Download Dilated Cardiomyopathy

5
5
Dilated Cardiomyopathy
Biykem Bozkurt and Douglas L. Mann
Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Epidemiology of Dilated Cardiomyopathy . . . . . . . . . .
Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1233
1234
1235
1236
Key Points
• Dilated cardiomyopathy (DCM) refers to a spectrum of
heterogenous myocardial disorders that are characterized
by ventricular dilation and depressed myocardial contractility in the absence of abnormal loading conditions
(such as hypertension or valvular disease) or ischemic
heart disease sufficient to cause global systolic
impairment.
• The dilated cardiomyopathies constitute the largest
group of myopathic disorders that are responsible for systolic heart failure. The reported incidence of DCM varies
annually from about five to eight cases per 100,000 of the
population. In most multicenter, randomized trials in
heart failure, approximately one third of the enrolled
patients have nonischemic dilated cardiomyopathy.
• Once DCM patients become symptomatic, the available
evidence suggests that the prognosis is relatively poor,
with 25% mortality at 1 year and 50% mortality at 5
years. More recent studies suggest that the prognosis for
patients with DCM and mild left ventricular dilation
may be more favorable, perhaps reflecting earlier diagnosis and better treatment.
• Ventricular enlargement, ejection fraction, persistent S3
gallop, right-sided heart failure, elevated left ventricle
(LV) filling pressures, mitral regurgitation, pulmonary
hypertension, electrocardiogram (ECG) fi ndings of atrioventricular block or intraventricular conduction delay,
recurrent ventricular tachycardia, elevated levels of neurohormones, cytokines or markers of myocardial cell
death, impaired peak oxygen consumption, hyponatremia, New York Heart Association (NYHA) class, age >64
years are among a number of parameters that predict a
poor prognosis in patients with DCM.
• The most important point in the treatment of DCM
patients would be to determine the underlying etiology
for which there may be a specific form of treatment. The
differential treatment benefit seen in DCM patients compared with patients with ischemic cardiomyopathy that
Myocardial Diseases Presenting as Dilated
Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237
Clinical Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1247
Treatment Strategies for Dilated Cardiomyopathy . . . 1249
has been observed in several randomized clinical trials
such as with digoxin or amiodarone suggests that there
may be therapeutic differences between ischemic and
nonischemic heart failure (HF).
• Existing studies suggest that both patients with ischemic
cardiomyopathy or DCM have significant survival benefit
from the use of angiotensin-converting enzyme (ACE)
inhibitors and beta-blockers.
• Similarly, in patients with advanced heart failure, aldosterone antagonism with spironolactone or eplerenone
has been reported to reduce mortality; and angiotensin
receptor blockade, when added to background therapy
with ACE-inhibitors, have been shown to reduce combined morbidity and mortality, both in dilated or ischemic cardiomyopathy patients.
• The role of implantable defibrillators for secondary prevention of sudden cardiac death or the use of resynchronization therapy with biventricular pacing to improve
outcomes in a subgroup of patients is clearly established
both for ischemic and nonischemic cardiomyopathy
patients; however, similar evidence supporting the role
of prophylactic implantable cardiodefibrillator (ICD)
implantation in patients with DCM is controversial.
• Treatment modalities using growth hormone, gene
therapy, angiogenesis or cell therapy, immunosuppression, or immunomodulation are promising but remain
investigational at the present time.
Definition
The term dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders (Table 55.1) that
are characterized by ventricular dilation and depressed myocardial contractility in the absence of abnormal loading conditions (such as hypertension or valvular disease) or ischemic
heart disease sufficient to cause global systolic impairment.1,2
The dilated cardiomyopathies constitute the largest group of
myopathic disorders that are responsible for systolic heart
12 3 3
CAR055.indd 1233
11/24/2006 1:28:32 PM
12 3 4
chapter
TABLE 55.1. Etiologies of dilated cardiomyopathy
Idiopathic
Idiopathic dilated cardiomyopathy
Idiopathic arrhythmogenic right ventricular dysplasia
Familial (hereditary)
Autosomal dominant
X-chromosomal
Polymorphism
Toxic
Ethanol
Cocaine
Adriamycin
Catecholamine excess
Phenothiazines, antidepressants
Cobalt
Carbon monoxide
Lead
Lithium
Cyclophosphamide
Methysergide
Inflammatory: infectious etiology
Viral (Coxsackie virus, parvovirus, adenovirus, echovirus,
influenza virus, HIV)
Spirochete (leptospirosis, syphilis)
Protozoal (Chagas’ disease, toxoplasmosis, trichinosis)
Inflammatory: noninfectious etiology
Collagen vascular disease (scleroderma, lupus erythematosus,
dermatomyositis, rheumatoid arthritis)
Kawasaki disease
Hypersensitivity myocarditis
Miscellaneous acquired cardiomyopathy
Postpartum cardiomyopathy
Obesity
Metabolic/nutritional
Thiamine
Kwashiorkor pellagra
Scurvy
Hypervitaminosis D
Selenium deficiency
Carnitine deficiency
Endocrine
Diabetes mellitus
Acromegaly
Thyrotoxicosis
Myxedema
Uremia
Cushing’s disease
Pheochromocytoma
Electrolyte imbalance
Hypophosphatemia
Hypocalcemia
Physiologic agents
Tachycardia
Heat stroke
Hypothermia
Radiation
Autoimmune disorders
failure. Indeed, more than 75 specific diseases can produce a
dilated cardiomyopathic phenotype. Thus, DCM can be envisioned as the final common pathway for a myriad of cardiac
disorders that either damage the heart muscle or, alternatively, disrupt the ability of the myocardium to generate
force and subsequently cause chamber dilation.
In clinical practice and recent multicenter trials in heart
failure (HF), the etiology of HF has often been categorized as
CAR055.indd 1234
55
either ischemic or nonischemic cardiomyopathy, and the
term dilated cardiomyopathy has been interchangeably used
with nonischemic cardiomyopathy. Though this approach
may be practical, it has certain drawbacks.3,4 It fails to recognize that the term nonischemic cardiomyopathy may include
cardiomyopathies due to volume or pressure overload—such
as hypertension or valvular heart disease—that are not conventionally accepted under the definition of DCM.2
Epidemiology of Dilated Cardiomyopathy
The reported incidence of DCM varies annually from about
five to eight cases per 100,000 of the population. The true
incidence may be underestimated due to underreporting or
underdetection of asymptomatic cases of DCM, which may
occur in as many as 50% to 60% of patients. In most multicenter randomized trials in HF, approximately one third of
the enrolled patients have nonischemic DCM.5–7 The ageadjusted prevalence of DCM in the United States averages 36
cases per 100,000 population and DCM accounts for 10,000
deaths annually.8
Compared with whites, African Americans have almost a
threefold increase in risk for developing DCM. This increased
risk for developing DCM in African Americans is not
explained by differences in hypertension, cigarette smoking,
alcohol use, or socioeconomic factors.9,10 Moreover, African
Americans have approximately a 1.5- to 2.0-fold higher risk
of dying from DCM when compared to age-matched whites
with DCM.11–13 Although the reason(s) for these differences
are not known, there are several potential explanations
including differences in the number of risk factors for development of HF, in the rate of progression of HF, the etiology of
HF, access to medical care, and response to therapy. Data
from the second Vasodilator–Heart Failure Trial (V-HeFT II),14
Beta-Blocker Evaluation of Survival Trial,15,16 and Studies of
Left Ventricular Dysfunction (SOLVD)17 suggest that AfricanAmerican patients with HF may not benefit from commonly
used doses of currently recommended therapies to the same
extent as white patients, although unanimity of opinion does
not exist with regard to this issue.18
In general, HF is more common in men than women.
Epidemiologic data suggesting gender-related differences in
the occurrence and prognosis of HF are conflicting and may
be confounded both by differing etiologies of HF. The overall
effect of female gender on the prognosis of HF is not clear at
this time, in large measure because many of the early clinical trials in HF have been comprised predominantly of male
subjects. Women with HF in the Framingham Heart Study
(even after controlling for age and etiology of HF)19 as well as
women in National Health and Nutrition Examination
Survey-I (NHANES-I)20 had improved survival compared
with men. Studies of Left Ventricular Dysfunction, in which
only 15% of the patients were women, reported no difference
in gender related survival.21 However, the SOLVD registry,
which included approximately 20% female patients, suggested that women had significantly higher annual risk of
HF-related mortality and higher rates of hospitalization than
age-matched male subjects.22 In the Italian Multicenter Cardiomyopathy Registry, women with idiopathic DCM presented with more advanced HF; and had a trend toward worse
11/24/2006 1:28:32 PM
12 3 5
di l at e d c a r diom yopat h y
Natural History
The natural history of DCM is not well established for two
reasons: first, as noted at the outset, DCM represents a heterogeneous spectrum of myocardial disorders that may each
progress at different rates; second; the onset of the disease
may be insidious, particularly in the case of familial or idiopathic dilated cardiomyopathies. Indeed, approximately 4%
to 13% of patients with DCM present with asymptomatic
left ventricular dysfunction and left ventricular dilatation.
For these patients, the overall prognosis is unclear. However,
once DCM patients become symptomatic, the available evidence suggests that the prognosis is relatively poor, with 25%
mortality at 1 year and 50% mortality at 5 years (Fig. 55.1).26
The cause of death appears to be primarily pump failure in
approximately 70% of patients with DCM, whereas sudden
cardiac death accounts for approximately 30% of all deaths
in patients with DCM.33,34 However, it should be recognized
that many of the natural history studies of DCM were performed before angiotensin-converting enzyme (ACE) inhibitors and beta-blockers were routinely used. More recent
studies suggest that the prognosis for patients with DCM and
mild left ventricular dilation may be more favorable, perhaps
reflecting earlier diagnosis and better treatment.28,34 Furthermore, it should be recognized that approximately 25% of
CAR055.indd 1235
100
80
Survival (%)
survival.23 Analyses from Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF)24
and Cardiac Insufficiency Bisoprolol Study (CIBIS II)25 betablocker treatment trials in HF suggest that female gender
may be a significant independent predictor of survival in
patients with HF, independent of ischemic or nonischemic
etiology. Thus, further studies will be necessary to defi ne the
role of gender in the prognosis of DCM.
Advancing age is a risk factor for mortality in HF. As
reported in the SOLVD registry, the risk of death at 1 year
for a person over the age of 64 years with HF was 1.5 times
greater than for subjects who were ≥64 years of age.22 Advancing age has been reported as an independent risk factor
for mortality in DCM in several studies.26,27 Indeed, Sugrue
et al.28 reported the relative risk of dying from HF increases
by 0.51 with every 10 years of increase in age.
The prevalence, etiology, and prognosis of DCM can
differ according to the geographic location and sociodemographics of the affected populations. For example, in Western
developed countries, dilated nonischemic cardiomyopathy
accounts for approximately 30% to 40% of the HF population, of which idiopathic cardiomyopathy is the most frequent etiology. The prevalence of DCM in Japan appears to
be about half,29 and in Africa and Latin America approximately double, that of the Western populations.30 As populations go through epidemiologic, socioeconomic transitions
and health care modifications, the features of DCM will
continue to change.31 Failure of treatment and eradication of
AIDS globally and especially in Africa, the rising prevalence
of ethanol or substance abuse in Western countries, the
development of new metabolic and dietary trends in North
America,32 and the success in treatment of protozoal diseases
in Latin America will continue to play a dynamic role in the
epidemiology of DCM.
A
(n = 50)
B
(n = 40)
60
C (n = 201)
40
D (n = 169)
E (n = 104)
F (n = 77)
G (n = 152)
20
0
1
2
3 4
5
6 7
8
9 10
Years after presentation
FIGURE 55.1. Survival of patients with idiopathic dilated cardiomyopathy in seven published series (A to G). n, number of patients
enrolled. To identify each specific series, see Dec and Fuster.26
DCM patients with the recent onset of symptoms of HF will
improve spontaneously, including patients who have been
referred for cardiac transplantation.35 This statement notwithstanding, patients with symptoms lasting more than 3
months who present with severe clinical decompensation
generally have less chance of recovery.35
As shown in Table 55.2 there are a number of other
parameters that predict a poor prognosis in patients with
TABLE 55.2. Factors predicting a poor prognosis in patients with
dilated cardiomyopathy
Left ventricular enlargement
Right ventricular enlargement
Left and right ventricular ejection fraction
Elevated LV fi lling pressures
Persistent S3 gallop
Right-sided heart failure
Pulmonary hypertension
Moderate to severe mitral regurgitation
ECG fi ndings: fi rst- or second-degree atrioventricular block, or
LBBB
Recurrent ventricular tachycardia
Reduced heart rate variability
Late potentials of QRS in signal average ECG
Myocytolysis on endomyocardial biopsy
Elevated levels of neurohormones [brain natriuretic peptide (BNP),
norepinephrine (NE), plasma renin activity (PRA) and
endothelin 1 (ET-1)]
Elevated levels of cytokines (TNF-α and IL-6)
Elevation of serum CK/MB, troponin T, troponin I levels
Peak oxygen consumption <10 to 12 mL/kg/min
Reduced contractile response with dobutamine
Serum sodium <137 mmol/L
Advanced New York Heart Association class
Advanced age (>64 years)
11/24/2006 1:28:32 PM
12 3 6
chapter
DCM, including left ventricular (LV) and right ventricular
(RV) enlargement,26,27,36,37 LV and RV ejection fraction,38 persistent S3 gallop, right-sided HF, elevated LV filling pressures,39 moderate to severe mitral regurgitation,40 pulmonary
hypertension, electrocardiogram (ECG) fi ndings of first- or
second-degree atrioventricular block, left bundle branch
block (LBBB) or marked intraventricular conduction delay,
recurrent ventricular tachycardia,41 reduced heart rate variability,42 late potentials of QRS in signal average ECG,43
myocytolysis on endomyocardial biopsy,44 elevated levels of
neurohormones (norepinephrine, plasma renin activity, atrial
natriuretic peptide, brain natriuretic peptide and endothelin1),45,46 elevated levels of cytokines (tumor necrosis factor-α
and interleukin-6),47,48 persistently elevated markers of myocardial cell death (elevation of serum troponin T levels),49 an
increased ratio of creatine kinase MB2/MB1,50 peak oxygen
consumption <10 to 12 mL/kg/min,51–53 serum sodium
<137 mmol/L,54 New York Heart Association class rating,55
age >64 years,22 and reduced contractile response with dobutamine.56–60 Concomitant renal or hepatic dysfunction may
limit the use of optimal diuretics or ACE inhibitors and
therefore may have an impact on prognosis that is not easily
appreciated. Finally, it should be emphasized that comorbid
conditions such as diabetes and hypertension increase the
risk of developing HF approximately fivefold.
Ischemic vs. Dilated Cardiomyopathy
In general practice and clinical research trials, the term ischemic cardiomyopathy is defined as cardiomyopathy due to
ischemic heart disease. The classification of cardiomyopathies proposed by the World Health Organization/International Society and Federation of Cardiology (WHO/ISFC)
Task Force in 1995,2 however, defi nes ischemic cardiomyopathy as “a dilated cardiomyopathy with impaired contractile
performance not explained by the extent of coronary disease
or ischemic damage” reserved for the remodeling process of
the noninfarcted myocardium. In this chapter, we use the
term ischemic cardiomyopathy defined as cardiomyopathy
due to ischemic heart disease rather than the WHO/ISFC
task force definition.
The existing clinical studies suggest that patients with
idiopathic DCM have a lower total mortality.61 The risk of
sudden cardiac death, however, appears to be relatively higher
in patients with DCM in some studies.61 The differential
treatment benefit seen in DCM patients compared with
patients with ischemic cardiomyopathy that has been
observed in several randomized clinical trials such as with
digoxin62,63 or amiodarone64 suggest that there may be therapeutic differences between ischemic and nonischemic HF.
Similar earlier reports of survival difference with betablockers7 or amlodipine65 in patients with dilated but not
ischemic cardiomyopathy have not been reproduced in subsequent large-scale randomized trials,5,7,66 in which the
benefit was similar in both the ischemic and nonischemic
HF patients. This has raised the question of whether there
truly is a difference in response to treatment according to
etiology of HF. On the other hand, the absence of a rigorous
definition of nonischemic HF in many studies may account
for this discrepancy and make interpretation of the results
CAR055.indd 1236
55
difficult. Further studies to clarify the effects of the etiology
of HF could be particularly important to achieve further
treatment benefit over and above the conventional treatment
strategies that target HF as a single disease entity.
Pathophysiology
Dilated cardiomyopathy may be viewed as a progressive disorder that is initiated after an “index event” either damages
the heart muscle, with a resultant loss of functioning cardiac
myocytes, or alternatively disrupts the ability of the myocardium to generate force, thereby preventing the heart from
contracting normally. This index event may have an abrupt
onset, as in the case of acute exposure to toxins, or it may
have a gradual or insidious onset, as in the case of hemodynamic pressure or volume overloading, or it may be hereditary, as in the case of many of the familial cardiomyopathies.
Regardless of the nature of the inciting event, the feature that
is common to each of these index events is that they all, in
some manner, produce a decline in pumping capacity of the
heart.
The anatomic and pathophysiologic abnormalities that
occur in LV remodeling are discussed in another chapter.
Patients with DCM generally present with dilation of all four
chambers of the heart (Fig. 55.2). Despite the fact that there
is thinning of the left ventricular wall in patients with DCM,
there is massive hypertrophy at the level of the intact heart,
as well as at the level of the cardiac myocyte, which has a
characteristic elongated appearance that is observed in myocytes obtained from hearts subjected to chronic volume overload (Fig. 55.3). The coronary arteries are usually normal in
DCM, although it should be emphasized that the end-stage
FIGURE 55.2. Pathology of normal heart (left) and a dilated cardiomyopathic ventricle (right). The dilated cardiomyopathic ventricle
is characterized by enlargement of all four cardiac chambers, and a
more spherical shape, in comparison to the normal ventricle.
11/24/2006 1:28:32 PM
di l at e d c a r diom yopat h y
12 37
Idiopathic Dilated Cardiomyopathy
A
B
FIGURE 55.3. Cardiac myocyte structure (A) in normal myocardium and in dilated cardiomyopathy (B). Cardiac myocytes isolated
from myocardium from patients with DCM have an elongated
shaped as the result of the sarcomeres being formed in series.
Although the term idiopathic DCM has become synonymous with that of DCM in some HF parlance, the word
idiopathic was originally intended to characterize the subset
of DCM patients in whom no known etiologic cause for
ventricular dilation and depressed myocardial contractility
was apparent. However, with increasing sophistication in
diagnostic testing, clinicians have become aware that many
cases of so-called idiopathic DCM may occur as the result
of inherited or spontaneous mutations of genes that regulate
cardiac structure or function, such as the genes for cytoskeletal proteins, or as a consequence of undiagnosed hypertension, autoimmune diseases, viral illness, or toxin exposure.
Nonetheless, in the context of this chapter, we use the term
idiopathic DCM to refer to those patients with DCM whose
etiologic cause remains unknown. As shown in Figure 55.4,
idiopathic DCM represents the largest subset of patients
with DCM; however, as alluded to immediately above, it is
likely that the proportion of patients with idiopathic DCM
will diminish with increased sophistication in diagnostic
testing.
Familial Cardiomyopathy
“ischemic cardiomyopathies” may also present with a dilated
phenotype. The cardiac valves are anatomically normal;
however, there is usually tricuspid and mitral annular dilatation due to cavity enlargement, distortion of subvalvular
apparatus, and stretching of the papillary muscles giving rise
to valvular regurgitation. Intracavitary thrombi are common,
usually in the ventricular apex.
Myocardial Diseases Presenting as
Dilated Cardiomyopathy
Alcoholic/Toxic Cardiomyopathy
As shown in Figure 55.4, the most common causes of DCM
are idiopathic, alcoholic/toxic, inflammatory, familial, and
miscellaneous (inflammatory noninfections, acquired, metabolic, and nutritional) causes. However, it should be recognized that the exact prevalence of the various forms of DCM
varies based on the demographics of the patient population.
In the subsections that follow, we review that various specific etiologies that lead to the development of DCM.
Idiopathic
Viral
Alcoholic/toxic
Miscellaneous
Familial
FIGURE 55.4. Etiologies of dilated cardiomyopathy. As shown, the
most frequent causes of DCM are idiopathic dilated cardiomyopathy, familial cardiomyopathy, alcoholic/toxic cardiomyopathy, viral
cardiomyopathy, and miscellaneous (inflammatory noninfections,
acquired, metabolic, and nutritional causes).
CAR055.indd 1237
There is growing evidence that many cases of previously
diagnosed “idiopathic” DCM have a genetic basis. Indeed,
although the familial occurrence of idiopathic DCM was
first recognized by Battersby and Glenner in 1961,67 it has
not been until recently that investigators have been able to
delineate the molecular basis for genetic cardiomyopathies.
It is estimated that at least 20% to 30% of DCM cases are
familial.68
Alcoholic Cardiomyopathy
Chronic alcoholism is one of the most important causes of
DCM in the Western world.69 It is estimated that two thirds
of the adult population use alcohol to some extent and more
than 10% are heavy users.70 In the United States, in both
sexes and all races, long-term heavy alcohol consumption (of
any beverage type) has been cited by some investigators as the
leading cause of a nonischemic DCM.69 A large proportion of
chronic alcoholics demonstrate impairment of cardiac function. The clinical diagnosis of alcoholic cardiomyopathy can
be made when biventricular dysfunction and dilation are
persistently observed in a heavy drinker, in the absence of
other known causes for myocardial disease.71 Thus, the diagnosis of alcoholic cardiomyopathy remains a diagnosis of
exclusion. The prevalence of alcoholic cardiomyopathy is
variable and ranges from 23% to 40%. In some series, as many
as 21% of subjects with excessive alcohol intake were reported
to have clinical evidence of HF.72 Alcoholic cardiomyopathy
most commonly occurs in men 30 to 55 years of age who have
been heavy consumers of alcohol for more than 10 years.73
Women represent approximately 14% of the alcoholic cardiomyopathy cases, but women may be more vulnerable to the
development of alcohol-related cardiomyopathy, since it has
been reported that alcoholic cardiomyopathy develops in
11/24/2006 1:28:33 PM
12 3 8
chapter
women with a lower total lifetime exposure to alcohol compared to men.69 In all races, death rates due to alcoholic heart
muscle disease are greater in men compared to women, and
are greater in African-American men and women compared
to white men and women with alcoholic cardiomyopathy.69
Even before the clinically overt HF, LV contractile dysfunction can be demonstrated in alcoholics. Although chronic
alcoholic liver disease and HF usually are not observed clinically in the same patient, cirrhotic patients may present with
asymptomatic LV dysfunction, in which case atrial fibrillation is usually the initial presenting manifestation of cardiac
dysfunction.74 The point at which these abnormalities appear
during the course of an individual’s lifetime of drinking, such
that the abnormalities can be called a DCM, is not well established and is highly individualized.
The risk of developing alcoholic cardiomyopathy is
related to both the mean daily alcohol intake and the duration of drinking. In general, alcoholic patients consuming
>90 g of alcohol a day (approximately seven to eight standard
drinks per day) for more than 5 years are at risk for the development of asymptomatic alcoholic cardiomyopathy. Those
who continue to drink may become symptomatic and develop
signs and symptoms of HF. However, it bears emphasis that
there is significant individual susceptibility to the toxic
effects of alcohol. For example, it is not known whether the
persistent DCM that develops in only 1% to 2% of chronic
drinkers occurs because of genetic predisposition or because
of the presence of synergistic cardiovascular risk factors such
as hypertension or arrhythmias.
Studies in experimental animals have demonstrated
that both acute and chronic ethanol administration impairs
cardiac contractility. Alcohol results in acute as well as
chronic depression of myocardial contractility even when
ingested by normal individuals in quantities consumed
during social drinking.75 Compensatory mechanisms such as
vasodilation or sympathetic stimulation may mask the direct
acute myocardial depressant effects of alcohol. Despite the
known deleterious effects of alcohol, it has been difficult to
produce HF in animal models in which ethanol has been
administered. Thus, the direct causal relationship between
alcohol consumption and the development of cardiomyopathy has not been rigorously demonstrated in experimental
models, despite the long-recognized clinical relationship
between alcohol consumption and the development of DCM.
The pathophysiology and progression of alcoholic cardiomyopathy is complex and involves changes in many aspects of
myocyte function.
The potential mechanisms that have been invoked to
explain the depressed myocardial function include the direct
toxic effects of alcohol on striated muscle, since most alcoholics have manifestations of skeletal myopathy and cardiomyopathy.76,77 Shifts in the relative expression of the
contractile proteins β-myosin heavy chain (β-MHC) to αMHC have been reported in animal models after exposure
to ethanol.69 Alcohol and its metabolite acetaldehyde can
also cause alterations in cellular calcium, magnesium, or
phosphate homeostasis. The toxic effects of acetaldehyde or
the formation of fatty acid ethyl esters may also impair mitochondrial oxidative phosphorylation. In acute ethanol toxicity, free radical damage or ischemia may occur, possibly due
to increased xanthine oxidase activity or β-adrenergic stimu-
CAR055.indd 1238
55
lation, respectively.78 In addition, ethanol and its metabolites
interfere with numerous membrane and cellular functions
such as transport and binding of calcium, mitochondrial
respiration, lipid metabolism, myocardial protein synthesis,
signal transduction, and excitation contraction coupling.70,76,79
Both autopsy and endomyocardial biopsy specimens from
alcoholic cardiomyopathy patients reveal marked mitochondrial swelling, with fragmentation of cristae, swelling of
endoplasmic reticulum, cytoskeletal disorganization, and
destruction of myofibrils.78 Several studies suggest that heavy
drinking alters both lymphocyte and granulocyte production
and function, raising the possibility that myocardial damage
secondary to prolonged alcohol consumption might initiate
autoreactive mechanisms comparable to those observed
in viral or idiopathic myocarditis. The point at which the
changes in mitochondrial, sarcoplasmic reticulum, contractile protein, and calcium homeostasis culminate in intrinsic
cell dysfunction is incompletely understood. There are
several early reports that support the role for myocyte loss
as a final mechanism underlying alcohol-induced cardiac
dysfunction.80 Apoptosis has been proposed as a critical
mechanism for the development of fetal alcohol syndrome.81
Application of insulin-like growth factor-1 (IGF-1) has been
reported to attenuate the apoptotic effects of ethanol in
primary neonatal myocyte cell cultures.69
Recent reports suggest that certain genetic traits influence the occurrence, pathogenesis, and progression of alcoholic cardiomyopathy, which may explain interindividual
variations in the sensitivity of the myocardium to alcoholinduced myocardial damage. These include multiple point
mutations in the mitochondrial DNA, which have been associated with the occurrence of other cardiomyopathies.82 In
addition, nutritional deficiencies, commonly thiamine deficiency, may play an additive role to the direct myocardial
damage of ethanol. Thus, the cardiomyopathy that develops
following chronic alcohol consumption may be multifactorial in origin.
The management of patients with alcohol cardiomyopathy begins with total abstinence from alcohol, in addition to
the conventional management of HF, as described below.
There are currently no studies of specific pharmacotherapies
in patients with alcoholic cardiomyopathy other than the
standard therapy for HF; however, there are numerous reports
that detail the reversibility of depressed left ventricular
dysfunction after the cessation of drinking.83,84 Even if the
depressed left ventricular function does not normalize completely, the symptoms and signs of congestive HF improve
after abstinence.84 However, the overall prognosis remains
poor, with a mortality of 40% to 50% within 3 to 6 years, if
the patient is not abstinent.69 Survival is significantly lower
for patients who continue to drink compared to patients with
idiopathic DCM or alcoholic cardiomyopathy patients who
abstain.69,85
Cocaine Cardiomyopathy
Long-term abuse of cocaine, a drug that causes postsynaptic
nervous system norepinephrine reuptake blockade and possible presynaptic release of dopamine and norepinephrine,
may eventuate in DCM even without the presence of coronary artery disease, vasculitis, or regional myocardial injury.
11/24/2006 1:28:33 PM
di l at e d c a r diom yopat h y
This has been termed “cocaine-related cardiomyopathy” and
perhaps reflects the direct toxicity of the cocaine on the
myocardium. In 84 asymptomatic cocaine abusers studied at
least 2 weeks after abstinence from the drug, Bertolet and
colleagues86 found that 7% had left ventricular dysfunction.
These patients were young and did not have evidence of
myocardial infarction or coronary arterial disease. Depressed
LV function (LV ejection fraction <45%) has been reported in
4% to 9% of asymptomatic cocaine abusers.87,88 Similarly,
Moliterno et al.89 reported 18% of cocaine abusers who
underwent cardiac catheterization had normal coronary
arteries with low ejection fraction and global hypokinesia.
The cardiovascular evaluation of a patient with cocaine
abuse usually reflects the following. The ECG may reveal
increased QRS voltage, early repolarization, ischemic or nonspecific ST-T changes, or pathologic Q waves. Episodes of ST
elevation may be seen during Holter monitoring. The echocardiogram usually reveals left ventricular hypertrophy. Segmental wall motion abnormalities usually suggest myocardial
injury; however, as mentioned above, approximately 18% of
patients with cocaine abuse manifest global hypokinesia
and depressed myocardial function. Cardiac catheterization
in these patients may reveal normal coronaries or mild coronary artery disease not significant enough to explain the
extent of myocardial dysfunction. However, accelerated coronary atherosclerosis, coronary vasculitis, coronary spasm,
or coronary thrombosis are perhaps more common fi ndings
in cocaine-related heart disease.
Cocaine may produce left ventricular dysfunction
through its direct toxic effects on the myocardium, by provoking coronary arterial spasm (and hence myocardial ischemia), and by causing increased release of catecholamines,
which may be directly toxic to cardiac myocytes.90 These
effects decrease myocardial oxygen supply and may increase
demand if heart rate and blood pressure rise. The vasoactive
effects of cocaine are further complicated with enhanced
platelet aggregation, anticardiolipin antibody formation, and
endothelial release of potent vasoconstrictors such as endothelin-1. Upregulation of tissue plasminogen activator inhibitors, increased platelet aggregation, and decreased fibrinolysis
by cocaine predispose to coronary thrombosis and/or microvascular disease.87,91 Myocarditis with inflammatory lymphocyte and eosinophils has also been reported in 20% of
patients dying of natural or homicidal causes in whom
cocaine was detected, raising the possibility of hypersensitivity myocarditis due to cocaine or associated contaminants.92 Alternatively, the myocarditis may occur directly in
response to the necrosis that is caused by cocaine. Scattered
foci of myocyte necrosis, contraction band necrosis, and foci
of myocyte fibrosis have been reported in patients with
cocaine abuse. Additionally, experimental studies and clinical case reports suggest that cocaine may also cause lethal
arrhythmias. Cocaine prolongs repolarization by a depressant effect on potassium current and may generate early
afterdepolarizations.87
Other than abstinence, very little is known about the
treatment of cocaine-induced cardiac dysfunction. Indeed,
there are case reports of reversibility of cardiac function after
cessation of drug use.93 In patients who develop cardiomyopathy, the traditional therapy for LV dysfunction is appropriate. Given that some of the toxicity of cocaine is caused
CAR055.indd 1239
12 3 9
by catecholamine excess or myocardial ischemia, the use of
β-adrenergic blocking agents appeared to be a logical treatment, both in terms of preventing further disease progression
as well as treating the ventricular arrhythmias that are prone
to develop in this setting. Two decades ago, the treatment
of cocaine-induced cardiovascular effects favored the use of
beta-blockers, especially propranolol. As the clinical use of
propranolol increased, reports of accentuation of cocaineinduced hypertension and myocardial ischemia began to
surface, blaming the unopposed alpha effects of the betablockers. Although these reports were isolated, the routine
use of propranolol and subsequently all β-adrenergic blockers
decreased to the point that beta-blockers were considered
relatively contraindicated in treating cocaine-induced cardiovascular emergencies. The end result is that an entire
generation of potent and selective β-adrenergic blocking
agents have been overlooked, for both acute and chronic
treatment of cocaine-related cardiac disease, all in the name
of “unopposed alpha effects.” The focus of treatment shifted
from the cardiovascular effects to combating central nervous
stimulation. As a result, benzodiazepines have been the drug
of choice in treating the cerebrovascular and subsequent
systemic hyperadrenergic complications of cocaine, and
nitroprusside or phentolamine has been advocated for peripheral vasodilatory effects. It is now becoming apparent that
the treatment of cardiovascular effects of cocaine should
involve a multifactorial approach to combat both central
nervous system and peripheral vasospastic effects of cocaine.
In this regard, β-adrenergic blocking agents, especially betablocking agents with both alpha- and beta-blocking properties such as labetalol or carvedilol, may play an important
role in treating cocaine-related cardiomyopathies.94
Anthracycline
Anthracyclines, such as doxorubicin (Adriamycin) and daunorubicin, produce cardiac toxicity, possibly by increasing
oxygen free radical generation, platelet-activating factor,
prostaglandins, histamine, calcium, and C-13 hydroxy
metabolites, or by interfering with sarcolemmal sodium
potassium pump and mitochondrial electron transport
chain.95 The formation of oxygen free-radicals that are generated by iron-catalyzed pathways appears to be the most
important pathway in the pathogenesis of anthracyclineinduced cardiomyopathy, as it has been noted that ironchelating agents that prevent generation of oxygen
free-radicals, such as dexrazoxane, are cardioprotective.
Due to their high antineoplastic activity, anthracycline
antibiotics are the most widely used agents in oncology practice. During the recent clinical trials, the prevalence of anthracycline-induced cardiomyopathy has been noted to increase.96
This may be due to mainly the improvement of diagnostic
methods, the tendency to use high doses of anthracyclines,
limited cardioprotection, and prolonged survival time of
patients with malignancies, as well as combined treatment
methods characterized by synergistic cardiotoxicity.
The toxic effect of anthracyclines on the heart may occur
at any stage of treatment. Three major types of anthracycline
cardiotoxicity are distinguished—acute, chronic, and late
onset—which differ considerably as to clinical picture and
prognosis.96,97 Acute complications are observed in 0.4% to
11/24/2006 1:28:33 PM
12 4 0
chapter
41% of patients, and their occurrence is directly connected
with the administration of these agents. Arrhythmias occur
during or several hours after the infusion and most frequently
manifest as repolarization abnormalities, low-voltage QRS
complex, sinus tachycardia, accessory ventricular and supraventricular beats, or QT prolongation. Acute myocardial
ischemia is rarely observed. These electrocardiographic
disturbances are usually asymptomatic and reversible, withdrawing spontaneously several hours (arrhythmia) or several
weeks (changes in ST-T) after the completion of chemotherapy. In some cases, the cardiotoxicity may progress into fulminant cardiac failure, which may be fatal in some cases.
Chronic cardiotoxicity is a result of repeated exposure of
cardiomyocytes to anthracycline antibiotics; it is observed
in 0.4% to 23% of the patients treated.96,97 Several weeks or
months after chemotherapy, severe congestive HF develops
(it usually affects the left ventricle, or rarely both ventricles),
with features of biventricular overload and low QRS voltage.
The clinical picture of post-anthracycline cardiomyopathy is
not distinct; the most common symptoms include decreased
exercise tolerance, effort dyspnea, cardiomegaly on chest xray, and lower left ventricular ejection fraction (LVEF) on
echocardiography. The pharmacologic treatment of HF can
improve the quality of life and reduce the frequency of HF
complications; however, cardiomyopathy due to anthracycline still carries a very poor outcome, with mortality
rates ranging from 27% to 61% despite aggressive medical
treatment. A less favorable prognosis is associated with
early-onset HF developing within the first 4 weeks after
chemotherapy. Late cardiotoxicity is diagnosed within
several years after chemotherapy. It may occur in children or
adults who received relatively low total doses of doxorubicin
(<480 mg/m2) and may clinically manifest as congestive HF,
arrhythmia, or conduction abnormalities, such as atrioventricular block, ventricular, tachycardia, or fibrillation.
Approximately 5% of the patients treated with doxorubicin
may develop HF or symptomatic arrhythmia in 10 years.97
The prognosis of anthracycline-induced cardiomyopathy
relates to the time course of treatment and preexisting additional risk factors for myocardial injury such as radiation,
coexisting coronary artery disease, and preexisting cardiac
dysfunction. In general, patients with anthracycline-induced
cardiomyopathy generally have a worse survival than that
seen with idiopathic DCM. Cardiomyopathy develops more
frequently in the patients under age 15 or over age 65 during
doxorubicin treatment. Among children treated with anthracyclines, girls are more sensitive to cardiotoxic effects of
this agent than boys, although the reason for this is
unknown.98 The pharmacokinetic data demonstrate that
cardiotoxicity increases with higher drug concentrations in
the serum. Thus, high single doses or short-term intravenous infusions of doxorubicin may be associated with
more cardiotoxicity than continuous low-dose infusions.
Prior irradiation of mediastinum is also associated with
increased cardiotoxicity. It was estimated that risk of postanthracycline cardiomyopathy increased by 1.6 when there
was a history of radiation of the heart. Improper nutrition,
diabetes, or simultaneous administration of other antineoplastic agents damaging the myocardium such as cyclophosphamide, actinomycin D, mitomycin C, mithramycin,
dacarbazine, bleomycin, etoposide, cisplatin, busulphan,
CAR055.indd 1240
55
methotrexate, melphalan, and vincristine have been associated with increased cardiotoxicity.
The most powerful predictor of anthracycline toxicity is
the total cumulative dose administered. Clinically apparent
cardiotoxicity is rare (less than 3%) below cumulative doses
of 400 mg/m2, and toxicity becomes more frequent at higher
doses. Nonetheless, it bears emphasis that subclinical cardiac
toxicity or myocardial damage can be demonstrated even at
lower doses. For example, Bristow et al.99 demonstrated evidence of myocyte damage on endomyocardial biopsy in 93%
of the patients who received greater than 272 mg/m2 and in
3% of the patients who received as little as 45 mg/m2.
Available data suggest that circulating markers such as
cardiac troponins and brain natriuretic peptide (BNP) could
potentially be useful for predicting cardiac toxicity with
anthracycline. Elevated levels of cardiac troponin have been
positively correlated with the dose of anthracycline administered. Cardiac troponin T (cTnT) levels were reported to be
elevated in about 30% of children treated with doxorubicin,
and cardiac troponin I (cTnI) in about one third of adults 12
to 72 hours after high-dose chemotherapy. Raised concentrations of cardiac troponins sometimes persist for months,
suggesting long-term myocardial injury.100 Moreover, elevated levels of troponins correlated also with anthracyclineinduced cardiac damage; a raised cTnI indicated a significantly
greater decrease in LVEF (by an absolute 16% on average
compared with only 5% when the cTnI was not raised).100
Clinical trials are currently evaluating the role of these
markers in predicting both early and late clinical and subclinical damage associated with anthracyclines.
The current guidelines for administration and monitoring of patients receiving doxorubicin is as follows: doxorubicin should not be administered to patients with a baseline
LVEF of ≤30%. If the baseline LVEF is between ≥31% and
<50%, LV function should be assessed prior to each subsequent dose, and doxorubicin therapy should be discontinued
if the LVEF declines by ≥10% or to a value <30%. If, on the
other hand, the patient has a baseline LVEF of ≥50%, an
assessment of the LVEF should be repeated after the patient
has received a total dose of 300 to 350 mg/m2, and then again
after each subsequent dose of doxorubicin. Therapy should
be discontinued if the LVEF declines by ≥10% or to a value
<50%. In addition to the guidelines for administration of
doxorubicin outlined above, patients who develop HF should
be managed with conventional HF management, which may
lead to symptomatic improvement in 65% to 87% of
patients.101,102 Indeed, complete reversal of left ventricular
dysfunction has been reported in anecdotal cases.101
Prevention of anthracycline-induced myocardial damage
by use of free radical “scavengers” and antioxidants may
reduce cardiotoxicity in some patients. The investigations of
vitamin E, ascorbic acid, Q-10 coenzyme and N-acetylcysteine have not proved them to be cardioprotective.102 At present,
the most effective protection of cardiomyocytes during chemotherapy with anthracyclines is with dexrazoxane (ICRF187-cardioxan).103 This preparation chelates intracellular iron
in vitro and in vivo and it decreases the level of free radicals;
additionally, it regulates topoisomerase II activity and has an
immunomodulating effect on myocarditis secondary to the
administration of anthracycline. Randomized clinical trials
showed a cardioprotective effect of dexrazoxane reflected in,
11/24/2006 1:28:33 PM
di l at e d c a r diom yopat h y
for example, a two- to threefold decrease in the risk of anthracycline-induced cardiomyopathy as well as a significantly
lower percentage of severe damage of cardiomyocytes in
heart biopsies. However, further studies are necessary before
introducing dexrazoxane into wide clinical practice. Although
the drug proved efficient in the prevention of early anthracycline cardiotoxicity, its role in the prophylaxis of late myocardial damage remains unknown. Another antioxidant
raising hope for selective cardioprotection during chemotherapy with anthracyclines is probucol, a vitamin E derivative used in the treatment of lipid disorders.104 Preclinical
studies revealed that it increased possible neutralization
of free radicals in cardiocytes by stimulating the activity of
glutathione peroxidase and superoxide dismutase. Although
the results of preclinical studies are promising, no randomized trials were conducted with probucol in humans.104 The
cardioprotective activity of the compounds without antioxidant preparations, such as β-adrenergic receptor inhibitors,
calcium channel antagonists, antihistamine and antiinflammatory drugs, digitalis glycosides, prednisone, bipyridine
derivatives (amrinone, milrinone), and carnitine have not
demonstrated efficacy for prevention of anthracyclineinduced cardiomyopathy.97,104 Synthesis of doxorubicin analogues with lesser cardiotoxic characteristics have not been
very promising thus far either.96
Other chemotherapeutic agents in cancer associated with
cardiac toxicity complication are the monoclonal antibody
trastuzumab (Herceptin), high-dose cyclophosphamide,
mitomycin-C, 5-fluorouracil, and the interferons. These
agents can cause decreased left ventricular function, which
in some cases may result in clinical manifestations of congestive HF. Trastuzumab has proved to be a useful palliative
treatment for metastatic breast cancers that overexpress
HER2/neu protein (about 30% of all breast cancers), and it is
the first new agent to improve survival for patients with
metastatic breast cancer in the past 25 years.105 The occurrence of cardiac toxicity was unexpectedly high (28%) in
patients treated with trastuzumab (Herceptin), either as a
single agent or in combination with chemotherapy, especially in patients previously or concomitantly treated with
anthracyclines.105 This was a surprising finding as cardiac
toxicity could not be predicted on the basis of the putative
mechanism of action of the antibody. The mechanism of
trastuzumab-associated cardiac dysfunction is unknown.
Although the family of human epidermal growth factors, of
which HER2/neu is a member, has an important role in
cardiac embryogenesis, there is little evidence of localization
of anti-HER2/neu to cardiac tissue. Importantly, this toxic
effect seems to respond better to medical therapy for congestive HF than does anthracycline-induced dysfunction.100
Other Myocardial Toxins
In addition to the classic toxins described above, as shown
in Table 55.1, there are a number of other toxic agents that
may lead to left ventricular dysfunction and HF, including
cobalt and catecholamines.
Inflammation-Induced Cardiomyopathy
Over the past 10 to 15 years, there has been increasing evidence that suggests that inflammation or inflammatory pro-
CAR055.indd 1241
12 41
cesses may contribute to the overall pathogenesis of DCM.
Moreover, there is increasing evidence that biologic properties of inflammatory mediators, such as proinflammatory
cytokines, are also sufficient to produce a dilated cardiac
phenotype.106,107 As will be discussed below, both infectious
and noninfectious inflammatory processes may lead to the
development of DCM. Although a great many infections and
noninfectious processes may impact the myocardium, and
may transiently lead to systolic dysfunction and congestive
symptomatology, the great majority of these infections and
noninfectious processes do not lead to the development of
DCM. Therefore, in the section that follows, we focus primarily on those disease states that are considered to lead to
DCM.
Infectious Causes
VIRAL CARDIOMYOPATHY
The subject of viral myocarditis is covered in detail in
another chapter.
ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)
Several investigators have reported that there is an association between AIDS and DCM.108,109 Reviews and studies published before the introduction of highly active antiretroviral
therapy (HAART) regimens have correlated the incidence
and course of human immunodeficiency virus (HIV) infection in relation to DCM in both children and adults. In a
long-term echocardiographic follow-up by Barbaro and
coworkers,110 8% of initially asymptomatic HIV-positive
patients were diagnosed with DCM during the 60-month
follow-up. All patients with DCM were in NYHA functional
class III (84%) or IV (16%). The mean annual incidence rate
was 15.9 cases per 1000 patients. The extent of immunodeficiency of the patients, as assessed by the CD4 count, influenced the incidence of DCM; specifically, there was a higher
incidence among patients with a CD4 count of less than 400
cells per cubic millimeter.
Current hypotheses concerning the pathogenesis of cardiomyopathy associated with infection with HIV include
infection of myocardial cells with HIV type 1 (HIV-1) or coinfection with other cardiotropic viruses, postviral cardiac
autoimmunity, autonomic dysfunction, cardiotoxicity from
illicit drugs and pharmacologic agents (such as nucleoside
analogues and pentamidine), nutritional deficiencies, and
prolonged immunosuppression. It has been demonstrated
that targeted myocardial expression of HIV transactivator in
transgenic mice results in cardiomyopathy and mitochondrial damage,111,112 emphasizing the role of the HIV infection
itself in AIDS cardiomyopathy. The role of myocarditis in
the development of DCM in HIV has not been fully characterized.113 Lymphocytic myocarditis can be found at autopsy
in 46% to 52% of patients with AIDS, as reported in a review
of the literature.114 Autopsy series of persons dying from
AIDS-related illnesses demonstrate histologic evidence of
myocarditis in approximately 50% of the patients. Symptomatic HF is seen in approximately half of these patients with
myocardial involvement. Whether early treatment with ACE
inhibitors or beta-blockers will prevent or retard disease progression in these patients is unknown at this time. The
treatment of patients with symptomatic HIV cardiomyopa-
11/24/2006 1:28:34 PM
12 4 2
chapter
thy is the same as the conventional treatment for patients
with DCM.
CHAGAS’ DISEASE
Although Chagas’ disease is a relatively uncommon cause of
DCM in North America, it remains a leading cause of death
in many areas of Central and South America. Indeed, 50,000
people die of Chagas’ disease each year.115 Trypanosoma
cruzi, the causative organism for Chagas’ disease, is found
only in the Western Hemisphere, where it primarily infects
wild and domestic mammals and insects. Humans become
involved when infected vectors infest the simple houses that
are common in Latin America. It is estimated that 16 to 18
million people have chronic T. cruzi infection. Chagas
control programs in certain South American countries have
demonstrated significant decline in the seropositive subjects
from 47.8% to 17.1%, which is most marked among children
and teenagers, declining from 29.9% to 1.9%, suggesting
reduction in transmission of the disease.116
There are three different clinical and pathophysiologic
phases of disease: acute, indeterminate, and chronic. Sudden
cardiac death can occur during each phase; however, DCM
is a late manifestation of the disease and is generally seen
during the chronic phase. Acute Chagas’ disease is usually
a mild illness with a case fatality rate of less than 5%. The
systemic spread of the parasites from the site of entry and
their initial multiplication may be accompanied by fever,
malaise, and edema of the face and lower extremities, as well
as generalized lymphadenopathy and hepatosplenomegaly.
Muscles, including the heart, are often heavily parasitized,
and severe myocarditis develops in a small proportion of
patients. The acute illness resolves spontaneously over a
period of 4 to 6 weeks in most patients, who then enter the
indeterminate phase of T. cruzi infection. In this phase, there
are no symptoms, but there are lifelong, low-grade parasitemias in association with antibodies to many T. cruzi antigens. Many people in this phase have subtle signs of cardiac
or gastrointestinal involvement long before the disease
becomes symptomatic. Most infected people remain in the
indeterminate phase for life. However, this carrier state can
be a major cause of transfusion-associated transmission of
the parasite.117 Symptomatic chronic Chagas’ disease develops in an estimated 10% to 30% of infected persons, years
or even decades after the T. cruzi infection is acquired. The
heart is most commonly affected, and the pathologic changes
may include biventricular enlargement, thinning of ventricular walls, apical aneurysms, and mural thrombi. Widespread
lymphocytic infiltration is often seen in stained specimens
of cardiac tissue, as well as diffuse interstitial fibrosis and
atrophy of myocardial cells. The conduction system is often
affected, typically resulting in right bundle-branch block,
left anterior fascicular block, or complete atrioventricular
block. The symptoms reflect the dysrhythmias, cardiomyopathy, and thromboembolism that develop over time. Death
usually results from rhythm disturbances (∼40% of patients)
or progressive HF (∼60% of patients). The overall prognosis
for patients with Chagas cardiomyopathy and HF is poor,
with 50% of patients dying within a period of 47 months.
The presence of complete heart block, atrial fibrillation,
LBBB, and complex ventricular ectopy augurs a poor
prognosis.
CAR055.indd 1242
55
The leading hypothesis with respect to the pathogenesis
of Chagas’ cardiomyopathy is that patients develop progressive myocardial damage due to parasite persistence and autoimmune responses.115 Individuals with parasite persistence
and no myocardial damage or very limited damage on endomyocardial biopsies (indeterminate phase) have a nearly
normal life expectancy. In contrast, those patients, who have
parasite persistence and diffuse myocardial damage (arrhythmic phase) or end-stage heart disease, have dramatically
diminished survival at 12 years of follow-up.116 The neurogenic hypothesis of Chagas’ cardiomyopathy suggests that
the cardiac parasympathetic neurons are irreversibly damaged
by the parasite during the acute phase of the disease. As a
consequence, the cardiac sympathetic nervous system is
unopposed, and the cardiotoxic effects of a permanent and
excessive sympathetic activation are responsible for the
relentless progression of myocardial damage. However, activation of the sympathetic nervous system and of the reninangiotensin-aldosterone system is a late event in the natural
history of Chagas’ disease, and patients with parasite persistence but no segmental myocardial damage do not have neurohormonal activation.115 Myocardial ischemia and coronary
microcirculation abnormalities have also been demonstrated
in animal models and in humans with Chagas’ disease.
The pharmacologic treatment of T. cruzi infection
remains unsatisfactory. Extensive clinical experience has
been accumulated with two drugs, benznidazole and nifurtimox. Both shorten the acute phase of T. cruzi infection and
decrease mortality, but they achieve parasitologic cures in
only about 50% of treated patients; moreover, these drugs
cause substantial toxicity. There is no evidence that drug
treatment of persons with chronic T. cruzi infection alters
the natural course of the disease, and a sizable proportion of
such patients remain positive for parasites indefinitely.118
Treatment of Chagas cardiomyopathy is the same as the
conventional treatment for patients with DCM. Placebo-controlled clinical investigations and short-term pharmacologic
studies have consistently shown that ACE inhibitors improve
and prolong the life of Chagas’ patients with end-stage heart
disease.119
Noninfectious Causes
HYPERSENSITIVITY MYOCARDITIS
Hypersensitivity to a variety of agents may result in allergic
reactions that involve the myocardium, characterized by
peripheral eosinophilia, and a perivascular infiltration of the
myocardium by eosinophils, lymphocytes, and histiocytes.
These infiltrates may be occasionally associated with necrosis. A variety of drugs, most commonly the sulfonamides,
penicillins, methyldopa, and other agents such as amphotericin B, streptomycin, phenytoin, isoniazid, tetanus toxoid,
hydrochlorothiazide, and chlorthalidone, have been reported
to cause allergic hypersensitivity myocarditis. Most patients
are not clinically ill, but may die suddenly, presumably secondary to an arrhythmia. Hypersensitivity myocarditis is
recognized only rarely clinically, but may be sufficient to
produce global or regional myocardial dysfunction detected
by noninvasive methods. This entity is often first diagnosed
on postmortem examination, and occasionally on endomyocardial biopsy.120
11/24/2006 1:28:34 PM
di l at e d c a r diom yopat h y
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Although a number of cardiac abnormalities have been
reported in patients with SLE, the development of DCM is
not a prominent manifestation of this disease process. Global
LV dysfunction has been reported in 5%, segmental LV wall
motion abnormalities in 4%, and RV enlargement in 4% of
patients with SLE. In general the abnormalities in cardiac
function usually correlate with disease activity. The myocardial involvement is frequently found at autopsy or at endomyocardial biopsy and is less easily detected clinically. The
myocardial lesions are characterized by an increase in interstitial connective tissue and myocardial scarring. Recent
studies suggest that depolarization abnormalities on signal
average ECG accompanied with echocardiographic evidence
of abnormal LV filling may reflect the presence of myocardial
fibrosis and could be a marker of subclinical myocardial
involvement in SLE patients.121
Cardiac involvement may manifest itself by conduction
system abnormalities such as complete atrioventricular
heart block. Especially neonatal lupus is characterized by
congenital heart block, as well as cardiomyopathy, cutaneous
lupus lesions, hepatobiliary disease, and thrombocytopenia.
Accumulating evidence indicates that the disease is probably
caused by maternal autoantibodies.122
SCLERODERMA
The development of DCM is rare in patients with scleroderma. A recent echocardiographic study showed that
although there was no difference in LV dimensions or fractional shortening in patients with scleroderma, there was
indication of systolic impairment by systolic time intervals
with an increased preejection period to LV ejection time
(LVET) ratio and also an increased isovolumic contraction
time to LVET ratio in the majority of patients.123 A distinctive focal myocardial lesion ranging from contraction band
necrosis to replacement fibrosis without morphologic abnormalities of the coronary arteries is noted in approximately
half of the patients with scleroderma. This is postulated to
be due to intermittent vascular spasm with intramyocardial
Raynaud’s phenomenon.124 Thus, progressive systemic sclerosis can lead to conduction abnormalities, arrhythmias, HF,
angina pectoris with normal coronary arteries, myocardial
fibrosis, pericarditis, and sudden death. Late contrast
enhancement with gadolinium may be used to characterize
patchy fibrosis and myocardial edema interspersed with
normal myocardium in scleroderma. Cardiac involvement in
systemic sclerosis portends an ominous prognosis, and is
probably most directly related to the extent of myocardial
fibrosis.
R HEUMATOID A RTHRITIS
Cardiac involvement in rheumatoid arthritis generally
results from the development of myocarditis or pericarditis.
However, the development of DCM is rare in these patients.
In a retrospective study of 172 patients with juvenile rheumatoid arthritis, symptomatic cardiac involvement occurred
in 7.6% of patients, including pericarditis, perimyocarditis,
and myocarditis. Both myocarditis and pericarditis are
regarded as poor prognostic factors in rheumatoid arthritis.125
Myocardial involvement in rheumatoid arthritis is thought
to be secondary to disturbances in the microcirculation sec-
CAR055.indd 1243
12 4 3
ondary to microvasculitis, and occurs in the absence of any
clinical symptoms of ECG changes.
K AWASAKI DISEASE
Kawasaki disease is an acute febrile illness associated with
mucosal inflammation, skin rash, and cervical lymphadenopathy. This disease is recognized most often in children
younger than 4 years of age. Kawasaki disease represents
an acute vasculitic syndrome of unknown etiology that primarily affects small and medium-sized arteries, including
coronary arteries. Coronary arterial aneurysms are seen in
25% to 55% of the acute Kawasaki cases. Of these, 4.7%
progress to premature atherosclerotic ischemic heart disease.
Myocardial infarction is noted in approximately 2% of
patients, and cardiovascular death is reported in 0.8%.
Although the development of DCM is not typical for Kawasaki disease, repetitive infarctions secondary to coronary
arterial aneurysms may lead to a dilated cardiomyopathic
phenotype.
PERIPARTUM CARDIOMYOPATHY
Peripartum cardiomyopathy is a disease of unknown cause
in which severe LV dysfunction occurs during the last trimester of pregnancy or the early puerperium. It is reported
in one in 1300 to one in 4000 live births. In the past, the
diagnosis of this entity was made on clinical grounds;
however, modern echocardiographic techniques have allowed
more accurate diagnoses by excluding cases of diseases that
mimic the clinical symptoms and signs of HF. Risk factors
for peripartum cardiomyopathy include advanced maternal
age, multiparity, African descent, twinning, and long-term
tocolysis. Anticoagulation is strongly recommended, especially if ventricular function is persistent. Although its etiology remains unknown, most theories have focused on the
hemodynamic126 and immunologic stresses of pregnancy.127
An immune pathogenesis is supported by the frequent finding
of lymphocytic myocarditis on myocardial biopsy128 and the
fact that multiparity or previous exposure to fetal antigens
is a significant risk factor.129
The prognosis of peripartum cardiomyopathy is related
to the recovery of ventricular function. In contrast to patients
with idiopathic DCM, significant improvement in myocardial function is seen in 30% to 50% of patients in the first
6 months after presentation.129 However, for those patients
who do not recover to normal or near-normal function, the
prognosis is similar to other forms of DCM.130 Cardiomegaly
that persists for more than 4 months after diagnosis indicates
a poor prognosis, with a 50% mortality at 6 years. Caution
is advised in recommending subsequent pregnancy, especially if LV dysfunction is persistent. Heart failure recurs
during subsequent pregnancies in more than 50% of the
patients.127
Endocrine and Metabolic Causes
of Cardiomyopathy
Obesity
Heart failure in the markedly obese usually develops over a
long period of time, and can be directly related to the duration of obesity. Initially, the dyspnea and edema in these
11/24/2006 1:28:34 PM
12 4 4
chapter
patients is simply related to alterations in LV compliance
with resultant elevated filling pressures. However, with
chronicity, these patients develop a DCM phenotype, with
further worsening of the patient’s volume overload status.
Although the precise reasons for obesity-related HF are not
known, it is thought that the chronic increase in cardiac
work and chronic increase in systemic blood pressure ultimately lead to myocardial failure.131 In addition, there is an
increased prevalence of hypertension and coronary artery
disease in obese patients, which may also contribute to the
development of DCM in these patients. Obesity-related
hypoventilation and sleep apnea may also contribute to
the pathophysiology. Although there are anecdotal reports
regarding symptomatic improvement following weight
reduction in obesity-induced HF, large-scale clinical trials on
the role of weight loss in obesity have not yet been performed. A study examining the relationship between obesity
and HF in participants in the Framingham Heart Study132
reported that after adjustment for established risk factors,
there was an increase in the risk of HF of 5% for men and
7% for women for each increment of 1 in body mass index.
When compared with subjects with a normal body mass
index, obese subjects had a doubling of the risk of HF. Obesity
alone was estimated to account for 11% of cases of HF in
men and 14% of those in women.132 Nearly 60% of the adult
population of the United States is overweight or obese, resulting in high morbidity and mortality.133 Given the high prevalence of obesity in the United States, strategies to promote
optimal body weight may reduce the population burden of
HF. It is recognized that obesity, particularly truncal obesity,
has been associated with the metabolic syndrome, which is
characterized by insulin resistance and particularly atherogenic dyslipidemia; with high levels of low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol,
and triglycerides; and low levels of high-density lipoprotein
cholesterol.134 The metabolic syndrome has emerged as a
major risk factor for cardiovascular events and may be
the precursor of undetected atherosclerotic cardiovascular
disease ultimately resulting in HF.
Diabetic Cardiomyopathy
Since its first description in 1972,135 a considerable amount of
experimental, pathologic, epidemiologic, and clinical data
have accumulated to support the existence of diabetic cardiomyopathy. So far, a large body of literature suggests that the
occurrence of diabetic cardiomyopathy is an independent
phenomenon from macroangiographic changes in coronary
arteries and hypertension. Diabetes is now well recognized
as an independent risk factor for the development of HF
despite correcting for age, hypertension, obesity, hypercholesterolemia, and coronary artery disease. Diabetic men have
more than twice the frequency of HF compared with nondiabetic cohorts, whereas diabetic women have a fivefold
increased risk of developing HF.135,136 Possible mechanisms
that have been implicated in the pathogenesis of diabetic
cardiomyopathy include microangiopathic changes in the
small vessels of the heart, such as microvascular constriction
or microaneurysms; changes in fatty-acid metabolism;
unavailability of glucose as an energy substrate, and shifting
the intracellular metabolism from glycolysis to free fatty acid
CAR055.indd 1244
55
oxidation, thus resulting in inadequate adenosine triphosphate (ATP) generation and increased production of oxygen
free radicals; alterations in calcium and potassium transport
and calcium handling; cardiac hypertrophy and increase in
LV mass independent of loading conditions; defects in collagen structure resulting in myocardial, perivascular, and
interstitial fibrosis; abnormalities in the conducting system;
and a decrease in the function of autonomic nerves and
reduced sympathetic innervation.135 The frequency and pace
by which these preclinical abnormalities progress to clinically evident myocardial dysfunction in patients with diabetes is not well established. Moreover, the role of metabolic
control of diabetes mellitus in the prevention or the reversal
of myocardial dysfunction is unclear. It is interesting to note,
however, that diabetic patients have broader indications for
initiation of ACE inhibitors other than LV dysfunction, such
as diabetic nephropathy or proteinuria. Perhaps the more
widespread and earlier use of ACE inhibitors in diabetic
patients, before the appearance of the cardiomyopathy phenotype, will reduce the propensity to develop clinical diabetic
cardiomyopathy in this high-risk population.
Hyperthyroidism
Hyperthyroidism has been implicated in causing DCM;
however, in view of the increased cardiac contractile function
of patients with hyperthyroidism, the development of HF is
unexpected and raises the question of whether there truly is
a direct causal association between hyperthyroidism and
cardiomyopathy.137 Patients with hyperthyroidism may occasionally have exertional dyspnea or other symptoms and
signs of HF. Many of these clinical manifestations may be
attributed to the direct effects of thyroid hormone on cardiovascular hemodynamics. In most patients with hyperthyroidism, cardiac output is high, and the subnormal response to
exercise may be the result of an inability to increase heart
rate maximally or to lower vascular resistance further, as
normally occurs with exercise.138 The term high-output
failure is not appropriate for all cases of cardiomyopathy
related to hyperthyroidism, because the ability of the heart
to maintain increased cardiac output at rest and with exercise
is usually preserved.137 Occasional patients with severe, longstanding hyperthyroidism have poor cardiac contractility,
low cardiac output, and symptoms and signs of HF, including
a third heart sound and pulmonary congestion.139 This
complex of findings most commonly occurs with persistent
sinus tachycardia or atrial fibrillation and is the result of socalled rate-related HF. In older patients with heart disease,
the increased workload that results from hyperthyroidism
may further impair cardiac function and thus result in DCM.
The presence of ischemic or hypertensive heart disease may
compromise the ability of the myocardium to respond to the
metabolic demands of hyperthyroidism.137 Histologic examination usually reveals a nonspecific pattern, including foci
of lymphocytic and eosinophilic infiltration, fibrosis, fatty
infiltration, and myofibril hypertrophy. Although enhanced
adrenergic activity contributes to the hyperdynamic state in
hyperthyroidism, β-adrenergic blockade does not fully return
the heart rate or contractility to normal, which may suggest
a primary cardiac effect of thyroid hormone with contributory effects of cathecolamines.137
11/24/2006 1:28:34 PM
di l at e d c a r diom yopat h y
Hypothyroidism
Abnormalities in cardiac systolic and diastolic performance
have been reported both in experimental and in clinical
studies of hypothyroidism; however, the classic findings of
myxedema does not usually indicate cardiomyopathy.137 The
most common signs are bradycardia, mild hypertension, a
narrowed pulse pressure, and attenuated activity on the precordial examination. Pericardial effusions and nonpitting
edema (myxedema) can occur in patients with severe, longstanding hypothyroidism. The low cardiac output is caused
by bradycardia, a decrease in ventricular filling, and a decrease
in cardiac contractility. Systemic vascular resistance may
increase by as much as 50%, and diastolic relaxation and
filling are slowed.137 However, HF is rare, because the cardiac
output is usually sufficient to meet the lowered demand for
peripheral oxygen delivery. Positron emission tomographic
studies of oxygen consumption in patients with hypothyroidism have revealed that myocardial work efficiency is lower
than in normal subjects. From 10% to 25% of patients have
diastolic hypertension, which, combined with the increase in
vascular resistance, raises cardiac afterload and cardiac
work.137 Abnormal systolic force may improve with thyroid
hormone replacement but does not return to normal levels,
suggesting the possibility of persistent myocardial dysfunction.140 Thyroid hormone replacement should be initiated at
low doses and titrated slowly as LV failure may be precipitated.
Interestingly, patients with HF also have low serum triiodothyronine concentrations, and the decrease is proportional to
the degree of HF, as assessed by the NYHA functional classification. Whether such changes in thyroid hormone metabolism contribute to further impairment of cardiovascular
function in patients with HF is not known.137
Acromegaly and Growth Hormone Deficiency
Impaired cardiovascular function has recently been demonstrated to potentially reduce life expectancy both in patients
with growth hormone deficiency and in those with a growth
hormone excess. Experimental and clinical studies have supported the evidence that growth hormone and IGF-1 are
implicated in cardiac development.141 In most patients with
acromegaly, a specific cardiomyopathy, characterized by
myocardial hypertrophy with interstitial fibrosis, lymphomononuclear infiltration, and areas of monocyte necrosis,
results in biventricular concentric hypertrophy.141 Myocardial dysfunction is a major cause of morbidity and mortality
in acromegaly and appears to be related to both the severity
and duration of growth hormone excess. In contrast, patients
with childhood- or adulthood-onset growth hormone deficiency may suffer from both structural cardiac abnormalities, such as narrowing of cardiac walls, and functional
impairment, which combine to reduce diastolic filling and
impair LV response to peak exercise.141 In addition, growth
hormone deficiency patients may have an increase in vascular intima-media thickness and a higher occurrence of
atheromatous plaques, which can further aggravate the
hemodynamic conditions and contribute to increased cardiovascular and cerebrovascular risk. Several studies have suggested that the cardiovascular abnormalities can be partially
reversed by suppressing growth hormone and IGF-1 levels in
acromegaly or after growth hormone replacement therapy in
CAR055.indd 1245
12 4 5
growth hormone deficiency patients.141 Receptors for both
growth hormone and IGF-1 are expressed by cardiac myocytes; therefore, growth hormone may act directly on the
heart or via the induction of local or systemic IGF-1, whereas
IGF-1 may act by endocrine, paracrine, or autocrine mechanisms. Animal models of pressure and volume overload have
demonstrated upregulation of cardiac IGF-1 production and
expression of growth hormone and IGF-1 receptors, implying
that the local regulation of these factors is influenced by
hemodynamic changes.142 Moreover, experimental studies
suggest that growth hormone and IGF-1 have stimulatory
effects on myocardial contractility, possibly mediated by
changes in intracellular calcium handling. Thus recently,
much attention has been focused on the ability of growth
hormone to increase cardiac mass, suggesting its possible use
in the treatment of chronic HF. Initial studies demonstrated
that treatment with growth hormone may result in improvement in hemodynamic and clinical status of patients with
HF; however, recently, two randomized, placebo-controlled
studies did not show any significant growth hormone–mediated improvement in cardiac performance in patients with
DCM, despite significant increases in IGF-1. Although these
data need to be confirmed in more extensive studies, such
promising results seem to open new perspectives for growth
hormone treatment in humans.143
Nutritional Causes of Cardiomyopathy
Thiamine Deficiency
Thiamine serves as a cofactor for several enzymes involved
primarily in the carbohydrate catabolism and is found in high
concentrations in the heart, skeletal muscle, liver, kidneys,
and brain.144 The most common cause of thiamine deficiency
in Western countries is chronic alcoholism and anorexia
nervosa. AIDS and pregnancy can account for other rare
causes of thiamine deficiency.145 A state of severe depletion
can develop in patients on a strict thiamine-deficient diet in
approximately 18 to 21 days. The major manifestations of
thiamine deficiency in humans involve the cardiovascular
(wet beriberi) and nervous (dry beriberi, or neuropathy, or
Wernicke-Korsakoff syndrome) systems. The cardiovascular
signs and symptoms include dyspnea, fatigue, leg edema, and
palpitations. Tachycardia is common and there is usually
increased jugular venous pressure along warm extremities.
Biventricular HF is present and the circulation is usually
hyperkinetic. Ultimately, circulatory collapse, metabolic acidosis, or shock can develop, at which time, the disease has
advanced from chronic beriberi to fulminating beriberi HF
(Shoshin beriberi). Severe lactic acidemia in the presence of a
high cardiac output and extremely low oxygen consumption
are the classic features of acute fulminant cardiovascular
beriberi, which, if unrecognized and untreated, can lead to
high cardiac output failure and death. Treatment for Beriberi
should consist of administration of thiamine along with other
conventional treatments of circulatory support and HF.146
Carnitine Deficiency
l-carnitine and its derivative, propionyl-l-carnitine, are
organic amines necessary for oxidation of fatty acids, the
11/24/2006 1:28:34 PM
12 4 6
chapter
deficiency of which may be associated with a syndrome of
progressive skeletal myopathy and lipid vacuoles on muscle
biopsy.147 They have also been shown to reduce intracellular
accumulation of toxic metabolites during ischemia, demonstrate protective effect on muscle metabolism injuries,
inhibit caspases, and decrease the levels of TNF-α and sphingosine, as well as reduce apoptosis of skeletal muscles cells
and thus have been impliated in the treatment of congestive
HF.148 It has been shown that several metabolic genes, including the muscle carnitine palmitoyltransferase-I (CPT-I), are
downregulated in the failing human heart.149 Inhibitors of
CPT-I, the key enzyme for the transport of long-chain acylcoenzyme A (acyl-CoA) compounds into mitochondria, have
been developed as agents for treating diabetes mellitus.
Interestingly, a CPT inhibitor, etomoxir, has been reported
to enhance levels of the sarcoplasmic reticulum Ca(2+)–
adenosine triphosphatase (ATPase), a key protein in calcium
cycling, and of the α-MHC in normal and pressureoverloaded rat myocardium.150 This finding can be attributed
to selective changes in the dysregulated gene expression of
hypertrophied cardiomyocytes.
Selenium Deficiency
Selenium deficiency is associated with cardiomyopathy and
congestive HF in geographic areas where dietary selenium
intake is low.151 This has been named the Keshan disease,
due to the geographic prevalence of a specific form of DCM
in northeast China, where the soil has a low selenium
content. Chronic selenium deficiency may also occur in individuals with malabsorption and long-term seleniumdeficient parenteral nutrition.152 Selenium deficiency is
implicated in causing cardiomyopathy as a result of the
depletion of selenium-associated antioxidant enzymes, selenoenzymes, which protect cell membranes from damage by
free radicals. The cardiomyopathy is manifested by the insidious onset of congestive HF or a complication of sudden
death or thromboembolic phenomena. The heart shows
biventricular enlargement and histologically exhibits edema,
mitochondrial swelling, hypercontraction bands, widespread
myocytolysis, and extensive fibrosis.151
Hematologic Causes of Cardiomyopathy
Cardiomyopathy Due to Iron Overload:
Hemochromatosis and Thalassemia
Iron-overload cardiomyopathy manifests itself as systolic or
diastolic dysfunction secondary to increased deposition of
iron in the heart and occurs with common genetic disorders
such as primary hemochromatosis and β-thalassemia major.
Hereditary hemochromatosis is an inherited disorder of
iron metabolism and is the most common hereditary disease
of Northern Europeans, with a prevalence of approximately
5 per 1000. It is an autosomal recessive disorder of iron
metabolism characterized by increased iron absorption and
deposition in the liver, pancreas, heart, joints, and pituitary
gland. Without treatment, death may occur from cirrhosis,
primary liver cancer, diabetes, or cardiomyopathy. In 1996,
HFE, the gene for hereditary hemochromatosis, was mapped
on the short arm of chromosome 6.154 The H63D mutation
is significantly increased in patients with idiopathic DCM.153
CAR055.indd 1246
55
The high correlation of the HFE to hemochromatosis has
caused it to be considered as a candidate gene for populationbased genetic testing for diagnosis and detection of predisposition to hemochromatosis. Although the exact mechanism
of iron-induced HF remains to be elucidated, the toxicity of
iron in biologic systems is attributed to its ability to catalyze
the generation of oxygen free radicals. It was shown that
chronic iron-overload results in dose-dependent increases in
myocardial iron burden, decreases in the protective antioxidant enzyme activity, increased free-radical production, and
increased mortality.154 These findings suggest that the mechanism of iron-induced heart dysfunction involves in part free
radical-mediated processes.154 This also implies that the
disease process is reversible if the tissue iron concentration
can be controlled. Myocardial iron deposits do not occur
until other organs such as liver, pancreas, and connective
tissues are saturated with iron. Thus, the extracardiac manifestations are present before the cardiomyopathy develops.154
During the initial phases of the cardiomyopathy, the hemodynamic profile represents a restrictive pattern. As the severity of cardiomyopathy advances, DCM with biventricular
enlargement and HF ensue. The spectrum of arrhythmia
ranges from minor abnormalities on the electrocardiogram
to supraventricular arrhythmia, atrioventricular conduction
block, and ventricular tachyarrhythmia, presumably due to
myocardial dysfunction and iron deposition in the conduction system and AV node.155 The ECG most commonly shows
decreased voltage and nonspecific ST and T wave changes; Q
waves are uncommon.
The diagnosis of hemochromatosis is suggested by elevated serum ferritin and an increased ratio of iron to total
iron binding capacity (TIBC). The most sensitive screening
test for hemochromatosis is saturation of the transferrin with
iron; a fasting value greater than 50% is strongly suggestive
of the disease. The most definitive test for calculation of iron
stores in the body is measurement of iron concentration by
liver biopsy. Magnetic resonance imaging (MRI) can also be
very useful in identifying the iron-laden organs and cardiac
involvement.156 Though not required to demonstrate cardiac
involvement in every case, endomyocardial biopsy can be
useful in assessment of cardiac iron deposition.157 Before phlebotomy and chelation therapy, survival among patients with
hemochromatosis and HF was less than 20% in 5 years. In
patients with thalassemia major, cardiac failure is one of the
most frequent causes of death.158 Chelation therapy, including
newer forms of oral chelators, such as deferoxamine, and
phlebotomy have dramatically improved the outcome of
hemochromatosis. It is important to start therapy early, as
treatment may prevent or reverse cardiac involvement. Early
diagnosis and treatment by phlebotomy before tissue damage
has occurred is essential, because life span seems to be normal
in treated patients but markedly shortened in those who are
not. Additionally, genetic counseling with evaluation of firstdegree relatives is mandatory.154
Physical Agents
Tachycardia-Induced Dilated Cardiomyopathy
The concept that incessant or chronic tachycardia can lead
to reversible LV dysfunction is supported both by animal
11/24/2006 1:28:34 PM
di l at e d c a r diom yopat h y
models of chronic pacing as well as by human studies documenting improvement in ventricular function with tachycardia rate or rhythm control. Sustained rapid pacing in
experimental animal models can produce severe biventricular systolic dysfunction.159,160 In humans, descriptions of
reversal of cardiomyopathy with rate or rhythm control of
incessant or chronic tachycardias have been reported with
atrial tachycardias, accessory pathway reciprocating tachycardias, atrioventricular node reentry, and atrial fibrillation
with rapid ventricular responses.161 Control of the rapid ventricular responses in atrial fibrillation has been shown to
improve ventricular function, following conversion to sinus
rhythm, pharmacologic ventricular rate control, and AV
junction ablation and permanent ventricular pacing.162,163
The investigation of potential tachycardia-induced cardiomyopathy in patients with HF requires further prospective
confirmation in larger numbers of patients, with study of
mechanisms, patient groups affected, and optimal therapies.
Tachycardia-induced cardiomyopathy may be a more common
mechanism of LV dysfunction than recognized, and aggressive treatment of the arrhythmia should be considered.
12 47
inferences regarding cause and effect are, invariably, indirect
and circumstantial.
Clinical Recognition
The most common initial presenting manifestations of DCM
are related to the presence of left HF, and include progressive
exertional dyspnea, fatigue, weakness, diminished exercise
capacity, orthopnea, paroxysmal nocturnal dyspnea, and nocturnal cough. With the development of right HF, abdominal
distention, right upper quadrant pain, early satiety, postprandial fullness, and nausea appear. Some cases will eventually
develop cardiac cachexia and wasting from advanced HF.
Systemic embolization, pulmonary emboli can be seen in 1%
to 4% of cases and are more commonly seen with cardiomegaly. Palpitations can occur with atrial fibrillation
and ventricular arrhythmias. Ventricular arrhythmias are
common toward advanced stages of cardiomyopathy; however,
syncope and sudden cardiac death are rare initial
presentations.
Autoimmune Mechanisms
Diagnostic Evaluation
There has been increasing evidence suggesting that abnormalities in cellular and humoral immunity may contribute
to the overall pathogenesis of DCM. Circulating autoantibodies to a variety of cardiac antigens including G-protein–
linked receptors (such as those to β1-adrenoreceptors and
muscarinic receptors), mitochondrial antigens, adenosine
diphosphate, adenosine triphosphate carrier proteins,
and cardiac MHC have been identified in patients with
DCM.164–167 In this regard, it is interesting to note that
immunization with certain cardiac muscle (but not skeletal)
antigens such as α-MHC can result in the development of a
dilated cardiac phenotype in certain susceptible strains of
mice. Moreover, a recent meta-analysis has shown that there
is increased expression of the antigens of genes located at
the major histocompatibility complex on chromosome 6,
which is the locus that is responsible for regulating immune
responses. This study showed that human leukocyte antigens (HLA) class II such as DR4 or DQw4 were present in
63% of the patients with cardiomyopathy as compared to
26% in the control subjects.168 Features that support an autoimmune etiology in patients who present with myocarditis
and DCM include familial aggregation, a weak association
with HLA-DR4 haplotype, abnormal expression of HLA
class II in cardiac tissue, and detection of organ- and diseasespecific cardiac autoantibodies by immunofluorescence and
immunoabsorption techniques. Nonetheless, a precise interpretation of the above fi ndings has been complicated by the
knowledge that low titers of autoantibodies, which can be
part of the normal immunologic repertoire, are not always
pathogenic. For example, tissue injury secondary to ischemia or infection may lead to autoantibody production
because of alterations of self-antigens or exposure of antigens that are normally sequestered from the immune system.
In such situations, the generation of autoantibodies is the
result, and not the cause, of the tissue injury. Furthermore,
observations about autoimmune responses are generally
made in patients with established disease; accordingly, any
The diagnostic evaluation of patients with DCM, in general,
is similar to that for patients with ischemic heart disease
and is discussed in another chapter.
CAR055.indd 1247
Laboratory Testing
Initial Laboratory Tests
Initial screening laboratory studies for DCM patients should
include a routine assessment of serum electrolytes, liver
function tests, white blood cell count, and a hemoglobin and
hematocrit. Beyond these routine tests, the positive predictive value or utility of additional laboratory studies remains
low unless supported by specific elements of the history and
physical exam. One possible exception to this statement is
the use of the BNP as a biochemical marker for both its
diagnostic and prognostic properties in HF patients.
Brain Natriuretic Peptide
B-type BNP is a neurohormone secreted mainly in the cardiac
ventricles in response to volume expansion and pressure
overload. It can be used for identifying patients with asymptomatic LV systolic dysfunction169–171 or for patients with
symptomatic HF, as a marker for prognosis and risk stratification of patients with HF, and as a tool for tailoring inpatient and outpatient therapy in HF.172,173
In conjunction with other clinical information, rapid
measurement of B-type natriuretic peptide is very useful in
establishing or excluding the diagnosis of congestive HF in
patients with acute dyspnea with excellent specificity and
high negative predictive values.173 Brain natriuretic peptide
has been shown to be a powerful marker for prognosis and
risk stratification in the setting of HF.45 Elevated levels have
been correlated with increased HF mortality and sudden
cardiac death.172 Because BNP is a volume-sensitive hormone
with a short half-life, BNP levels can be used in guiding
11/24/2006 1:28:35 PM
12 4 8
chapter
55
myocarditis or when there is extensive LV fibrosis even
without a discrete myocardial scar.178 A variety of atrial and
ventricular tachyarrhythmias and atrioventricular conduction disturbances may also be seen. Atrial fibrillation develops in approximately 20% of the patients. Premature
ventricular contractions (PVCs) are not an uncommon finding
on routine ECGs in patients with DCM.
diuretic and vasodilator therapy on presentation with decompensated HF. Falling BNP levels during hospitalization
correlate with clinical improvement and predict lower
readmission rates.172 Brain natriuretic peptide can also be
used in the outpatient setting to guide “tailored therapy”
such as titration of beta-blockers. This has been demonstrated by the Australia–New Zealand Heart Failure Group,
which reported that BNP was the best prognostic predictor
of the success or failure of carvedilol.174 Troughton et al.175
randomized 69 patients to N-terminal BNP (N-BNP)–guided
treatment versus symptom-guided therapy. Patients receiving N-BNP–guided therapy had lower N-BNP levels, along
with reduced incidence of cardiovascular death, readmission,
and new episodes of decompensated HF. Studies have shown
that elevated levels of these markers have a sensitivity of
≥80% to 90% and a specificity of ≥70% to 90% for detecting
patients with ejection fractions <30%.171 The negative predictive value of BNP levels under 100 pg/mL is the strongest
feature of this peptide. Although the positive predictive value
in a given patient at a cutoff of 100 pg/mL is 80%, most
patients with significant congestive heart failure (CHF) as a
cause of their dyspnea will have levels of >400 pg/mL.172
Brain natriuretic peptide is elevated probably in all forms of
cardiomyopathy including DCM. One study reported higher
BNP levels in patients with hypertrophic cardiomyopathy
than patients with idiopathic DCM.176 This may be related
to the difference in proportional production of BNP by markedly hypertrophied and pressure-loaded ventricles.
There is an inverse relationship between the severity of ventricular arrhythmia and LV ejection fraction.178,179 Thus, it is
perhaps not surprising that the majority of DCM patients
have PVCs when monitored over a 24-hour period; moreover,
approximately half of the patients with DCM have nonsustained ventricular tachycardia on routine ambulatory 24hour Holter monitoring. However, the predictive value of
ambulatory Holter monitoring as a routine screening tool in
asymptomatic patients for identification of risk for sudden
cardiac death has not been validated. There are conflicting
data from studies involving small groups of patients regarding the role of routine ambulatory ECG monitoring as a significant independent risk factor for sudden cardiac death.180–182
Thus, at the present time, routine screening with Holter
monitoring in asymptomatic HF patients is not recommended as a reliable means to predict those patients who will
develop sudden cardiac death.
Chest Radiography
Signal Averaged ECG
In the early phases of DCM, cardiac enlargement may be
minimal and may not be detected by chest radiography.
However, in general, the chest x-ray usually reveals LV
enlargement or generalized cardiomegaly that involves all
four cardiac chambers. Depending on the patient’s volume
status, there may or may not be findings of pulmonary congestion. Cephalization of blood flow or pulmonary vascular
redistribution are early signs of volume overload, followed by
the development of interstitial edema with appearance of
Kerley B lines and fluid in the interlobar fissures, followed
by frank alveolar edema in advanced volume overload. Pleural
effusions may be present and the azygos vein and superior
vena cava may be dilated, especially with RV failure.
In patients with syncope or coronary artery disease, the presence of late potentials on a signal average ECG identifies
those patients at high risk for developing ventricular tachycardia and sudden death. Although late potentials are less
frequent in patients with DCM, the current evidence suggests that an abnormal signal average ECG can predict ventricular arrhythmias and sudden cardiac death also in
patients with DCM. However, studies evaluating the utility
of a positive signal averaged ECG to identify a subgroup of
dilated HF patients at risk for sudden death have yielded
disparate results.183–185 Those studies that have demonstrated
an increased risk of sudden death in subjects in the presence
of late potentials on signal averaged ECG have used different
signal averaging methods than those that have not shown
the signal averaged ECG to have predictive value. Indeed, the
sensitivity of the signal average ECG varies between 22%
and 100% and the specificity ranges from 45% to 96% in
various studies.182,183,186–188 Thus, although the signal average
ECG may be useful for predicting future events in some
patients with DCM, the inherent problems with the sensitivity, specificity, and predictive value suggest that the signal
average ECG may not be a reliable tool for screening asymptomatic patients who are at a high risk for sudden cardiac
death.
Electrocardiography
If the patient with DCM presents with signs or symptoms
referable to HF, the ECG usually reveals sinus tachycardia.
However, it is important to note that sinus bradycardia may
also be present in many patients with end-stage DCM. The
ECG morphology is seldom normal, and often shows nonspecific repolarization or ST segment abnormalities. Conduction abnormalities, especially LBBB, left anterior hemiblock,
and nonspecific intraventricular conduction delays, and
occasionally first-degree atrioventricular block are common
in patients with long-standing symptoms, and they may be
markers of increasing interstitial fibrosis or myocyte hypertrophy. Right bundle branch block is rare.177 Left atrial or
biatrial enlargement may be present. Pathologic anterior,
anterolateral, or diffuse Q waves mimicking myocardial
infarction, or poor R wave progression may be seen with viral
CAR055.indd 1248
Ambulatory Electrocardiographic
(Holter) Monitoring
Two-Dimensional and Doppler Echocardiography
Two-dimensional (2D) and Doppler echocardiography are
extremely useful techniques for assessing LV function, LV
dimensions, and valvular structures in DCM patients. Generally, patients will have global LV dilation, LV wall thin-
11/24/2006 1:28:35 PM
di l at e d c a r diom yopat h y
ning, global hypokinesis, and an LV ejection fraction of
less than 35% to 40%. Segmental wall motion abnormalities
may be seen with altered regional wall stress due to elevated
filling pressures and depressed contractility, or with acute
myocarditis due to segmental myocardial injury. Interestingly, the presence of segmental wall motion abnormalities
suggests a more favorable outcome than if global hypokinesis
is present.189 Left ventricular apical thrombi can be identified
in as many as 40% of the patients with DCM.190 Small pericardial effusion can sometimes be demonstrated, especially
if an infectious or noninfectious inflammatory etiology is
responsible for producing the DCM.
Doppler echocardiography usually reveals mild degrees
of mitral and tricuspid regurgitation and sometimes trace
pulmonary insufficiency. The mechanisms of mitral and tricuspid regurgitation have been attributed to ventricular
enlargement, annular dilatation, lengthening of chordae tendinea, abnormalities in contractility of the papillary muscles,
and displacement of the coaptation point of the mitral leaflets. The Doppler mitral inflow patterns can also provide
useful information on elevated LV filling pressures, which
are suggested by the appearance of a high E/A ratio (“pseudonormalization”), and a short isovolumic relaxation time and
deceleration time.191,192 The elevated early filling wave results
from elevated left atrial pressures, whereas the rapid deceleration time reflects further decrease in LV compliance.
These Doppler findings have been associated with a poor
prognosis in DCM.
Radionuclide Techniques
Multigated radionuclide angiocardiography (MUGA) is a very
useful test for the initial assessment of LVEF in patients with
DCM. Both the right and left ventricular ejection fractions
can be quantified reliably with this technique; moreover, the
interobserver and inter-test variability appear to be less than
with echocardiography.193 Thallium-201 myocardial scintigraphy is not a reliable technique for differentiating patients
with ischemic heart disease from those with DCM, insofar
as patients with DCM may have both reversible and fi xed
perfusion abnormalities that are related to the presence of
myocardial fibrosis.194 In addition to the above methodology,
radionuclide techniques have also been used to detect the
presence of myocardial inflammation. Both gallium-67– (a
marker for inflammation) and indium-III–labeled antimyosin antibodies (a marker for myocyte necrosis) have been
used to detect myocarditis in small uncontrolled studies.195,196
These techniques are supportive of the diagnosis of myocarditis when clinically suspected, but do not have the specificity or the sensitivity to be used reliably as screening tools for
patients with myocarditis.196
Cardiac Catheterization
Coronary arteriography is primarily used as a basis for planning further treatment options in patients who have ischemic heart disease. In the majority of patients with DCM,
the coronary arteries are normal with no atherosclerotic
lesions; however, in a small portion, there may be evidence
of mild, nonobstructive, isolated atherosclerotic lesions that
may not be sufficient to explain the extent of cardiomyopathy. Therefore, in these cases, other etiologies for the cardio-
CAR055.indd 1249
12 4 9
myopathy should be sought. The ventriculogram generally
reveals a dilated ventricle with depressed contractility. The
LV end-diastolic pressures are usually elevated. Right heart
catheterization is a useful means for adjusting medical
therapy in patients with advanced symptoms,197 especially
when they are considered for vasodilator, inotropic, or
mechanical support, or for assessing the suitability of certain
patients for cardiac transplantation.
Endomyocardial Biopsy
The routine use of RV endomyocardial biopsy as a diagnostic
tool for evaluating patients with newly diagnosed DCM has
fallen out of favor in many laboratories because of the apparent lack of benefit of immunosuppressive therapy in patients
with myocarditis.198 Moreover, the current criteria for diagnosing myocarditis by myocardial biopsy may be overly specific and lack sensitivity. Indeed, the reported incidence of
biopsy-verified myocarditis ranges from 1% to 70%, with an
average detection rate of 10%. The countervailing argument
that has been raised in support of the use of endomyocardial
biopsy in DCM is that this technique may yield a new diagnosis (i.e., different from idiopathic cardiomyopathy) in up to
20% of patients, and may provide a potentially new or beneficial form of therapy in 5% of the patients.197,199 Thus, myocardial biopsy should be considered in patients with suspected
treatable systemic or infiltrative myocardial diseases, such
as sarcoidosis, hypereosinophilic syndrome, hypersensitivity
myocarditis, amyloidosis, hemochromatosis, doxorubicininduced cardiomyopathy, or fulminant myocarditis. Moreover, as noted above, in certain types of fulminant
myocarditis, especially giant cell myocarditis, there is the
suggestion that aggressive immunosuppression may attenuate disease progression.200 Therefore, endomyocardial biopsies may be extremely useful in diagnosing patients who
present with a fulminant course, or who progressively
decompensate despite optimal medical therapy.
In experienced laboratories, the risk of perforation of the
heart from the biopsy is approximately 1/200 (0.5%) and the
risk of death from the procedure is 3 in 10,000 (0.03%).199
Therefore, in electing to perform a myocardial biopsy, the
clinician must weigh the potential benefits of rendering a
new diagnosis for which a specific form of therapy exists
against the risks associated with performing myocardial
biopsy.199
Treatment Strategies for
Dilated Cardiomyopathy
The first priority in implementing treatment strategies for
patients with DCM is to determine if the condition has an
etiology for which there is a specific form of treatment. Table
55.3 lists a number of “etiology specific” treatment strategies
designed to treat the underlying disease process that is
responsible for causing the DCM. The second priority in
implementing treatment strategies for DCM is to initiate
supportive HF therapy, the goals of which should be to (1)
improve the quality of life, (2) avoid the need for future
hospitalizations, (3) prolong life, and (4) to prevent HF progression. In this section, we discuss only those treatment
11/24/2006 1:28:35 PM
12 5 0
chapter
55
TABLE 55.3. Primary treatment approaches to dilated cardiomyopathies
Etiology of DCM
Primary treatment
Alcoholic
Cocaine
Anthracycline
Systemic lupus erythematosus
Viral myocarditis
Abstinence
Abstinence, beta-blockers?
Cessation of anthracycline therapy
Steroids, cytotoxic agents
Prednisone and immunosuppressant therapy for
fulminant course
Benzonidazole, nifurtimox
Steroids, Ca channel blockers for Raynaud's
phenomenon
IV immunoglobulin
Replacement
Achieve euthyroid state
Increase CD4 count
Dialysis
Removal of tumor
AV nodal ablation, beta-blockers
Chagas’ disease
Scleroderma
Kawasaki disease
Thiamine, selenium, or carnitine deficiency
Hyperthyroidism/hypothyroidism
AIDS
Uremia
Pheochromocytoma
Tachycardia induced
strategies that are unique to the treatment of HF for patients
with DCM.
Standard Medical Therapy
Existing studies suggest that patients with ischemic cardiomyopathy and patients with DCM have significant survival
benefit from the use of ACE inhibitors and betablockers.5,6,15,16,21,201–203 In addition to the ACE inhibitors and
beta-blockers, the four-drug approach including digoxin and
diuretics are advocated for all suitable patients with LV dysfunction and symptomatic HF regardless of the etiology (Fig.
55.5). There is no information on the effects of diuretics on
Favors treatment medication
Favors placebo
SOLVD-T (Enalapril)
V-HeFT-II (Enalapril)
MERIT HF (Metoprolol-XL)
CIBISII (Bisoprolol)
BEST (Bucindolol)
US Carvedilol (Carvedilol)
PRAISE I (Amlodipine)
PRAISE II (Amlodipine)
0.2
0.4
0.6
0.8
1.0
1.2
Hazard ratio
Val-HeFT (Valsartan)
RALES (Spironolactone)
1.4
1.6 1.8
Ischemic
Nonischemic
FIGURE 55.5. Hazard ratio and 95% confidence intervals for overall
mortality or combined end point of overall and cardiovascular mortality for ischemic cardiomyopathy and nonischemic cardiomyopathy from recent multicenter randomized trials with different
treatment strategies for heart failure. Medications used are shown
in parentheses next to the trial names. Ischemic cardiomyopathy is
represented as the black square with solid line, the nonischemic
cardiomyopathy as the white square with dashed line.
CAR055.indd 1250
morbidity or mortality in ischemic versus nonischemic HF.
Pooled results from the Prospective Randomized Study of
Ventricular Function and Efficacy of Digoxin (PROVED) and
the Randomized Assessment of Digoxin and Inhibitors of
Angiotensin-Converting Enzyme (RADIANCE) trials indicate that digoxin increases LVEF more in patients with DCM
than in patients with ischemic heart disease, and that withdrawal of digoxin leads to significantly greater likelihood of
clinical deterioration in the DCM patients.204 In the Digitalis
Investigators’ Group trial,63 digoxin was associated with a
significant reduction in a combined end point of death or
hospitalization as a result of worsening HF in patients in
sinus rhythm. This benefit was somewhat greater in patients
with nonischemic etiology than in those with ischemic etiology. That is, patients with DCM were noted to have a 33%
risk reduction in the combined end point of death and HF
hospitalization compared to a 21% risk reduction in patients
with ischemic cardiomyopathy. The cause of this therapeutic
difference is not clear at this point.
Aldosterone antagonism with spironolactone has been
reported to reduce mortality in patients with advanced
HF, both in dilated and ischemic cardiomyopathy.205 According to the results of the Randomized Aldactone Evaluation
Study (RALES) trial,205 spironolactone (25 to 50 mg/day) is
recommended for patients with recent or current symptoms
of HF at rest despite the use of ACE inhibitors, diuretics,
digoxin, and a beta-blocker, regardless of the etiology of HF,
in patients with NYHA class III to IV HF and LVEF <35%,
with adjustment of potassium supplements and close laboratory follow-up.
In the last decade, several studies have shown that angiotensin receptor blockers (ARBs), when added to background
therapy with ACE inhibitors, can result in improvement in
combined morbidity and mortality in patients with chronic
HF6,206 in both ischemic and nonischemic DCM patients,
similar to the benefit shown with spironolactone. It is important to recognize that in chronic HF, the ARB trials6,206,207
were conducted predominantly in patients with mild to moderate HF (NYHA class II to III), whereas the RALES trial205
11/24/2006 1:28:35 PM
di l at e d c a r diom yopat h y
(the only aldosterone receptor antagonist trial in chronic HF
including patients with nonischemic etiology), was conducted in patients with severe HF (NYHA class III to IV). At
the present time, there are no large-scale, prospective, randomized clinical trials with aldosterone receptor blockers in
mild to moderate chronic HF patients, and there are no headto-head trials comparing ARBs and aldosterone receptor
blockers in the treatment of HF, either for ischemic or
nonischemic patients. Thus, it is not feasible to compare the
efficacy or safety of these two treatment strategies in mild
to moderate HF at the present time.
The use of first-generation calcium antagonists (diltiazem, verapamil, or nifedipine) is potentially harmful in all
patients with HF.208 Recent studies with second-generation
calcium channel blockers, such as amlodipine and felodipine, suggest that these agents may be safer but do not confer
survival benefit in patients with HF. Initial reports of survival benefit with amlodipine [Prospective Randomized
Amlodipine Survival Evaluation Study (PRAISE-I)]65 in
patients with dilated but not ischemic cardiomyopathy have
failed to reproduce the subsequent large-scale randomized
trial (PRAISE-II),66 in which the survival was similar in both
the ischemic and nonischemic HF patients. Studies with
felodipine showed similar results. In the V-HeFT III trial,209
felodipine, when used as supplementary vasodilator therapy
in patients with chronic HF, was safe but had no additional
benefit. Recently, the addition of a fi xed dose of isosorbide
dinitrate plus hydralazine to standard therapy for HF including ACE inhibitors and beta-blockers was shown to be efficacious in increasing survival among black patients with
advanced (NYHA class III to IV) HF.210 Interestingly, in 77%
to 78% of the patients in this trial, the etiology of HF was
nonischemic (40% due to hypertension), but the subgroup
analysis of outcomes according to the etiology of HF has not
been reported.210
Antiarrhythmic Therapy: Implantable Devices
The role of implantable defibrillators for secondary prevention of sudden cardiac death is clearly established for both
ischemic and nonischemic cardiomyopathy patients. Implantable defibrillators decrease sudden death risk in patients with
LV dysfunction who have survived sudden cardiac death,
or sustained ventricular tachycardia or fibrillation.211 For
primary prevention, there is a large body of literature supporting the prophylactic use of implantable defibrillators to
prevent sudden cardiac death in ischemic cardiomyopathy
patients with reduced LVEF and post–myocardial infarction.212,213 Similar evidence supporting the role of prophylactic ICD implantation in patients with DCM, however, is
controversial. Two earlier studies have examined the role of
ICD therapy in patients with nonischemic cardiomyopathy
and HF, the Amiodarone Versus Implantable Cardioverter–
Defibrillator Trial (AMIOVIRT)214 and the DEFINITE trial215
failed to show a significant survival benefit, whereas the
Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)216
provided the first large-scale evidence of survival benefit
with ICDs for primary prevention of sudden cardiac death
in patients with DCM. In this trial, in patients with
NYHA class II or III HF and a LVEF of 35%, the single-lead,
shock-only ICD therapy reduced overall mortality by 23%,
CAR055.indd 1251
12 51
whereas amiodarone had no favorable effect on survival. The
cause of HF was ischemic in 52% and nonischemic in 48%,
and the results did not vary according to either ischemic or
nonischemic causes of HF. Subsequently, the Center for
Medicare and Medicaid Services (CMS) expanded its ICD
coverage substantially to reflect the results of this trial,
including coverage for patients with nonischemic DCM with
duration over 9 months and measured LVEF ≤30%, if the
patient is enrolled in either a clinical trial or a qualifying
national database.217
Medical Antiarrhythmic Therapy
Studies addressing the role of antiarrhythmic therapy in prolonging survival or preventing sudden death in HF have
yielded disparate results. The Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure with Amiodarone
(CHF-STAT)64 revealed that amiodarone treatment was effective in suppressing ventricular arrhythmias and improving
ventricular function; however, it did not reduce the incidence
of sudden death or prolong survival among patients with HF,
except for a trend toward reduced mortality among those
with nonischemic cardiomyopathy. In the trial by Grupo
de Estudio de la Sobrevida en la Insuficiencia Cardiaca en
Argentina (GESICA),218 low-dose amiodarone resulted in
reduction in total mortality, sudden cardiac death, and HF
death in both the dilated nonischemic and ischemic patients.
As mentioned above, in the SCD-HeFT trial,216 amiodarone
failed to have any beneficial effect on survival when compared with placebo in HF patients regardless of etiology.
Presently, antiarrhythmic medical therapy is reserved for
individualized treatment of symptomatic arrhythmias, especially for suppression of ventricular arrhythmias after ICD
implantation or supraventricular arrhythmias such as atrial
fibrillation.
It is important to emphasize that beta-blockers have also
been shown to reduce sudden cardiac death risk, by approximately 30%, in patients with ischemic or nonischemic HF
in addition to their overall benefit in reducing mortality and
HF hospitalizations.5,7,15,203
Cardiac Resynchronization Therapy
Many patients with DCM have cardiac conduction abnormalities, such as LBBB or intraventricular conduction delays
(IVCDs) that can lead to ventricular dyssynchrony and
reduction in stroke volume as a consequence. In patients
with HF, the presence of LBBB or IVCD further degrades
ventricular function, contributing directly to the severity of
their HF symptoms. Biventricular pacing with transvenous
leads in the right atrium, right ventricle, and left ventricle
via the coronary sinus can restore cardiac resynchronization. Several recent studies—the Multicenter InSync
Randomized Clinical Evaluation (MIRACLE),219 Multisite
Stimulation in Cardiomyopathy (MUSTIC),220 Comparison
of Medical Therapy, Pacing, and Defibrillation in Heart
Failure (COMPANION),221 and the Cardiac Resynchronization–Heart Failure (CARE-HF)222 trials—validated the safety
and efficacy of cardiac resynchronization therapy in advanced
HF. Data from these studies have shown statistically
significant improvements in LVEF, NYHA class, exercise
11/24/2006 1:28:35 PM
12 5 2
chapter
tolerance, and quality of life. Furthermore, the COMPANION trial demonstrated that in patients with advanced HF
and a prolonged QRS interval, cardiac-resynchronization
therapy decreased the combined risk of death from any cause
or first hospitalization, and when combined with an implantable defibrillator, significantly reduced mortality.221 However,
in the COMPANION trial, the decrease in the risk of death
was not significant with cardiac resynchronization therapy
alone. The more recent CARE-HF trial222 demonstrated
that in patients with HF, class III or IV HF due to left
ventricular systolic dysfunction (LVEF <35%), and cardiac
dyssynchrony (QRS >120 ms and/or other evidence of dyssynchrony), cardiac resynchronization improved the symptoms and the quality of life, and reduced the risk of death.
In these trials, the benefit was present in both ischemic and
nonischemic HF patients. The proposed mechanisms
involved in improving ventricular function with biventricular pacing include improved septal contribution to ventricular ejection, increased diastolic filling times, reduced mitral
regurgitation, and prevention of progressive remodeling.
Resynchronization therapy may also reduce arrhythmias by
stabilization of the arrhythmia substrate and by improving
the HF status.
Anticoagulants
Patients with DCM have multiple factors that predispose
them to thromboembolic events. However, the appropriateness of chronic anticoagulant therapy in DCM has been
controversial.223 The Warfarin and Antiplatelet Therapy in
Chronic Heart failure (WATCH) trial, a multicenter, randomized, international trial comparing the efficacy of aspirin,
clopidogrel, and warfarin in HF patients, was the largest trial
of antithrombotic therapies conducted in chronic HF patients.
It reportedly failed to show major differences among the
three medications to prevent the combined end point of nonfatal myocardial infarction, stroke, and mortality.224 In the
absence of controlled trials, the available data support the
use of anticoagulants in the presence of atrial fibrillation,
previous stroke or other thromboembolic events, or visible
protruding or mobile thrombus on echocardiography.
Immunosuppression and Immunomodulation
Although an autoimmune pathogenesis has been postulated
for DCM, immunosuppressive therapy has not been shown
to be effective in clinical trials. The failure of the Myocarditis Treatment Trial225 to show a significant benefit for immunosuppressive therapy is discussed in another chapter. Based
on its possible immunomodulatory effects, intravenous
immunoglobulin has been studied as a potential beneficial
agent in patients with DCM. Although the exact mechanism
of action of intravenous immunoglobulin is not known, a
number of different mechanisms have been proposed, including Fc receptor blockade, neutralization of autoantibodies,
modulation of cytokine activity, and activation of an inhibitory Fc receptor. Based on an initial report that intravenous
immunoglobulin was beneficial in acute cardiomyopathy,
Gullestad and colleagues226 conducted a double-blind trial
with intravenous immunoglobulin for 26 weeks in 47 patients
with moderate HF who were receiving conventional therapy
CAR055.indd 1252
55
for HF, including ACE inhibitors and beta-blockers. They
observed that, in comparison to placebo, intravenous immunoglobulin induced a marked rise in plasma levels of the
antiinflammatory mediators (interleukin-10, and interleukin-1 receptor antagonist), and that these changes were
accompanied by a significant increase in LV ejection performance by 10%, and a decrease in N-terminal pro-atrial
natriuretic peptide levels. Thus, in this small study, immunomodulatory therapy with intravenous immunoglobulin
was effective in patients with HF. Immune modulatory
therapy with immune globulin is an effective therapy for
Kawasaki disease in children, and it has been reported to
improve ventricular function in children with new-onset
DCM,227 in adults228 with recent onset of symptoms of HF,
and in women with postpartum cardiomyopathy.229 However,
the initial promising results observed in the adult population
were not confirmed by the randomized, placebo-controlled,
multicenter Intervention in Myocarditis and Acute Cardiomyopathy (IMAC) trial.230 In this trial, no significant treatment effect could be seen with intravenous immune globulin
over placebo. Both groups had a 14% increase in LVEF.
Whether the observed differences represent differences in
patient selection or dosing is not known at this time.
The technique of immunoadsorption, removal of autoantibodies with immunoadsorption by passing a patient’s
plasma over columns that contain immobilized antibodies
against immunoglobulin (IgG) kappa and lambda light chains
and IgG heavy chains, has been reported to be beneficial
in DCM. Wallukat et al.231 were the first to show that this
technique efficiently removed circulating antibodies directed
against the β1-adrenoreceptor and were associated with an
improvement in NYHA functional class in patients with
DCM. This study was soon followed by another pilot study
that reported an improvement in short-term hemodynamic
effects in patients with severe HF who were refractory to
conventional medical therapy.232 However, these early studies
lacked a concurrent control group. Felix and coworkers233
showed that immunoadsorption and intravenous IgG administration resulted in a significant improvement in cardiac
hemodynamics in 18 patients with DCM who were randomized for 3 months to immunoadsorption and subsequent IgG
replacement or conventional medical therapy. Most recently,
Muller and coworkers234 reported that within 1 year of treatment, immunoadsorption therapy resulted in a significant
lowering of anti–β1-adrenoreceptor antibodies, a significant
(70%) increase in ejection fraction, and a significant (15%)
decrease in LV end-diastolic dimension in the treatment
group.
Taken together, the above studies suggest that immunoadsorption leads to improvements not only in LV structure
and function but also in functional status in selected
patients with DCM. However, it is important to identify the
existing gaps in our knowledge with respect to immunoadsorption in patients with DCM. First, at the present time,
it is unclear whether all patients with DCM will benefit from
immunoadsorption therapy, or whether patients with elevated levels of circulating autoantibodies should be treated.
Second, the mechanism(s) of action of immunoadsorption
is not known. Although studies have demonstrated
decreases in circulating autoantibodies, it is not at all clear
that a cause-and-effect relationship has been established.
11/24/2006 1:28:35 PM
di l at e d c a r diom yopat h y
Immunoadsorption can lead to a decline in systemic vascular
resistance independent of the removal of circulating autoantibodies.167 Thus, part of the hemodynamic benefit that has
been observed may be related to vasodilation and not an
improvement in LV function. Third, the optimal strategy
for immunoadsorption has yet to be determined. Different
investigators use different protocols and different immunoadsorbent devices. It is not clear from existing studies whether
immunoadsorption alone, which would be expected to modulate humoral immunity, will be sufficient in the long term,
or whether it may be necessary to incorporate strategies that
lead to suppression of cellular-mediated immunity as
well.167
Growth Hormone
There has been growing enthusiasm for the use of growth
hormone in patients with DCM, based on the rationale that
there may be inadequate compensatory cardiac hypertrophy
in this disorder. Growth hormone and IGF-1 are involved in
several physiologic processes such as the control of muscle
mass and function, body composition, and regulation of
nutrient metabolism. Earlier reports suggested that growth
hormone therapy could increase myocardial mass and reduce
the size of the LV chamber, resulting in improvement in
hemodynamics, myocardial energy metabolism, and the
clinical status of the patients with HF.235 More recently, two
randomized, placebo-controlled studies of recombinant
human growth hormone did not show significant improvement in cardiac performance or clinical status of patients
with DCM, despite significant increases in LV mass related
to changes in serum IGF-1 concentrations.143,236 Whether
longer treatment with recombinant growth hormone would
result in an improved clinical outcome in the patients with
DCM is unknown.
Gene Therapy
After a decade of preclinical and early phase one clinical
investigations, gene therapy is proving likely to be a viable
alternative to conventional therapies for HF. So far in preclinical studies, three types of gene transfer studies have
been investigated to enhance myocardial contractility: modulating calcium homeostasis (overexpression of SERCA2a by
rat or transgenic mice DCM models), manipulating β-adrenergic receptor signaling (transfection or overexpression of βadrenergic receptor gene in rat or rabbit DCM models), and
augmenting cardiomyocyte resistance to apoptosis (adenoviral gene transfer of antiapoptotic Bcl-2 and Akt in gp130
knockout mice, with DCM associated with massive cardiomyocyte apoptosis).237 However, at present, it has been difficult to develop highly effective gene delivery techniques in
the myocardium.
Since the identification of the gene for Duchenne muscular dystrophy in 1987, many groups have reported successful
approaches for the adenoviral vector delivery of dystrophin,
the Duchenne muscular dystrophy gene product, resulting in
restoration of dystrophin-associated glycoprotein complex
proteins to the sarcolemma and amelioration of muscular
dystrophy symptoms in animal models.238 Although dystrophin is the most extensively studied gene that is implicated
CAR055.indd 1253
12 5 3
in DCM, correction of the dystrophin defects, associated
with X-linked cardiomyopathy, has not been studied in
humans yet.237,238
Angiogenesis and Cell Therapy
These modalities are discussed in another chapter.
Acknowledgments
The authors would like to thank Dr. Andrew I. Schafer for
his past and present guidance and support. The research
reviewed herein was supported, in part, by research funds
from the Department of Veterans Affairs and the National
Institutes of Health (P50 HL-O6H, RO1 HL58081-01A1, and
RO1 HL61543-01).
References
1. Report of the WHO/ISFC task force on the defi nition and classification of cardiomyopathies. Br Heart J 1980;44(6):672–673.
2. Richardson P, McKenna W, Bristow M, et al. Report of the 1995
World Health Organization/International Society and Federation of Cardiology Task Force on the Defi nition and Classification of cardiomyopathies. Circulation 1996;93(5):841–842.
3. Maisch B. [Classification of cardiomyopathies according to the
WHO/ISFC Task Force—more questions than answers?] Med
Klin 1998;93(4):199–209.
4. Boffa GM, Tarantini G, Abbasciano A, Razzolini R, Chioin R,
Thiene G. Ischemic cardiomyopathy: lack of clinical applicability of the WHO/ISFC classification of cardiomyopathies. Ital
Heart J 2001;2(10):778–781.
5. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol
CR/XL Randomised Intervention Trial in Congestive Heart
Failure (MERIT-HF). Lancet 1999;353(9169):2001–2007.
6. Cohn JN, Tognoni G. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J
Med 2001;345(23):1667–1675.
7. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353(9146):9–13.
8. Manolio TA, Baughman KL, Rodeheffer R, et al. Prevalence and
etiology of idiopathic dilated cardiomyopathy (summary of a
National Heart, Lung, and Blood Institute workshop. Am J
Cardiol 1992;69(17):1458–1466.
9. Coughlin SS, Gottdiener JS, Baughman KL, et al. Black-white
differences in mortality in idiopathic dilated cardiomyopathy:
the Washington, DC, Dilated Cardiomyopathy Study. J Natl
Med Assoc 1994;86(8):583–591.
10. Dries DL, Exner DV, Gersh BJ, Cooper HA, Carson PE, Domanski MJ. Racial differences in the outcome of left ventricular
dysfunction. N Engl J Med 1999;340(8):609–616.
11. Coughlin SS, Myers L, Michaels RK. What explains blackwhite differences in survival in idiopathic dilated cardiomyopathy? The Washington, DC, Dilated Cardiomyopathy Study.
J Natl Med Assoc 1997;89(4):277–282.
12. Watkins LO, Williams RA. Cardiomyopathy in blacks. Cardiovasc Clin 1991;21(3):279–296.
13. Yancy CW, Fowler MB, Colucci WS, et al. Race and the response
to adrenergic blockade with carvedilol in patients with chronic
heart failure. N Engl J Med 2001;344(18):1358–1365.
14. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences
in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study
Group. J Card Fail 1999;5(3):178–187.
15. A trial of the beta-blocker bucindolol in patients with advanced
chronic heart failure. N Engl J Med 2001;344(22):1659–1667.
11/24/2006 1:28:36 PM
12 5 4
chapter
16. Braunwald E. Expanding indications for beta-blockers in heart
failure. N Engl J Med 2001;344(22):1711–1712.
17. Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response
to angiotensin-converting-enzyme inhibitor therapy in black
as compared with white patients with left ventricular dysfunction. N Engl J Med 2001;344(18):1351–1357.
18. Dries DL, Strong MH, Cooper RS, Drazner MH. Efficacy of
angiotensin-converting enzyme inhibition in reducing progression from asymptomatic left ventricular dysfunction to symptomatic heart failure in black and white patients. J Am Coll
Cardiol 2002;40(2):311–317.
19. Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham
Heart Study subjects. Circulation 1993;88(1):107–115.
20. Schocken DD, Arrieta MI, Leaverton PE, Ross EA. Prevalence
and mortality rate of congestive heart failure in the United
States. J Am Coll Cardiol 1992;20(2):301–306.
21. Effect of enalapril on survival in patients with reduced
left ventricular ejection fractions and congestive heart
failure. The SOLVD Investigators. N Engl J Med 1991;325(5):
293–302.
22. Bourassa MG, Gurne O, Bangdiwala SI, et al. Natural history
and patterns of current practice in heart failure. The Studies of
Left Ventricular Dysfunction (SOLVD) Investigators. J Am Coll
Cardiol 1993;22(4 Suppl A):14A–19A.
23. De Maria R, Gavazzi A, Recalcati F, Baroldi G, De Vita C,
Camerini F. Comparison of clinical fi ndings in idiopathic
dilated cardiomyopathy in women versus men. The Italian
Multicenter Cardiomyopathy Study Group (SPIC). Am J Cardiol
1993;72(7):580–585.
24. Ghali JK, Pina IL, Gottlieb SS, Deedwania PC, Wikstrand JC.
Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation
2002;105(13):1585–1591.
25. Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex
differences in the prognosis of congestive heart failure: results
from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation 2001;103(3):375–380.
26. Dec GW, Fuster V. Idiopathic dilated cardiomyopathy. N Engl
J Med 1994;331(23):1564–1575.
27. Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Brandenburg RO, Frye
RL. The natural history of idiopathic dilated cardiomyopathy.
Am J Cardiol 1981;47(3):525–531.
28. Sugrue DD, Rodeheffer RJ, Codd MB, Ballard DJ, Fuster V,
Gersh BJ. The clinical course of idiopathic dilated cardiomyopathy. A population-based study. Ann Intern Med 1992;117(2):
117–123.
29. Miura K, Nakagawa H, Morikawa Y, et al. Epidemiology of
idiopathic cardiomyopathy in Japan: results from a nationwide
survey. Heart 2002;87(2):126–130.
30. Amoah AG, Kallen C. Aetiology of heart failure as seen from
a National Cardiac Referral Centre in Africa. Cardiology 2000;
93(1–2):11–18.
31. Mendez GF, Cowie MR. The epidemiological features of heart
failure in developing countries: a review of the literature. Int J
Cardiol 2001;80(2–3):213–219.
32. Nelson DE, Bland S, Powell-Griner E, et al. State trends in
health risk factors and receipt of clinical preventive services
among US adults during the 1990s. JAMA 2002;287(20):
2659–2667.
33. Saxon LA, De Marco T. Arrhythmias associated with dilated
cardiomyopathy. Card Electrophysiol Rev 2002;6(1–2):18–25.
34. Saxon LA, Stevenson WG, Middlekauff HR, et al. Predicting
death from progressive heart failure secondary to ischemic or
idiopathic dilated cardiomyopathy. Am J Cardiol 1993;72(1):
62–65.
CAR055.indd 1254
55
35. Steimle AE, Stevenson LW, Fonarow GC, Hamilton MA, Moriguchi JD. Prediction of improvement in recent onset cardiomyopathy after referral for heart transplantation. J Am Coll
Cardiol 1994;23(3):553–559.
36. Romeo F, Pelliccia F, Cianfrocca C, et al. Determinants of endstage idiopathic dilated cardiomyopathy: a multivariate analysis of 104 patients. Clin Cardiol 1989;12(7):387–392.
37. Lewis JF, Webber JD, Sutton LL, Chesoni S, Curry CL. Discordance in degree of right and left ventricular dilation in patients
with dilated cardiomyopathy: recognition and clinical implications. J Am Coll Cardiol 1993;21(3):649–654.
38. Juilliere Y, Barbier G, Feldmann L, Grentzinger A, Danchin N,
Cherrier F. Additional predictive value of both left and
right ventricular ejection fractions on long-term survival
in idiopathic dilated cardiomyopathy. Eur Heart J 1997;18(2):
276–280.
39. Werner GS, Schaefer C, Dirks R, Figulla HR, Kreuzer H. Prognostic value of Doppler echocardiographic assessment of left
ventricular fi lling in idiopathic dilated cardiomyopathy. Am J
Cardiol 1994;73(11):792–798.
40. Junker A, Thayssen P, Nielsen B, Andersen PE. The hemodynamic and prognostic significance of echo-Doppler-proven
mitral regurgitation in patients with dilated cardiomyopathy.
Cardiology 1993;83(1–2):14–20.
41. De Maria R, Gavazzi A, Caroli A, Ometto R, Biagini A, Camerini F. Ventricular arrhythmias in dilated cardiomyopathy as
an independent prognostic hallmark. Italian Multicenter Cardiomyopathy Study (SPIC) Group. Am J Cardiol 1992;69(17):
1451–1457.
42. Yi G, Goldman JH, Keeling PJ, Reardon M, McKenna WJ, Malik
M. Heart rate variability in idiopathic dilated cardiomyopathy:
relation to disease severity and prognosis. Heart 1997;77(2):
108–114.
43. Fauchier L, Babuty D, Cosnay P, Poret P, Rouesnel P, Fauchier
JP. Long-term prognostic value of time domain analysis of
signal-averaged electrocardiography in idiopathic dilated cardiomyopathy. Am J Cardiol 2000;85(5):618–623.
44. Hammond EH, Menlove RL, Anderson JL. Predictive value of
immunofluorescence and electron microscopic evaluation of
endomyocardial biopsies in the diagnosis and prognosis of myocarditis and idiopathic dilated cardiomyopathy. Am Heart J
1987;114(5):1055–1065.
45. Koglin J, Pehlivanli S, Schwaiblmair M, Vogeser M, Cremer P,
vonScheidt W. Role of brain natriuretic peptide in risk stratification of patients with congestive heart failure. J Am Coll
Cardiol 2001;38(7):1934–1941.
46. Bahler RC. Assessment of prognosis in idiopathic dilated cardiomyopathy. Chest 2002;121(4):1016–1019.
47. Deswal A, Petersen NJ, Feldman AM, Young JB, White BG,
Mann DL. Cytokines and cytokine receptors in advanced
heart failure: an analysis of the cytokine database from the
Vesnarinone Trial (VEST). Circulation 2001;103(16):2055–
2059.
48. Seta Y, Shan K, Bozkurt B, Oral H, Mann DL. Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail
1996;2(3):243–249.
49. Sato Y, Yamada T, Taniguchi R, et al. Persistently increased
serum concentrations of cardiac troponin T in patients with
idiopathic dilated cardiomyopathy are predictive of adverse
outcomes. Circulation 2001;103(3):369–374.
50. Hossein-Nia M, Baig K, Goldman JH, et al. Creatine kinase
isoforms as circulating markers of deterioration in idiopathic
dilated cardiomyopathy. Clin Cardiol 1997;20(1):55–60.
51. Likoff MJ, Chandler SL, Kay HR. Clinical determinants of
mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol
1987;59(6):634–638.
11/24/2006 1:28:36 PM
di l at e d c a r diom yopat h y
52. Cohn JN, Johnson GR, Shabetai R, et al. Ejection fraction, peak
exercise oxygen consumption, cardiothoracic ratio, ventricular
arrhythmias, and plasma norepinephrine as determinants of
prognosis in heart failure. The V-HeFT VA Cooperative Studies
Group. Circulation 1993;87(6 Suppl):VI5–16.
53. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr,
Wilson JR. Value of peak exercise oxygen consumption for
optimal timing of cardiac transplantation in ambulatory
patients with heart failure. Circulation 1991;83(3):778–786.
54. Lee WH, Packer M. Prognostic importance of serum sodium
concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation
1986;73(2):257–267.
55. van den Broek SA, van Veldhuisen DJ, de Graeff PA, Landsman
ML, Hillege H, Lie KI. Comparison between New York Heart
Association classification and peak oxygen consumption in the
assessment of functional status and prognosis in patients with
mild to moderate chronic congestive heart failure secondary to
either ischemic or idiopathic dilated cardiomyopathy. Am J
Cardiol 1992;70(3):359–363.
56. Naqvi TZ, Goel RK, Forrester JS, Siegel RJ. Myocardial contractile reserve on dobutamine echocardiography predicts late
spontaneous improvement in cardiac function in patients with
recent onset idiopathic dilated cardiomyopathy. J Am Coll
Cardiol 1999;34(5):1537–1544.
57. Marmor A, Schneeweiss A. Prognostic value of noninvasively
obtained left ventricular contractile reserve in patients with
severe heart failure. J Am Coll Cardiol 1997;29(2):422–428.
58. Nagaoka H, Isobe N, Kubota S, et al. Myocardial contractile
reserve as prognostic determinant in patients with idiopathic
dilated cardiomyopathy without overt heart failure. Chest
1997;111(2):344–350.
59. Scrutinio D, Napoli V, Passantino A, Ricci A, Lagioia R, Rizzon
P. Low-dose dobutamine responsiveness in idiopathic dilated
cardiomyopathy: relation to exercise capacity and clinical
outcome. Eur Heart J 2000;21(11):927–934.
60. Drozdz J, Krzeminska-Pakula M, Plewka M, Ciesielczyk M,
Kasprzak JD. Prognostic value of low-dose dobutamine echocardiography in patients with idiopathic dilated cardiomyopathy. Chest 2002;121(4):1216–1222.
61. Ehlert FA, Cannom DS, Renfroe EG, et al. Comparison of
dilated cardiomyopathy and coronary artery disease in patients
with life-threatening ventricular arrhythmias: Differences in
presentation and outcome in the AVID registry. Am Heart J
2001;142(5):816–822.
62. Follath F, Cleland JG, Klein W, Murphy R. Etiology and response
to drug treatment in heart failure. J Am Coll Cardiol 1998;
32(5):1167–1172.
63. The effect of digoxin on mortality and morbidity in patients
with heart failure. The Digitalis Investigation Group. N Engl J
Med 1997;336(8):525–533.
64. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in
patients with congestive heart failure and asymptomatic
ventricular arrhythmia. Survival Trial of Antiarrhythmic
Therapy in Congestive Heart Failure. N Engl J Med 1995;333(2):
77–82.
65. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine
on morbidity and mortality in severe chronic heart failure.
Prospective Randomized Amlodipine Survival Evaluation
Study Group. N Engl J Med 1996;335(15):1107–1114.
66. Thackray S, Witte K, Clark AL, Cleland JG. Clinical trials
update: OPTIME-CHF, PRAISE-2, ALL-HAT. Eur J Heart Fail
2000;2(2):209–212.
67. Michels VV, Moll PP, Miller FA, et al. The frequency of
familial dilated cardiomyopathy in a series of patients with
idiopathic dilated cardiomyopathy. N Engl J Med 1992;326(2):
77–82.
CAR055.indd 1255
12 5 5
68. Grunig E, Tasman JA, Kucherer H, Franz W, Kubler W, Katus
HA. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol 1998;31(1):186–194.
69. Piano MR. Alcoholic cardiomyopathy: incidence, clinical characteristics, and pathophysiology. Chest 2002;121(5):1638–1650.
70. Preedy VR, Atkinson LM, Richardson PJ, Peters TJ. Mechanisms of ethanol-induced cardiac damage. Br Heart J 1993;
69(3):197–200.
71. Wilke A, Kaiser A, Ferency I, Maisch B. [Alcohol and myocarditis]. Herz 1996;21(4):248–257.
72. Schenk EA, Cohen J. The heart in chronic alcoholism. Clinical
and pathologic fi ndings. Pathol Microbiol (Basel) 1970;35(1):
96–104.
73. Cerqueira MD, Harp GD, Ritchie JL, Stratton JR, Walker RD.
Rarity of preclinical alcoholic cardiomyopathy in chronic alcoholics less than 40 years of age. Am J Cardiol 1991;67(2):
183–187.
74. Regan TJ. Alcohol and the cardiovascular system. JAMA 1990;
264(3):377–381.
75. Lang RM, Borow KM, Neumann A, Feldman T. Adverse cardiac
effects of acute alcohol ingestion in young adults. Ann Intern
Med 1985;102(6):742–747.
76. Diamond I. Alcoholic myopathy and cardiomyopathy. N Engl J
Med 1989;320(7):458–460.
77. Fernandez-Sola J, Estruch R, Grau JM, Pare JC, Rubin E, UrbanoMarquez A. The relation of alcoholic myopathy to cardiomyopathy. Ann Intern Med 1994;120:529–536.
78. Patel VB, Why HJ, Richardson PJ, Preedy VR. The effects of
alcohol on the heart. Adverse Drug React Toxicol Rev 1997;
16:15–43.
79. Guarnieri T, Lakatta EG. Mechanism of myocardial contractile
depression by clinical concentrations of ethanol: a study in
ferret papillary muscles. J Clin Invest 1990;85:1462–1467.
80. Capasso JM, Li P, Guideri G, Malhotra A, Cortese R, Anversa
P. Myocardial mechanical, biochemical, and structural alterations induced by chronic ethanol ingestion in rats. Circ Res
1992;71(2):346–356.
81. Cartwright MM, Smith SM. Increased cell death and reduced
neural crest cell numbers in ethanol-exposed embryos: partial
basis for the fetal alcohol syndrome phenotype. Alcohol Clin
Exp Res 1995;19(2):378–386.
82. Teragaki M, Takeuchi K, Toda I, et al. Point mutations in mitochondrial DNA of patients with alcoholic cardiomyopathy.
Heart Vessels 2000;15(4):172–175.
83. Pavan D, Nicolosi GL, Lestuzzi C, Burelli C, Zardo F, Zanuttini
D. Normalization of variables of left ventricular function in
patients with alcoholic cardiomyopathy after cessation of
excessive alcohol intake: an echocardiographic study. Eur Heart
J 1987;85:535–540.
84. Nethala V, Brown EJ Jr, Timson CR, Patcha R. Reversal of
alcoholic cardiomyopathy in a patient with severe coronary
artery disease. Chest 1993;104:626.
85. Fauchier L, Babuty D, Poret P, et al. Comparison of long-term
outcome of alcoholic and idiopathic dilated cardiomyopathy.
Eur Heart J 2000;21(4):306–314.
86. Bertolet BD, Freund G, Martin CA, Perchalski DL, Williams
CM, Pepine CJ. Unrecognized left ventricular dysfunction in
an apparently healthy cocaine abuse population. Clin Cardiol
1990;13:323–328.
87. Chakko S, Myerburg RJ. Cardiac complications of cocaine
abuse. Clin Cardiol 1995;18(2):67–72.
88. Roldan CA, Aliabadi D, Crawford MH. Prevalence of heart
disease in asymptomatic chronic cocaine users. Cardiology
2001;95(1):25–30.
89. Moliterno DJ, Willard JE, Lange RA, et al. Coronary-artery
vasoconstriction induced by cocaine, cigarette smoking, or
both. N Engl J Med 1994;330(7):454–459.
11/24/2006 1:28:36 PM
12 5 6
chapter
90. Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects
on the biology of the adult mammalian cardiocyte. Circulation
1992;85(2):790–804.
91. Shin GY, Rice P. Cocaine use and acute coronary syndromes.
Lancet 2001;358(9290):1367–1368.
92. Virmani R, Robinowitz M, Smialek JE, Smyth DF. Cardiovascular effects of cocaine: an autopsy study of 40 patients. Am
Heart J 1988;115:1068–1076.
93. Henzlova MJ, Smith SH, Prchal VM, Helmcke FR. Apparent
reversibility of cocaine-induced congestive cardiomyopathy.
Am Heart J 1991;122:577–579.
94. Leikin JB. Cocaine and beta-adrenergic blockers: a remarriage
after a decade-long divorce? Crit Care Med 1999;27(4):
688–689.
95. Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of
prevailing hypotheses. FASEB J 1990;4:3076–3086.
96. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996;125(1):47–58.
97. Allen A. The cardiotoxicity of chemotherapeutic drugs. Semin
Oncol 1992;19(5):529–542.
98. Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and drug
dose as risk factors for late cardiotoxic effects of doxorubicin
therapy for childhood cancer. N Engl J Med 1995;332:1738–
1743.
99. Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern
Med 1978;88:168–175.
100. Sparano JA, Wolff AC, Brown D. Troponins for predicting
cardiotoxicity from cancer therapy. Lancet 2000;356(9246):
1947–1948.
101. Saini J, Rich MW, Lyss AP. Reversibility of severe left ventricular dysfunction due to doxorubicin cardiotoxicity. Report of
three cases. Ann Intern Med 1987;106:814–816.
102. Doroshow JH. Doxorubicin-induced cardiac toxicity. N Engl J
Med 1991;324:843–845.
103. Hellmann K. Anthracycline cardiotoxicity prevention by dexrazoxane: breakthrough of a barrier—sharpens antitumor profi le
and therapeutic index. J Clin Oncol 1996;14(2):332–333.
104. Nelson MA, Frishman WH, Seiter K, Keefe D, Dutcher J. Cardiovascular considerations with anthracycline use in patients
with cancer. Heart Dis 2001;3(3):157–168.
105. Schneider JW, Chang AY, Garratt A. Trastuzumab cardiotoxicity: Speculations regarding pathophysiology and targets for
further study. Semin Oncol 2002;29(3 suppl 11):22–28.
106. Bozkurt B, Kribbs S, Clubb FJ Jr, et al. Pathophysiologically
relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats.
Circulation 1998;97:1382–1391.
107. Kubota T, McTiernan CF, Frye CS, et al. Dilated cardiomyopathy in transgenic mice with cardiac specific overexpression of
tumor necrosis factor-alpha. Circ Res 1997;81:627–635.
108. Rerkpattanapipat P, Wongpraparut N, Jacobs LE, Kotler MN.
Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med 2000;160(5):602–608.
109. Panther LA. How HIV infection and its treatment affects the
cardiovascular system: what is known, what is needed. Am J
Physiol Heart Circ Physiol 2002;283(1):H1–H4.
110. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Incidence of
dilated cardiomyopathy and detection of HIV in myocardial
cells of HIV-positive patients. Gruppo Italiano per lo Studio
Cardiologico dei Pazienti Affetti da AIDS. N Engl J Med 1998;
339(16):1093–1099.
111. Raidel SM, Haase C, Jansen NR, et al. Targeted myocardial
transgenic expression of HIV Tat causes cardiomyopathy and
mitochondrial damage. Am J Physiol Heart Circ Physiol 2002;
282(5):H1672–H1678.
CAR055.indd 1256
55
112. Lewis W. AIDS cardiomyopathy: physiological, molecular, and
biochemical studies in the transgenic mouse. Ann N Y Acad
Sci 2001;946:46–56.
113. Herskowitz A, Wu T-C, Willoughby SB, et al. Myocarditis
and cardiotropic viral infection associated with severe left
ventricular dysfunction in late-stage infection with human
immunodeficiency virus. J Am Coll Cardiol 1994;24:1025–
1032.
114. Kaul S, Fishbein MC, Siegel RJ. Cardiac manifestations of
acquired immune deficiency syndrome: a 1991 update. Am
Heart J 1991;122:535–544.
115. Rossi MA, Bestetti RB. The challenge of chagasic cardiomyopathy. The pathologic roles of autonomic abnormalities, autoimmune mechanisms and microvascular changes, and
therapeutic implications. Cardiology 1995;86(1):1–7.
116. Carrasco HA, Parada H, Guerrero L, Duque M, Duran D,
Molina C. Prognostic implications of clinical, electrocardiographic and hemodynamic fi ndings in chronic Chagas’ disease.
Int J Cardiol 1994;43(1):27–38.
117. Kirchhoff LV. Current concepts: American trypanosomiasis
(Chagas’ Disease)—a tropical disease now in the United States.
N Engl J Med 1993;329:639–644.
118. Marr JJ, Docampo R. Chemotherapy for Chagas’ disease: a perspective on current therapy and considerations for future
research. Rev Infect Dis 1986;8:884–903.
119. Roberti RR, Martinez EE, Andrade JL, et al. Chagas cardiomyopathy and captopril. Eur Heart J 1992;13(7):966–970.
120. Burke AP, Saenger J, Mullick F, Virmani R. Hypersensitivity
myocarditis. Arch Pathol Lab Med 1991;115(8):764–769.
121. Paradiso M, Gabrielli F, Masala C, et al. Evaluation of myocardial involvement in systemic lupus erythematosus by signalaveraged electrocardiography and echocardiography. Acta
Cardiol 2001;56(6):381–386.
122. Lee LA. Neonatal lupus: clinical features, therapy, and pathogenesis. Curr Rheumatol Rep 2001;3(5):391–395.
123. Kazzam E, Caidahl K, Hallgren R, Gustafsson R, Landelius J,
Waldenstrom A. Non-invasive assessment of systolic left ventricular function in systemic sclerosis. Eur Heart J 1991;12:
151–156.
124. Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. Myocardial
lesions of progressive systemic sclerosis. A cause of cardiac
dysfunction. Circulation 1976;53:483–490.
125. Goldenberg J, Ferraz MB, Pessoa AP, et al. Symptomatic cardiac
involvement in juvenile rheumatoid arthritis. Int J Cardiol
1992;34:57–62.
126. Marin-Neto JA, Maciel BC, Urbanetz LL, Gallo JL, AlmeidaFilho OC, Amorim DS. High output failure in patients
with peripartum cardiomyopathy: a comparative study
with dilated cardiomyopathy. Am Heart J 1991;121(1 pt 1):
134–140.
127. Lampert MB, Lang RM. Peripartum cardiomyopathy. Am Heart
J 1995;130(4):860–870.
128. Melvin KR, Richardson PJ, Olsen EG, Daly K, Jackson G. Peripartum cardiomyopathy due to myocarditis. N Engl J Med
1982;307(12):731–734.
129. Elkayam U, Tummala PP, Rao K, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum
cardiomyopathy. N Engl J Med 2001;344(21):1567–1571.
130. O’Connell JB, Costanzo-Nordin MR, Subramanian R, et al.
Peripartum cardiomyopathy: clinical, hemodynamic, histologic and prognostic characteristics. J Am Coll Cardiol 1986;
8(1):52–56.
131. Alpert MA. Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome. Am J Med Sci 2001;321(4):
225–236.
132. Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of
heart failure. N Engl J Med 2002;347(5):305–313.
11/24/2006 1:28:36 PM
di l at e d c a r diom yopat h y
133. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz
WH. The disease burden associated with overweight and
obesity. JAMA 1999;282(16):1523–1529.
134. Abate N. Obesity and cardiovascular disease. Pathogenetic role
of the metabolic syndrome and therapeutic implications. J Diabetes Complications 2000;14(3):154–174.
135. Francis GS. Diabetic cardiomyopathy: fact or fiction? Heart
2001;85(3):247–248.
136. Devereux RB, Roman MJ, Paranicas M, et al. Impact of diabetes
on cardiac structure and function: the strong heart study. Circulation 2000;101(19):2271–2276.
137. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular
system. N Engl J Med 2001;344(7):501–509.
138. Ladenson PW. Recognition and management of cardiovascular
disease related to thyroid dysfunction. Am J Med 1990;88(6):
638–641.
139. Klein I, Ojamaa K. Clinical review 36: Cardiovascular manifestations of endocrine disease. J Clin Endocrinol Metab 1992;
75(2):339–342.
140. Lee RT, Plappert M, Sutton MG. Depressed left ventricular
systolic ejection force in hypothyroidism. Am J Cardiol
1990;65(7):526–527.
141. Colao A, Marzullo P, Di Somma C, Lombardi G. Growth
hormone and the heart. Clin Endocrinol (Oxf) 2001;54(2):
137–154.
142. Volterrani M, Giustina A, Manelli F, Cicoira MA, Lorusso R,
Giordano A. Role of growth hormone in chronic heart failure:
therapeutic implications. Ital Heart J 2000;1(11):732–738.
143. Osterziel KJ, Strohm O, Schuler J, et al. Randomised, doubleblind, placebo-controlled trial of human recombinant growth
hormone in patients with chronic heart failure due to dilated
cardiomyopathy. Lancet 1998;351(9111):1233–1237.
144. Singleton CK, Martin PR. Molecular mechanisms of thiamine
utilization. Curr Mol Med 2001;1(2):197–207.
145. Djoenaidi W, Notermans SL, Dunda G. Beriberi cardiomyopathy. Eur J Clin Nutr 1992;46(3):227–234.
146. Sole MJ, Jeejeebhoy KN. Conditioned nutritional requirements:
therapeutic relevance to heart failure. Herz 2002;27(2):
174–178.
147. Retter AS. Carnitine and its role in cardiovascular disease.
Heart Dis 1999;1(2):108–113.
148. Vescovo G, Ravara B, Gobbo V, et al. L-Carnitine: a potential
treatment for blocking apoptosis and preventing skeletal muscle
myopathy in heart failure. Am J Physiol Cell Physiol 2002;283(3):
C802–C810.
149. Razeghi P, Young ME, Ying J, et al. Downregulation of metabolic gene expression in failing human heart before and after
mechanical unloading. Cardiology 2002;97(4):203–209.
150. Zarain-Herzberg A, Rupp H. Therapeutic potential of CPT I
inhibitors: cardiac gene transcription as a target. Expert Opin
Invest Drugs 2002;11(3):345–356.
151. Cheng TO. Selenium deficiency and cardiomyopathy. J R Soc
Med 2002;95(4):219–220.
152. Manar MJ, MacPherson GD, Mcardle F, Jackson MJ, Hart CA.
Selenium status, kwashiorkor and congestive heart failure.
Acta Paediatr 2001;90(8):950–952.
153. Hetet G, Grandchamp B, Bouchier C, et al. Idiopathic dilated
cardiomyopathy: lack of association with haemochromatosis
gene in the CARDIGENE study. Heart 2001;86(6):702–703.
154. Gochee PA, Powell LW. What’s new in hemochromatosis. Curr
Opin Hematol 2001;8(2):98–104.
155. Wang TL, Chen WJ, Liau CS, Lee YT. Sick sinus syndrome as
the early manifestation of cardiac hemochromatosis. J Electrocardiol 1994;27(1):91–96.
156. Blankenberg F, Eisenberg S, Scheinman MN, Higgins CB. Use
of cine gradient echo (GRE) MR in the imaging of cardiac hemochromatosis. J Comput Assist Tomogr 1994;18(1):136–138.
CAR055.indd 1257
12 5 7
157. Lombardo T, Tamburino C, Bartoloni G, et al. Cardiac iron
overload in thalassemic patients: an endomyocardial biopsy
study. Ann Hematol 1995;71(3):135–141.
158. Mariotti E, Agostini A, Angelucci E, Lucarelli G, Sgarbi E.
Echocardiographic study in ex-thalassemic patients with iron
overload, preliminary observations during phlebotomy therapy.
Bone Marrow Transplant 1993;12(suppl 1):106–107.
159. Spinale FG, Tomita M, Zellner JL, Cook JC, Crawford FA, Zile
MR. Collagen remodeling and changes in LV function during
development and recovery from supraventricular tachycardia.
Am J Physiol 1991;261:H308–H318.
160. Mukherjee R, Crawford FA, Hewett KW, Spinale FG. Cell
and sarcomere contractile performance from the same cardiocyte using video microscopy. J Appl Physiol 1993;74:2023–
2033.
161. Shinbane JS, Wood MA, Jensen DN, Ellenbogen KA, Fitzpatrick
AP, Scheinman MM. Tachycardia-induced cardiomyopathy: a
review of animal models and clinical studies. J Am Coll Cardiol
1997;29:709–715.
162. Schumacher B, Luderitz B. Rate issues in atrial fibrillation:
consequences of tachycardia and therapy for rate control. Am
J Cardiol 1998;82:29N–36N.
163. Luchsinger JA, Steinberg JS. Resolution of cardiomyopathy
after ablation of atrial flutter. J Am Coll Cardiol 1998;32:205–
210.
164. Limas CJ, Goldenberg IF, Limas C. Autoantibodies against
β-adrenoceptors in human idiopathic dilated cardiomyopathy.
Circ Res 1989;64:97–103.
165. Caforio AL, Grazzini M, Mann JM, et al. Identification of
alpha- and beta-cardiac myosin heavy chain isoforms as major
autoantigens in dilated cardiomyopathy. Circulation 1992;85:
1734–1742.
166. Ansari AA, Wang YC, Danner DJ, et al. Abnormal expression
of histocompatibility and mitochondrial antigens by cardiac
tissue from patients with myocarditis and dilated cardiomyopathy. Am J Pathol 1991;139:337–354.
167. Mann DL. Autoimmunity, immunoglobulin adsorption and
dilated cardiomyopathy: has the time come for randomized
clinical trials? J Am Coll Cardiol 2001;38(1):184–186.
168. Carlquist JF, Menlove RL, Murray MB, O’Connell JB, Anderson
JL. HLA class II (DR and DQ) antigen associations in idiopathic
dilated cardiomyopathy. Circulation 1991;83:515–522.
169. Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic
peptides in assessment of patients with possible new heart
failure in primary care. Lancet 1997;350:1349–1353.
170. McDonagh TA, RObb SD, Murdoch DR, et al. Biochemical
detection of left-ventricular systolic dysfunction. Lancet 1998;
351:9–13.
171. Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic
peptide in assessment of acute dyspnoea [see comments]. Lancet
1994;343:440–444.
172. Maisel A. B-type natriuretic peptide levels: diagnostic and
prognostic in congestive heart failure: what’s next? Circulation
2002;105(20):2328–2331.
173. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis
of heart failure. N Engl J Med 2002;347(3):161–167.
174. Richards AM, Doughty R, Nicholls MG, et al. Neurohumoral
prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group.
Circulation 1999;99(6):786–792.
175. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by
plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355(9210):1126–1130.
176. Mizuno Y, Yoshimura M, Harada E, et al. Plasma levels of Aand B-type natriuretic peptides in patients with hypertrophic
11/24/2006 1:28:36 PM
12 5 8
chapter
cardiomyopathy or idiopathic dilated cardiomyopathy. Am J
Cardiol 2000;86(9):1036–40, A11.
177. Wilensky RL, Yudelman P, Cohen AI, et al. Serial electrocardiographic changes in idiopathic dilated cardiomyopathy confi rmed at necropsy. Am J Cardiol 1988;62:276–283.
178. Meinertz T, Hofmann T, Kasper W, et al. Significance of ventricular arrhythmias in idiopathic dilated cardiomyopathy. Am
J Cardiol 1984;53:902–907.
179. Mestroni L, Miani D, Neri R, Di Lenarda A, Camerini F.
Ambulatory ECG in cardiomyopathies. G Ital Cardiol 1987;17:
1139–1144.
180. Kron J, Hart M, Schual-Berke S, Niles NR, Hosenpud JD,
McAnulty JH. Idiopathic dilated cardiomyopathy. Role of programmed electrical stimulation and Holter monitoring in predicting those at risk of sudden death. Chest 1988;93:85–90.
181. Olshausen KV, Stienen U, Schwarz F, Kubler W, Meyer J. Longterm prognostic significance of ventricular arrhythmias in
idiopathic dilated cardiomyopathy. Am J Cardiol 1988;61:
146–151.
182. Ikegawa T, Chino M, Hasegawa H, et al. Prognostic significance of 24–hour ambulatory electrocardiographic monitoring
in patients with dilative cardiomyopathy: a prospective study.
Clin Cardiol 1987;10:78–82.
183. Mancini DM, Wong KL, Simson MB. Prognostic value of an
abnormal signal-averaged electrocardiogram in patients with
nonischemic congestive cardiomyopathy [see comments]. Circulation 1993;87(4):1083–1092.
184. Schmitt C, Barthel P, Ndrepepa G, et al. Value of programmed
ventricular stimulation for prophylactic internal cardioverterdefibrillator implantation in postinfarction patients preselected
by noninvasive risk stratifiers. J Am Coll Cardiol 2001;37(7):
1901–1907.
185. Bigger JT Jr. Prophylactic use of implanted cardiac defibrillators
in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft
(CABG) Patch Trial Investigators. N Engl J Med 1997;337(22):
1569–1575.
186. Keeling PJ, Kulakowski P, Yi G, Slade AK, Bent SE, McKenna
WJ. Usefulness of signal-averaged electrocardiogram in idiopathic dilated cardiomyopathy for identifying patients with
ventricular arrhythmias. Am J Cardiol 1993;72:78–84.
187. Middlekauff HR, Stevenson WG, Woo MA, Moser DK, Stevenson LW. Comparison of frequency of late potentials in idiopathic dilated cardiomyopathy and ischemic cardiomyopathy
with advanced congestive heart failure and their usefulness in
predicting sudden death. Am J Cardiol 1990;66:1113–1117.
188. Meinertz T, Treese N, Kasper W, et al. Determinants of prognosis in idiopathic dilated cardiomyopathy as determined by
programmed electrical stimulation. Am J Cardiol 1985;56:
337–341.
189. Wallis DE, O’Connell JB, Henkin RE, Costanzo-Nordin MR,
Scanlon PJ. Segmental wall motion abnormalities in dilated
cardiomyopathy. J Am Coll Cardiol 1989;13:311–315.
190. Takamoto T, Kim D, Urie PM, et al. Comparative recognition
of left ventricular thrombi by echocardiography and cineangiography. Br Heart J 1985;53:36–42.
191. Kono T, Sabbah HN, Rosman H, Alam M, Stein PD, Goldstein S.
Left atrial contribution to ventricular fi lling during the course
of evolving heart failure. Circulation 1992;86:1317–1322.
192. Nagueh SF, Kopelen HA, Zoghbi WA. Feasibility and accuracy
of Doppler echocardiographic estimation of pulmonary artery
occlusive pressure in the intensive care unit. Am J Cardiol
1995;75:1256–1262.
193. Pohost GM, Fallon JT, Strauss HW. The role of radionuclide
techniques in patients with myocardial disease. Cardiovasc
Clin 1979;10:149–163.
CAR055.indd 1258
55
194. Glamann DB, Lange RA, Corbett JR, Hillis LD. Utility of
various radionuclide techniques for distinguishing ischemic
from nonischemic dilated cardiomyopathy. Arch Intern Med
1992;152:769–772.
195. O’Connell JB, Henkin RE, Robinson JA, Subramanian R,
Scanlon PJ, Gunnar RM. Gallium-67 imaging in patients with
dilated cardiomyopathy and biopsy-proven myocarditis. Circulation 1984;70:58–62.
196. Dec GW, Palacios I, Yasuda T, et al. Antimyosin antibody
cardiac imaging: its role in the diagnosis of myocarditis. J Am
Coll Cardiol 1990;16:97–104.
197. Stevenson LW. Heart transplant centers: no longer the end of
the road for heart failure. J Am Coll Cardiol 1996;27:1198–
1200.
198. Quigley PJ, Richardson PJ, Meany BT. Long term follow up of
acute myocarditis. Correlation of ventricular function and
outcome. Eur Heart J Suppl J 1987;8:39–42.
199. Mason JW. Clinical merit of endomyocardial biopsy. Circulation 1989;79:971–979.
200. Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis—natural history and treatment. N Engl J Med 1997;
336:1860–1866.
201. Effects of enalapril on mortality in severe congestive heart
failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial
Study Group. N Engl J Med 1987;316(23):1429–1435.
202. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on
survival in severe chronic heart failure. N Engl J Med 2001;
344(22):1651–1658.
203. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol
on morbidity and mortality in patients with chronic heart
failure. U.S. Carvedilol Heart Failure Study Group. N Engl J
Med 1996;334(21):1349–1355.
204. Adams KF Jr, Gheorghiade M, Uretsky BF, et al. Patients with
mild heart failure worsen during withdrawal from digoxin
therapy. J Am Coll Cardiol 1997;30(1):42–48.
205. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone
on morbidity and mortality in patients with severe heart
failure. Randomized Aldactone Evaluation Study Investigators.
N Engl J Med 1999;341(10):709–717.
206. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced
left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;
362(9386):767–771.
207. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan
compared with captopril on mortality in patients with symptomatic heart failure: randomised trial–the Losartan Heart
Failure Survival Study ELITE II. Lancet 2000;355(9215):1582–
1587.
208. Packer M, Kessler PD, Lee WH. Calcium-channel blockade in
the management of severe chronic congestive failure: a bridge
too far. Circulation 1987;75(suppl V):V-56–V-64.
209. Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium
antagonist felodipine as supplementary vasodilator therapy in
patients with chronic heart failure treated with enalapril: VHeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study
Group. Circulation 1997;96(3):856–863.
210. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide
dinitrate and hydralazine in blacks with heart failure. N Engl
J Med 2004;351(20):2049–2057.
211. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable
Defibrillators (AVID) Investigators. N Engl J Med 1997;337(22):
1576–1583.
11/24/2006 1:28:36 PM
di l at e d c a r diom yopat h y
212. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation
of a defibrillator in patients with myocardial infarction
and reduced ejection fraction. N Engl J Med 2002;346(12):877–
883.
213. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN,
Hafley G. A randomized study of the prevention of sudden
death in patients with coronary artery disease. Multicenter
Unsustained Tachycardia Trial Investigators. N Engl J Med
1999;341(25):1882–1890.
214. Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone
versus implantable cardioverter-defibrillator: randomized trial
in patients with nonischemic dilated cardiomyopathy and
asymptomatic nonsustained ventricular tachycardia–AMIOVIRT. J Am Coll Cardiol 2003;41(10):1707–1712.
215. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator
implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350(21):2151–2158.
216. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N
Engl J Med 2005;352(3):225–237.
217. McClellan MB, Tunis SR. Medicare coverage of ICDs. N Engl
J Med 2005;352(3):222–224.
218. Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR,
Curiel R. Randomised trial of low-dose amiodarone in severe
congestive heart failure. Grupo de Estudio de la Sobrevida en
la Insuficiencia Cardiaca en Argentina (GESICA). Lancet
1994;344(8921):493–498.
219. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346(24):
1845–1853.
220. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the
MUltisite STimulation in cardiomyopathy (MUSTIC) study. J
Am Coll Cardiol 2002;40(1):111–118.
221. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in
advanced chronic heart failure. N Engl J Med 2004;350(21):
2140–2150.
222. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac
resynchronization on morbidity and mortality in heart failure.
N Engl J Med 2005;352(15):1539–1549.
223. Koniaris LS, Goldhaber SZ. Anticoagulation in dilated cardiomyopathy. J Am Coll Cardiol 1998;31(4):745–748.
224. Massie BM, Krol WF, Ammon SE, et al. The Warfarin and
Antiplatelet Therapy in Heart Failure trial (WATCH): rationale,
design, and baseline patient characteristics. J Card Fail 2004;
10(2):101–112.
CAR055.indd 1259
12 5 9
225. Mason JW, O’Connel JB, Herskowitz A, et al. A clinical trial
of immunosuppressive therapy for myocarditis. N Engl J Med
1995;333:269–275.
226. Gullestad L, Aass H, Fjeld JG, et al. Immunomodulating therapy
with intravenous immunoglobulin in patients with chronic
heart failure. Circulation 2001;103(2):220–225.
227. McCarthy RE III, Boehmer JP, Hruban RH, et al. Long-term
outcome of fulminant myocarditis as compared with acute
(nonfulminant) myocarditis. N Engl J Med 2000;342(10):
690–695.
228. McNamara DM, Holubkov R, Starling RC, et al. Controlled
trial of intravenous immune globulin in recent-onset dilated
cardiomyopathy. Circulation 2001;103(18):2254–2259.
229. Bozkurt B, Villaneuva FS, Holubkov R, et al. Intravenous
immune globulin in the therapy of peripartum cardiomyopathy. J Am Coll Cardiol 1999;34(1):177–180.
230. McNamara DM, Starling RC, Dec GW. Intervention in myocarditis and acute cardiomyopathy with immune globulin:
results from the randomized placebo controlled IMAC trial.
Circulation 1999;100(suppl I):I-21(abstr).
231. Wallukat G, Reinke P, Dorffel WV, et al. Removal of autoantibodies in dilated cardiomyopathy by immunoadsorption. Int J
Cardiol 1996;54(2):191–195.
232. Dorffel WV, Wallukat G, Baumann G, Felix SB. Immunoadsorption in dilated cardiomyopathy. Ther Apher 2000;4(3):
235–238.
233. Felix SB, Staudt A, Dorffel WV, et al. Hemodynamic effects of
immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three-month results from a
randomized study. J Am Coll Cardiol 2000;35(6):1590–1598.
234. Muller J, Wallukat G, Dandel M, et al. Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation 2000;101(4):385–391.
235. Fazio S, Sabatini D, Capaldo B, et al. A preliminary study of
growth hormone in the treatment of dilated cardiomyopathy.
N Engl J Med 1996;334:809–814.
236. Pinamonti B, Zecchin M, Di Lenarda A, Gregori D, Sinagra G,
Camerini F. Persistence of restrictive left ventricular filling
pattern in dilated cardiomyopathy: an ominous prognostic
sign. J Am Coll Cardiol 1997;29:604–612.
237. Isner JM. Myocardial gene therapy. Nature 2002;415(6868):
234–239.
238. Dubowitz V. Special Centennial Workshop—101st ENMC
International Workshop: Therapeutic Possibilities in Duchenne Muscular Dystrophy, 30th November–2nd December
2001, Naarden, The Netherlands. Neuromuscul Disord 2002;
12(4):421–431.
11/24/2006 1:28:37 PM
CAR055.indd 1260
11/24/2006 1:28:37 PM