition (MUGA) scanning. Many tests are capable of
18 The Blood Vessels and Heart 415
detecting subtle, subclinical changes in cardiac function. 2.0 Gy/day for 5 days/week, whereas large volumes may
Electrocardiography can reveal conduction abnormalities. tolerate only 40 Gy at 1.8 to 2.0 Gy/day.
Echocardiography can reveal changes in the thickness of In 1991, based on clinical observations available at that
the myocardium. Radionuclide angiocardiography and sin- time, volume-based estimates were published for the TD5/5
gle photon emission CT can reveal changes in myocardial (i.e., dose associated with a 5% risk of complications within
perfusion and in cardiac output through measurements of 5 years) and the TD50/5 (i.e., dose associated with a 50%
the left ventricular ejection fraction (LVEF).27-29 Exercise risk of complication within 5 years) for the heart.38 When
testing on a treadmill or bicycle ergometer with thallium pericarditis was used as the endpoint, the TD5/5 for con-
201 scintigraphy can demonstrate subclinical changes in ventionally fractioned radiation was estimated at 60 Gy for
cardiac output. Various radiographic imaging techniques, one third of the heart, 45 Gy for two thirds of the heart, and
including 64-slice CT and MRI, can more precisely charac- 40 Gy for the entire heart. The corresponding TD50/5 doses
terize pericardial abnormalities. Positron emission tomog- for the same volumes were 70 Gy, 55 Gy, and 50 Gy. Values
raphy can also demonstrate changes in the myocardium such as these have been used as cardiac dose limits in sev-
corresponding to areas of high-dose irradiation.30 eral clinical studies of radiation therapy for anatomic sites
near the heart. Plots of normal tissue complication prob-
Radiation Factors Related
abilities for late cardiac mortality versus dose have yielded
to Cardiac Injury
sigmoid curves of similar shape for 33%, 66%, and 100% of
Factors that influence the risk of cardiac injury resulting heart volume, suggesting that the volume dependence for
from radiation therapy include total dose, exposed volume, this end point is small.39 For breast cancer or other types of
and fraction size. cancer associated with long-term survival that may involve
incidental radiation to the heart, the TD5/5 values may be
Total Dose and Exposed Volume
set much lower (e.g., 25 Gy).
A probit analysis of 318 patients who underwent radia-
Fraction Size
tion therapy for Hodgkin disease yielded a sigmoid dose-
response curve for radiation-induced heart disease (Fig. Although the TD5/5 values discussed in the previous sec-
18-3).31 The curve shows a steep rise in radiation-induced tion suggest that the heart has a high dose tolerance, the
cardiac injury above a total dose of 40 Gy. These findings threshold for mild changes may be 20 Gy when exposed
have since been confirmed by other clinical and animal heart volumes exceed 50%. Theoretically, an alpha/beta
studies.14,32-36 ratio (defined in Chapter 1) of about 1 Gy suggests that
The dose-response curve also depends on the volume of fractionation of the radiation dose should spare the heart.
heart irradiated. When large cardiac volumes are irradiated, However, use of concurrent chemotherapy, particularly
as takes place in the treatment of Hodgkin disease, doses with cardiotoxic agents such as doxorubicin, can com-
lower than 40 Gy given over a 4-week period may induce pound radiation damage.
cardiac injury. However, when small cardiac volumes are Fraction size is an important determinant of the risk of
treated, as is the case in the postoperative treatment of radiation-induced cardiac injury. Larger doses per fraction
breast cancer, doses higher than 40 Gy in 4 weeks may be tend to cause more cardiac damage.37 Some of the high-
well tolerated.37 The tolerance dose (TD), which is the to- est rates of pericarditis have been reported among patients
tal dose causing a specific level of risk of radiation-related with Hodgkin disease treated with anteriorly weighted
cardiac injury, varies with the volume of heart irradiated. fields in which the anterior cardiac structures received a
Small heart volumes may tolerate 60 Gy given at 1.8 to larger dose per fraction than the midline tumor.32 Use of
equally weighted fields, lower total doses, daily treatments
of each field, and when possible, cardiac shielding has re-
duced the risk of cardiac damage in patients with Hodgkin
100
disease.31
Analyses of the effect of fraction size on radiation-
80
induced heart damage are complicated because of the re-
60
cent trends toward lower total doses and lower doses per
fraction. Nevertheless, reviews of the available clinical data
40
and observations of cardiac injury after fractionated irra-
diation of canine hearts confirm a fraction-size effect.3,40
20
A study of the effect of fractionated irradiation on the
number of adrenergic receptors, myocardial norepineph-
0
rine concentration, and cardiac function in rats also showed
0 20 40 60 80 100
that cardiac damage depends on radiation fraction size.33
Dose (Gy)
FIGURE 18-3. Probit analysis of the dose-response relationship
Effects of Irradiation on the Pericardium
for radiation-induced heart disease. The curve is derived by re-
plotting by probit of the analysis of 318 determinant cases of
Acute Pericardial Changes
Hodgkin disease. LD5 is the dose causing heart disease in 5% of
Radiation-induced acute pericarditis may appear a few
patients, and for 43.3 Gy, the 95% confidence interval is 40.3 to
weeks or several years after irradiation. If pericarditis is
46.4 Gy. Squares, data points; blue line, fitted probit curve; red
clinically overt, the patient may present with fever, tachy-
and green lines, 95% confidence limits. (Modified from Stewart
cardia, substernal pain, and pericardial friction rub. Peri-
JR. Normal tissue tolerance to irradiation of the cardiovascular
system. Front Radiat Ther Oncol 1989;23:302-309.) cardial effusion is common, and cardiac tamponade may
Percent carditis (RIHD)
416 PART 5 Thorax
develop as the effusion increases. The cardiac silhouette of the heart will develop chronic pericarditis.44 The treat-
is widened. The echocardiogram may show inversion and ment for chronic constrictive pericarditis depends on the
flattening of the T waves, elevation of the ST segment, and severity of the condition and consists of antipyretics in
decrease of the QRS segment. The course of acute pericar- the case of fever, pericardiocentesis in the case of tampon-
ditis is variable. The condition is self-limited in about one ade, and pericardiectomy in the case of severe constrictive
half of the patients who present with clinical symptoms; symptoms.
the remaining patients experience recurrence or progres-
Effects of Irradiation on the Myocardium
sion to chronic constrictive pericarditis.
The dose-time relationship for acute pericarditis has Three components of the myocardium are important in
been clarified by Stewart and Fajardo.41 Most patients the response of the myocardium to irradiation: the vascu-
with symptoms of acute pericarditis have received at least lar component, the connective tissue component, and the
40 Gy in 4 weeks to a major portion of the heart, but the muscle component. Gillette and colleagues2,3 found that all
observation that acute pericarditis is uncommon even after fractionation schedules tested with a variety of total radia-
50 Gy given in 5 to 6 weeks has led to a search for possible tion doses led to diminishment of the cardiac vasculature.
contributing factors. Cardiac venous and lymphatic path- The higher the fraction size and the higher the total dose,
ways drain to the mediastinal lymphatics, and tumor-related the greater the decrease in the vasculature. The amount
changes in these pathways may contribute to the forma- of connective tissue in the heart, which is distributed be-
tion of pericardial effusion. This may partially account for tween the muscle bundles throughout the heart, increased
the correlation between larger mediastinal tumor size and with increasing dose up to a maximum of about 44 Gy at
higher risk of pericardial effusion after radiation therapy to 4 Gy/fraction, after which further increases in dose pro-
the chest. The incidence of pericardial effusion increases duced smaller increases in connective tissue at 3 months
rapidly as doses increase above 50 Gy in 5 weeks.34,42 and at 6 months after irradiation. Subsequent studies of
Some cases of postirradiation pericardial effusion are fractionated irradiation of the beagle heart confirmed early
linked to myxedema, which may develop after thyroid and late myocardial damage, which manifested as increased
irradiation. Prolonged high iodide levels after lymphan- heart rates, increased heart wall thickness, conduction ab-
giography provoke thyroid hyperplasia and increase the normalities (early effects), and thinning of the cardiac wall
radiosensitivity of the thyroid gland.43 Patients with peri- and fibrosis with functional abnormalities (late effects).40
cardial effusion should be evaluated for thyroid function Cardiac and pulmonary functions are highly interde-
before the effusion is attributed solely to the effects of pendent. When the heart and the lung are included in the
heart irradiation. Nevertheless, studies of humans and ani- radiation field, subclinical levels of radiation-induced myo-
mal models confirm that most cardiac effects of radiation cardial injury may clinically manifest as a consequence of
are a result of direct cellular damage to the pericardium, radiation-induced changes in the pulmonary vasculature.
the epicardium, and the blood vessels of these layers rather Studies of rat and canine models have shown radiation-
than indirect mechanisms. induced reduction of pulmonary capillary volume, which
causes an increase in pulmonary artery pressure.14,45 The
Chronic Constrictive Pericarditis
radiation-damaged heart may not be able to overcome this
Chronic constrictive pericarditis usually manifests as increased resistance. Some of the volume effects discussed
chronic constrictive changes associated with myocardial previously under  Total Dose and Exposed Volume may
and endocardial fibrosis or with varying degrees of effusion. be partially related to the amount of lung irradiated at the
The latent period from the beginning of radiation therapy same time as the heart.46
to the onset of chronic pericarditis varies from 6 months Studies of rats in which autoradiography with tritium-
to several years. Chronic pericarditis may or may not be labeled thymidine was used have shown that radiation also
preceded by acute pericarditis. damages the myocardial capillary network; this damage
Symptoms and signs of chronic pericarditis can in- is followed by compensatory proliferation after a latency
clude dyspnea, chest pain, venous distention, and pleural period of 6 to 8 months.15,45 These changes precede myo-
effusion. Paradoxical pulse and fever may be present. The cardial degeneration, but the findings cannot be linked to
electrocardiogram may show decreased QRS voltage, flat hypoxia or radiation-induced mitotic death of endothelial
or inverted T waves, and elevation of the ST segment. The cells alone.
cardiac silhouette is enlarged. The morphologic changes Early reductions in Ä…- and ²-adrenergic receptors fol-
are not specific for radiation damage. The pericardium is lowed by upregulation of those receptors, which are
thickened as a result of deposition of collagen. The myo- located in endothelial cells, have been observed.15,47 In the
cardium and endocardium are often fused or adherent to early period after radiation therapy, catecholamines may be
each other, with a fibrinous exudate. The pericardium may released from sympathetic nerve endings, leading to deple-
be adherent to the heart and pleura. The blood vessels in tion of catecholamines and downregulation of the recep-
the pericardium show characteristic subendothelial con- tors. The subsequent upregulation of Ä…- and ²-adrenergic
nective tissue proliferation. The underlying myocardium receptors seen in later stages may be caused by a prolonged
usually appears normal on gross examination but may not decrease in sympathetic stimulation. The release of cate-
be microscopically or functionally normal. cholamines may be a direct effect of radiation on the sym-
Although the cause of chronic constrictive pericarditis pathetic nerve endings or may be mediated by radiation
is the same as that of acute pericarditis, fewer than half damage to the capillary network and resultant local hy-
of patients with chronic constrictive pericarditis have a poxia. The relationships among the vasculature, connective
history of previous acute pericarditis. Overall, about 5% tissue, and muscle of the myocardium at various times af-
of patients who receive more than 40 Gy to at least 50% ter irradiation are quite complex, and additional sequential
18 The Blood Vessels and Heart 417
studies are necessary to better understand the mechanism disease) have shown that any of the four heart valves may
of radiation-induced myocardial injury. be affected, but clinical evidence of valvular dysfunction is
The lack of mitotic activity in the cardiac muscle makes present in only about one half of the cases, with the dam-
the myocardium one of the more radioresistant tissues and age identified only at autopsy.55 Successful replacement of
suggests that most of the changes seen in heavily irradiated radiation-damaged valves is possible.56 As is the case for
myocardium result from radiation-induced vascular changes. radiation-induced injury to the other components of the
Direct radiation injury of the muscle fiber is presumed to heart, valvular radiation damage is related to dose and is
be a minor factor, but the degree of fibrosis between the rare when doses are less than 30 Gy.
muscle bundles does change with dose and with fraction-
Effects of Irradiation on the Coronary
ation.3,40 This connective tissue that forms in response to
Arteries
radiation is diffuse and does not resemble the fibrosis seen
after an infarct. Radiation-induced fibrosis may not neces- The effects of irradiation on the cardiac blood vessels
sarily result from small vessel occlusion and may not paral- are the same as the effects of irradiation on blood vessels
lel the severity of vascular occlusion.48 elsewhere in the body (see  Blood Vessels ). However,
In rhesus monkeys, total body irradiation led to high radiation-induced injury of cardiac vessels has more seri-
plasma levels of atrial natriuretic peptide that were associ- ous consequences than radiation-induced vascular injury in
ated with a change in cardiac dimensions and predicted most other sites and is therefore worthy of special attention.
cardiac damage.49 Serial measurements of atrial natriuretic No specific vessels are affected more often than others. The
peptide levels after cardiac radiation exposure in humans consequence of radiation-induced vessel occlusion is the
may serve as a surrogate marker for cardiac toxicity. Pro- same as vessel occlusion from other causes.
collagen I and III levels also may become elevated about The understanding of the relationship between coro-
6 months after heart irradiation, corresponding to the ap- nary artery disease and prior cardiac irradiation continues
pearance of fibrosis in myocardial connective tissue.50 to evolve. Although the issue remains somewhat contro-
The existence of subclinical abnormalities of heart versial, findings from several studies of large numbers of
function suggests that radiation-induced cardiac injury patients that often included appropriately matched control
is not a threshold phenomenon. Studies published in the subjects and cardiac function testing suggest that the risk of
early 1980s indicated that LVEF in clinically asymptom- coronary vessel damage is reduced when heart-sparing radi-
atic patients who had received more than 35 Gy to the ation therapy techniques are used.23,36,51-60 Earlier reviews
heart during mediastinal irradiation for Hodgkin disease summarized case reports of precocious coronary artery
was lower at 5 to 15 years after treatment than that in pa- disease in long-term survivors who had undergone medi-
tients who had not undergone mediastinal irradiation.35,36 astinal irradiation for Hodgkin disease and other malignan-
Abnormalities on radionuclide angiography have been cies.17,18 The number of affected patients in those studies
found years after treatment of Hodgkin disease with 40 was small, and many long-term survivors were without ap-
Gy in 4 weeks with a mantle field in one fourth of patients parent coronary artery disease. However, the observation of
who were 25 to 35 years old at the time of treatment.16 reproducible postirradiation coronary artery disease in ani-
Electrocardiography studies of patients with breast cancer mals17,45 suggested that the risk of coronary artery disease
treated with left-sided internal mammary node irradia- in humans may increase with longer-term follow-up.61 The
tion have shown subclinical T-wave changes, and bicycle early case reports showed that the mechanism of coronary
ergometry stress testing with technitium 99m sestamibi artery disease was accelerated coronary atherosclerosis and
scintigraphy has detected radiation-induced microvascular fibrosis. Some cases involved older patients with predispos-
myocardial damage.51-53 ing metabolic factors or familial risk for coronary disease.
Radiation given to patients previously treated with However, other cases involved young patients with no pre-
doxorubicin can worsen the drug s cardiac side effects. The disposing risk factors. Angiographic and pathologic findings
cardiac effects of doxorubicin, which are expressed in some suggested a localized process limited to the portion of the
patients but not others, appear about 6 months after treat- heart included in the radiation field. Concern was raised
ment and consist of a diffuse cardiomyopathy that can lead that occult early effects would predispose patients to ear-
to congestive heart failure. The cardiac vessels are usually lier or more severe coronary artery disease.
normal. The myocardium shows profound degeneration of Reviews of long-term follow-up information on patients
the muscle cells, combined with interstitial edema and fi- who underwent irradiation of the mediastinum for treat-
brosis. These effects can be worsened by radiation therapy. ment of Hodgkin disease, breast cancer, or seminoma have
Care should be taken to limit the cardiac dose and the vol- described the risk of coronary artery disease and death from
ume irradiated after doxorubicin has been given. acute myocardial infarction. Several factors make interpre-
tation and comparison of these reports difficult, however.
Effects of Irradiation on the Conduction
In some studies, the risk of coronary artery disease was
System and Heart Valves
compared with the risk in a control population that had
Conduction abnormalities, such as atrioventricular block, not received mediastinal irradiation. Some studies reported
occur in up to 5% of patients after mediastinal irradiation the total number of deaths from acute myocardial infarc-
that includes the heart; these abnormalities are thought tion in the treated population, and others reported the
to be related to late myocardial fibrosis.44,54 Valvular de- percentage of total deaths attributable to acute myocardial
fects, often subclinical, may be found in 15% to 20% of infarction. The risk of subclinical or nonfatal coronary ar-
patients who undergo mediastinal irradiation that includes tery disease could not always be discerned. Some reviews
the heart. Autopsy studies of hearts exhibiting radia- were based on information gleaned from death certificates,
tion injury (e.g., after mediastinal irradiation for Hodgkin which may be misleading. Additional details of studies of
418 PART 5 Thorax
radiation-induced coronary artery disease are reviewed in with radiation after lumpectomy from 1977 to 1994
the following sections. found no differences in the numbers of cardiac deaths in
patients treated for left-sided compared with right-sided
Irradiation for Esophageal Cancer
tumors for the first 20 years after treatment, but the risks
Improvements in combined-modality treatment for distal of coronary artery disease and myocardial infarction for
esophageal cancer have increased the number of long-term the patients with left-sided disease were twice those of
survivors. These patients provide a model of the effects the patients with right-sided disease.53 An analysis of more
of high-dose radiation to large heart volumes and of the than 300,000 patients with breast cancer registered in the
potential additive effects of concurrent chemotherapy on Surveillance, Epidemiology, and End Results (SEER) data-
acute and chronic cardiotoxicity. One study of 78 patients base found consistent increases in cardiac mortality ratios
with distal esophageal cancer in complete remission after among patients undergoing radiation for left-sided tumors
chemoradiation showed that at a median follow-up time of (compared with those with right-sided tumors), with the
53 months, 16 (20%) had grade 2 to 4 pericarditis and 2 had greatest difference among those diagnosed from 1973 and
died of myocardial infarction.62 Another study involving 1982 and treated with older radiation techniques.57 A simi-
MUGA scanning before and after platinum-based chemo- lar analysis of 8363 patients with left-sided breast cancer
radiation (50.4 Gy) for 20 patients with distal esophageal and 7909 with right-sided breast cancer diagnosed from
cancer showed a statistically significant drop in LVEF from 1986 to 1993 showed no differences in cardiac morbidity
59% to 54%, although no clinical evidence of functional rates during the first 15 years after irradiation.66 A multi-
change was observed.63 Dose-volume histograms showed national study of 2128 patients, the Multinational Monitor-
the median volume of heart that had received more than ing of Trends and Determinants in Cardiovascular Disease
40 Gy to be 53%. In a similar study,64 findings from MUGA (MONICA) project, also showed no differences in the in-
scans and dose-volume histograms revealed a significant cidence of cardiac morbidity and mortality at 10 years af-
reduction in LVEF from 63% to 58%. Moreover, use of ter lumpectomy and breast irradiation among patients with
three-dimensional conformal therapy with shielding was right- or left-sided breast cancer diagnosed from 1982 to
associated with a median cardiac dose of 27 Gy, compared 1989.60
with 35 Gy if conventional planning without shielding Echocardiography and myocardial perfusion scintigra-
blocks had been used. Use of a three-field treatment tech- phy, especially newer techniques that incorporate molecu-
nique further reduced the median cardiac dose to 22 Gy lar radioligands, may be useful for detecting and evaluating
and the volume of the heart receiving 70% of the total dose the severity of subclinical cardiotoxicity after irradiation.29
from 64% to 25%.64 Findings from functional imaging of the heart after post-
lumpectomy irradiation to the left breast have varied.
Irradiation for Breast Cancer
One study with thallium 201 angioscintigraphy failed to
In older series, postmastectomy radiation therapy for tu- show perfusion defects.68 However, a subsequent study
mors of the left breast was associated with an increased with technetium 99m sestamibi or tetrofosmin imaging
risk of death from heart disease.19,20 Much of this experi- revealed heart perfusion defects in about 40% of the pa-
ence was based on radiation given after radical mastectomy. tients studied, with the incidence varying from 10% to 20%
A 1994 meta-analysis of the effects of postmastectomy among those with less than 5% of the left ventricle in the
irradiation showed a significantly increased risk of death radiation field to as high as 50% to 60% when 75% of the
from heart disease among patients who survived at least left ventricle was in the field.69 Some wall motion abnor-
10 years after the treatment ended.21 Since that time, sev- malities were observed, although functional effects were
eral reviews of large numbers of patients with long-term not evident.69 A smaller study of myocardial perfusion af-
follow-up after radiation therapy for breast cancer have ter  modern technique radiotherapy for early-stage breast
been published describing the risks of cardiac morbidity cancer showed abnormalities in 17 (71%) of 24 patients
and mortality associated with incidental cardiac irradia- with left breast cancer who had had at least 1 cm of heart
tion.22,53,54,57,58,60,65,66 Some report increases in the risk of in the treatment field, but LVEF was normal in all patients,
cardiac events between 10 years and 20 years after treat- and the perfusion defects were not thought to require
ment, although not all studies included an age-matched treatment. By comparison, perfusion defects were seen in
control population for comparison. only 2 (17%) of 12 patients after treatment for right-sided
Increased cardiac risk has been associated with use of breast cancer (P = .002).28
older radiation dosimetric techniques, and presumably the
Irradiation for Hodgkin Disease
use of newer, more conformal techniques would be associ-
ated with less risk, even though the follow-up period for Compared with radiation therapy for breast cancer, radia-
many patients treated with the new techniques has yet to tion therapy for Hodgkin disease typically involves a some-
reach 10 years. The risk of radiation-induced cardiac injury what lower cardiac dose (35 to 45 Gy in 4 to 5 weeks) but
was increased among women undergoing left chest wall often includes a larger cardiac volume. In older reports, the
irradiation after mastectomy because large heart volumes cardiac doses often exceeded 50 Gy.32 More modern tech-
were included; the more conservative approach of lumpec- niques that include partial transmission block shielding of
tomy followed by postoperative partial-breast irradiation the heart, shrinking fields, or interrupted therapy generally
reduces exposure of the heart.23,67 expose smaller heart volumes, and the doses are often
Even with newer techniques, treatment of left-sided 35 Gy or less. Accordingly, follow-up of these patients sug-
breast cancer seems to cause more cardiac morbidity than gests a lower incidence of cardiac injury than in patients
treatment of right-sided breast cancer. A 2006 review of treated previously. For example, the relative risks of myo-
961 patients with stage I or stage II breast cancer treated cardial infarction or cardiac death for patients treated in
18 The Blood Vessels and Heart 419
the 1970s and 1980s ranged from 1.8 to 3.1.24,26,70 In seminoma who had been treated with mediastinal radia-
contrast, two later reviews found no differences in risk of tion showed an increase in the cardiac standardized mor-
coronary artery disease, abnormalities in myocardial per- tality ratio, but only beyond 15 years after the irradiation
fusion, or LVEF in patients with Hodgkin disease who (P < .01).79
were or were not given mediastinal radiation (median car-
Summary of Studies Concerning
diac dose, 35 Gy).52,71 However, a subsequent study that
the Cardiac Effects of Irradiation
included electrocardiography, echocardiography, and exer-
cise stress testing revealed that 47 of 48 long-term survi- Some older series show a modest but significant increase
vors of Hodgkin disease (median mediastinal dose, 40 Gy) in the risk of acute myocardial infarction after mediastinal
showed evidence of cardiac abnormalities in patients with irradiation, a risk that may be related to dose and volume.
no symptomatic heart disease at a median 14.3 years after Newer reviews report lower risk levels of cardiac damage
treatment.72 Clinically significant conduction defects were and less common functional effects among patients treated
present in 75% of patients, valvular disease in 42%, and for breast cancer or Hodgkin disease. For Hodgkin disease,
reduced peak oxygen uptake in 30%.72 Similarly, a group it seems that the previously reported increased risk of death
of 294 patients who had received at least 35 Gy to the resulting from heart disease may relate to the use of older
mediastinum between 1964 and 1994 were shown to have radiation therapy techniques involving higher total doses
a higher than expected incidence of valvular disease, espe- and no cardiac shielding. The use of death certificates to
cially in the aortic valve, on echocardiography; moreover, determine end points and the absence of clear information
the incidence increased over time, being higher among pa- about radiation techniques render these findings inconclu-
tients treated 20 years previously than among those treated sive. Treatment with adequate heart sparing yields minor
10 years previously.73 These 294 patients were also found subclinical functional effects. Because acute myocardial
to be at greater risk for diastolic dysfunction,74 stress- infarction has been reported at radiation doses of less than
induced signs of ischemia, and significant coronary artery 40 Gy, consideration of reducing the cardiac dose or the
disease.73-75 In another study of 286 patients with bulky volume irradiated should be a routine part of treatment
mediastinal disease given radiation therapy after induc- planning for all patients receiving mediastinal irradiation,
tion chemotherapy (median follow-up time, 24 years), the especially young patients with a good probability of long-
15-year actuarial risk of coronary artery disease requiring term survival.
surgical intervention was 4.1%.59
Coronary Irradiation to Prevent
A variety of cardiac abnormalities can appear years after
Restenosis
mediastinal radiation therapy, even though the risk is prob-
ably lower with newer radiation techniques that reduce An in-depth discussion of coronary irradiation to prevent
the cardiac dose and treatment volume. The relative risk of restenosis is beyond the scope of this chapter. However, the
cardiac morbidity increases with younger age at treatment, emergence of intravascular brachytherapy as an effective
longer follow-up, and higher cardiac dose-volumes.58 More- means of reducing the risk of coronary artery restenosis
over, these changes may be progressive. Despite the appar- after angioplasty or stenting for atherosclerotic narrowing
ent lack of clinical symptoms, special attention should be of the coronary arteries warrants discussion of the relevant
given to screening long-term survivors of Hodgkin disease radiobiologic mechanisms of action.
for cardiovascular disease. Findings from animal studies suggest that there is no
reason to believe that irradiation reverses established coro-
Irradiation for Seminoma
nary stenosis; however, irradiation is thought to prevent the
The experience with seminoma provides some information overexuberant healing response associated with balloon
about the effects of cardiac doses less than 30 Gy. Leder- injury or stent implantation. Studies of animals suggest
man and colleagues76 reported a 3.4% incidence of death that activated adventitial macrophages or monocytes are
resulting from acute myocardial infarction in a group of responsible for initiating the arterial neointimal hyperpla-
58 patients with seminoma treated with mediastinal irra- sia and vascular remodeling that occur after angioplasty.80
diation to 24 Gy compared with no cases of infarction in This reaction is the prerequisite for the initiation and per-
61 patients with seminoma treated to the abdomen only. petuation of atheromatous thickening, whether incited by
The relative risk of infarction was 1.97 (P = .019); how- balloon injury or occurring as a natural process. A cyto-
ever, this risk was not different from the risk in the large kine cascade, including platelet-derived growth factor, is
Framingham normal population study.77 In a comparison likely responsible for initiating the macrophage response.81
of risk of cardiovascular disease among more than 2500 Smooth muscle cells also are stimulated to migrate and
patients with seminoma who had received mediastinal ra- proliferate. Radiation delivered immediately after balloon
diation after multiagent chemotherapy versus that in the injury probably is effective because the macrophage popu-
general population,78 the standardized incidence ratio for lation is very radiosensitive; irradiation short-circuits this
coronary artery disease was higher among the irradiated process.
patients at a median follow-up time of 18.4 years. Medi- Several large trials showed that intravascular brachy-
astinal radiation was associated with a 3.7-fold increase in therapy reduced the rates of coronary restenosis after
risk of myocardial infarction compared with surgery alone the placement of stents.82-87 However, clinical tests have
or infradiaphragmatic radiation (neither of which was as- shown that medicated stents can also reduce restenosis
sociated with an increased risk of myocardial infarction). rates after angioplasty to less than 10%. These stents
However, the possible additive effect of the chemotherapy elute antiproliferative agents such as sirolimus or pacli-
regimen given (cisplatin, vinblastine, and bleomycin) was taxel and have the advantage of not requiring the use of
not clear.78 Another study of 453 long-term survivors of radiation-protection measures during their insertion.88-90
420 PART 5 Thorax
As a consequence, the use of intravascular brachytherapy
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