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Etiology

Dilated cardiomyopathy has many causes, including inherited disease, infections, and toxins. Finding a specific
cause for an individual case may be difficult, especially in patients with multiple risk factors.
Causes of dilated cardiomyopathy include the following:

Genetics
Secondary to other cardiovascular disease: ischemia, hypertension, valvular disease, tachycardia
induced

Infectious: viral, rickettsial, bacterial, fungal, metazoal, protozoal


Probable infectious: Whipple disease, Lyme disease
Metabolic: endocrine diseases (eg, hyperthyroidism, hypothyroidism, acromegaly, myxedema,
hypoparathyroidism, hyperparathyroidism), diabetes mellitus, electrolyte imbalance (eg, potassium, phosphate,
magnesium)
Nutritional: thiamine deficiency (beriberi), protein deficiency, starvation, carnitine deficiency
Toxic: drugs, poisons, foods, anesthetic gases, heavy metals, ethanol
Collagen vascular disease
Infiltrative: hemochromatosis, amyloidosis, glycogen storage disease
Granulomatous (sarcoidosis)
Physical agents: extreme temperatures, ionizing radiation, electric shock, nonpenetrating thoracic
injury
Neuromuscular disorders: muscular dystrophy (limb-girdle [Erb dystrophy], Duchenne dystrophy,
fascioscapulohumeral [Landouzy-Dejerine dystrophy]), Friedreich disease, myotonic dystrophy
Primary cardiac tumor (myxoma)
Senile
Peripartum
Immunologic: postvaccination, serum sickness, transplant rejection
In many cases of dilated cardiomyopathy, the cause remains unexplained. However, some idiopathic cases
may result from failure to identify known causes such as infections or toxins. The idiopathic category should
continue to diminish as more information explaining pathophysiologic mechanisms, specifically geneticenvironmental interactions, becomes available.
Toxins are a significant cause. Almost a third of cases may result from severe ethanol abuse.

Viral myocarditis
Viral myocarditis is an important entity within the category of infectious cardiomyopathy. Viruses have been
implicated in cardiomyopathies as early as the 1950s, when coxsackievirus B was isolated from the
myocardium of a newborn baby with a fatal infection. Advances in genetic analysis, such as polymerase chain
reaction testing, have aided in the discovery of several viruses that are believed to have roles in viral
cardiomyopathies.
Viral infections and viruses associated with myocardial disease may be caused by the following:

Coxsackievirus (A and B) [1]


Influenza virus (A and B)
Adenovirus
Echovirus
Rabies
Hepatitis
Yellow fever
Lymphocytic choriomeningitis
Epidemic hemorrhagic fever
Chikungunya fever

Dengue fever
Cytomegalovirus
Epstein-Barr virus
Rubeola
Rubella
Mumps
Respiratory syncytial virus
Varicella-zoster virus
Human immunodeficiency virus
Viral myocarditis can produce variable degrees of illness, ranging from focal disease to diffuse pancarditis
involving myocardium, pericardium, and valve structures. Viral myocarditis is usually a self-limited, acute-tosubacute disease of the heart muscle. Symptoms are similar to those of CHF and often are subclinical. Many
patients experience a flulike prodrome.
Confirming the diagnosis can be difficult because symptoms of heart failure can occur several months after the
initial infection. Patients with viral myocarditis (median age, 42 years) are generally healthy and have no
systemic disease.
Acute viral myocarditis can mimic acute myocardial infarction, with patients sometimes presenting in the
emergency department with chest pain; nonspecific electrocardiographic (ECG) changes; and abnormal, often
highly elevated serum markers such as troponin, creatine kinase, and creatine kinase-MB.
The diagnosis of viral myocarditis is mainly indicated by a compatible history and the absence of other potential
etiologies, particularly if it can be confirmed with acute or convalescent sera. An ECG demonstrates varying
degrees of ST-T wave changes reflecting myocarditis and, sometimes, varying degrees of conduction
disturbances. Echocardiography is a crucial aid in classifying this disease process, which manifests mostly as a
dilated type of cardiomyopathy.
Myocarditis is almost always a clinically presumed diagnosis because it is not associated with any
pathognomonic sign or specific, acute diagnostic laboratory test result. In the past, percutaneous transvenous
right ventricular endomyocardial biopsy has been used, but the Myocarditis Treatment Trial revealed no
advantage for immunosuppressive therapy in biopsy-proven myocarditis, so biopsy is not routinely performed in
most cases.
If a patient is thought to have viral myocarditis, the initial diagnostic strategies should be to evaluate cardiac
troponin I or T levels and to perform antimyosin scintigraphy. Positive troponin I or T findings in the absence of
myocardial infarction and the proper clinical setting confirm acute myocarditis. Negative antimyosin scintigraphy
findings exclude active myocarditis.
The exact mechanism for myocardial injury in viral cardiomyopathy is controversial. Several mechanisms have
been proposed based on animal models. Viruses affect myocardiocytes by direct cytotoxic effects and by cellmediated (T-helper cells) destruction of myofibers. Other mechanisms include disturbances in cellular
metabolism, vascular supply of myocytes, and other immunologic mechanisms.
Viral myocarditis may resolve over several months during the treatment of left ventricular systolic dysfunction.
However, it can progress to a chronic cardiomyopathy. The main issue in recovery is ventricular size. Reduction
of ventricular size is associated with long-term improvement; otherwise, the course of the disease is
characterized by progressive dilation.
Because of an immunologic mechanism of myocyte destruction, several trials have investigated the use of
immunomodulatory medications. (Other trials are currently being conducted.) According to Mason et al in 1995,
the Myocarditis Treatment Trial demonstrated no survival benefit with prednisone plus cyclosporine or
azathioprine in patients with viral (lymphocytic) myocarditis.[2] Randomized trials are under way to evaluate
intravenous immunoglobulin as treatment for viral myocarditis.

Familial cardiomyopathy
Familial cardiomyopathy is a term that collectively describes several different inherited forms of heart failure.
Familial dilated cardiomyopathy is diagnosed in patients with idiopathic cardiomyopathy who have 2 or more

first- or second-degree relatives with the same disease (without defined etiology). Establishing a diagnosis with
more-distant affected relatives (third degree and greater) simply requires identifying more family members with
the same disease. Genetic screening has been recommended for patients fulfilling the above criteria.
A study by van Spaendonck-Zwarts et al suggested that a subset of peripartum cardiomyopathy is an initial
manifestation of familial dilated cardiomyopathy. This may have important implications for cardiologic screening
in such families.[3]
Several forms of familial cardiomyopathy have been described, and theories postulate its association with other
causes of cardiomyopathy. Inheritance is autosomal dominant; however, autosomal recessive and sex-linked
inheritance have been reported.
Several different genes and chromosomal aberrations have been described in studied families. One example is
the gene that codes for actin, a cardiac muscle fiber component. Other forms of familial cardiomyopathy involve
a strong association with conduction system disease. As research continues, the knowledge database
regarding familial cardiomyopathies is likely to expand.[4, 5]

Doxorubicin-induced cardiomyopathy
Anthracyclines, which are widely used as antineoplastic agents, have a high degree of cardiotoxicity and cause
a characteristic form of dose-dependent toxic cardiomyopathy. Both early acute cardiotoxicity and chronic
cardiomyopathy have been described with these agents. Anthracyclines can also be associated with acute
coronary spasm. The acute toxicity can occur at any point from the onset of exposure to several weeks after
drug infusion. Radiation and other agents may potentiate the cardiotoxic effects of anthracyclines.
Cardiac injury occurs even at doses below the empiric limitation of 550 mg/m 2. However, whether injury results
in clinical CHF varies. The development of heart failure is very rare at total doses less than 450 mg/m 2 but is
dose dependent.
The history of these patients, in addition to having classic heart failure symptoms or symptoms of acute
myocarditis, involves a previous history of malignancy and treatment with doxorubicin.
Anatomically, these patients' hearts vary from having bilaterally dilated ventricles to being of normal size. The
mechanism of myocardial injury is related to degeneration and atrophy of myocardial cells, with loss of
myofibrils and cytoplasmic vacuolization. The generation of free radicals by doxorubicin has also been
implicated. Progressive deterioration is the norm for this toxic cardiomyopathy.
Prevention is based on limiting dosing after 450 mg/m 2 and on serial functional assessments (ie, resting and
exercise evaluation of ejection fraction). The drug should be discontinued if the ejection fraction is less than
0.45, if it falls by more than 0.05 from baseline, or if it fails to increase by more than 0.05 with exercise.
Dexrazoxane is an iron-chelating agent approved by the FDA to reduce toxicity; however, it increases the risk
of severe myelosuppression.

Cardiomyopathy associated with collagen-vascular disease


Several collagen-vascular diseases have been implicated in the development of cardiomyopathies. These
include the following:

Rheumatoid arthritis
Systemic lupus erythematosus
Progressive systemic sclerosis
Polymyositis
HLA-B12associated cardiac disease
Diagnosis is based on identification of the underlying disease in conjunction with appropriate clinical findings of
heart failure.

Granulomatous cardiomyopathy (sarcoidosis)


Endomyocardial biopsy may be helpful in establishing the diagnosis, especially in sarcoidosis in which the
myocardium may be involved. Involvement may be patchy, resulting in a negative biopsy finding. The diagnosis

can also be made if some other tissue diagnosis is possible or available in conjunction with the appropriate
clinical picture for heart failure. Cardiac involvement in sarcoidosis reportedly occurs in approximately 20% of
cases.
Patients have signs and symptoms of sarcoidosis and CHF. Patients rarely present with CHF without evidence
of systemic sarcoid. Bilateral mediastinal, paratracheal, and/or hilar lymphadenopathy may be evident.
Noncaseating granulomatous infiltration of the myocardium occurs as with other organs affected by this
disease. Sarcoid granulomas can show a localized distribution within the myocardium. The granulomas
particularly affect the conduction system of the heart, left ventricular free wall, septum, papillary muscles, and,
infrequently, heart valves. Fibrosis and thinning of the myocardium occurs as a result of the infiltrative process
affecting the normal function of the myocardium.
Diagnosis involves finding noncaseating granulomas from cardiac biopsy or other tissues. Often, patients
present with conduction disturbances or ventricular arrhythmias. In fact, in patients with normal left ventricular
function, these conduction disturbances may be the primary clinical feature.
Treatment of cardiac sarcoidosis with low-dose steroids may be beneficial, especially in patients with
progressive disease, conduction defects, or ventricular arrhythmias. The true benefit is unknown because of
the lack of placebo-controlled studies. This also holds true for the use of other immunosuppressive agents (eg,
chloroquine, hydroxychloroquine, methotrexate) in the treatment of cardiac sarcoidosis.

Carnitine deficiency
A carnitine transporter defect is characterized by severely reduced transport of carnitine into skeletal muscle,
fibroblasts, and renal tubules. All children with dilated cardiomyopathy or hypoglycemia and coma should be
evaluated for this transporter defect because it is readily amenable to therapy, which results in prolonged
prevention of cardiac failure. The prognosis for long-term survival in pediatric dilated cardiomyopathy is poor.

Tachycardia-induced cardiomyopathy
Generally, when detected early, this type of cardiomyopathy is reversible once treatment of the tachycardia is
successful. Common etiologies include chronic untreated atrial fibrillation with rapid ventricular response and
frequent (several thousand daily) premature ventricular contractions. Persistent tachycardia is known to lead to
myocyte dysfunction and cardiomyopathy. If the tachycardia-induced cardiomyopathy is left untreated, the left
ventricular dysfunction can become irreversible. The exact mechanisms by which tachycardia affects cell
function are poorly understood. The following are possible mechanisms by which myocyte dysfunction arises
from tachycardia:

Depletion of energy stores


Abnormal calcium channel activity
Abnormal subendocardial oxygen delivery secondary to abnormalities in blood flow
Reduced responsiveness to beta-adrenergic stimulation

Pathophysiology
Dilated cardiomyopathy is characterized by ventricular chamber enlargement and systolic dysfunction with
greater LV cavity size with little or no wall hypertrophy. Hypertrophy is judged as the ratio of LV mass to cavity
size; this ratio is decreased in persons with dilated cardiomyopathies.
The enlargement of the remaining heart chambers is primarily due to LV failure, but it may be secondary to the
primary cardiomyopathic process. Dilated cardiomyopathies are associated with both systolic and diastolic
dysfunction. The decrease in systolic function is by far the primary abnormality. This leads to an increase in the
end-diastolic and end-systolic volumes.

Progressive dilation can lead to significant mitral and tricuspid regurgitation, which may further diminish the
cardiac output and increase end-systolic volumes and ventricular wall stress. In turn, this leads to further
dilation and myocardial dysfunction.
Early compensation for systolic dysfunction and decreased cardiac output is accomplished by increasing the
stroke volume, the heart rate, or both (cardiac output = stroke volume heart rate), which is also accompanied
by an increase in peripheral vascular tone. The increase in peripheral tone helps maintain appropriate blood
pressure. Also observed is an increased tissue oxygen extraction rate with a shift in the hemoglobin
dissociation curve.
The basis for compensation of low cardiac output is explained by the Frank-Starling Law, which states that
myocardial force at end-diastole compared with end-systole increases as muscle length increases, thereby
generating a greater amount of force as the muscle is stretched. Overstretching, however, leads to failure of the
myocardial contractile unit.
These compensatory mechanisms are blunted in persons with dilated cardiomyopathies, as compared with
persons with normal LV systolic function. Additionally, these compensatory mechanisms lead to further
myocardial injury, dysfunction, and geometric remodeling (concentric or eccentric).

Neurohormonal activation
Decreased cardiac output with resultant reductions in organ perfusion results in neurohormonal activation,
including stimulation of the adrenergic nervous system and the renin-angiotensin-aldosterone system (RAAS).
Additional factors important to compensatory neurohormonal activation include the release of arginine
vasopressin and the secretion of natriuretic peptides. Although these responses are initially compensatory, they
ultimately lead to further disease progression.
Alterations in the adrenergic nervous system induce significant increases in circulating levels of dopamine and,
especially, norepinephrine. By increasing sympathetic tone and decreasing parasympathetic activity, an
increase in cardiac performance (beta-adrenergic receptors) and peripheral tone (alpha-adrenergic receptors)
is attempted.
Unfortunately, long-term exposure to high levels of catecholamines leads to down-regulation of receptors in the
myocardium and blunting of this response. The response to exercise in reference to circulating catecholamines
is also blunted. Theoretically, the increased catecholamine levels observed in cardiomyopathies due to
compensation may in themselves be cardiotoxic and lead to further dysfunction. In addition, stimulation of the
alpha-adrenergic receptors, which leads to increased peripheral vascular tone, increases the myocardial
workload, which can further decrease cardiac output. Circulating norepinephrine levels have been inversely
correlated with survival.
Activation of the RAAS is a critical aspect of neurohormonal alterations in persons with CHF. Angiotensin II
potentiates the effects of norepinephrine by increasing systemic vascular resistance. It also increases the
secretion of aldosterone, which facilitates sodium and water retention and may contribute to myocardial
fibrosis.
The release of arginine vasopressin from the hypothalamus is controlled by both osmotic (hyponatremia) and
nonosmotic stimuli (eg, diuresis, hypotension, angiotensin II). Arginine vasopressin may potentiate the
peripheral vascular constriction because of the aforementioned mechanisms. Its actions in the kidneys reduce
free-water clearance.
Natriuretic peptide levels are elevated in individuals with dilated cardiomyopathy. Natriuretic peptides in the
human body include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic

peptide. ANP is primarily released by the atria (mostly the right atrium). Right atrial stretch is an important
stimulus for its release. The effects of ANP include vasodilation, possible attenuation of cell growth, diuresis,
and inhibition of aldosterone. Although BNP was initially identified in brain tissue (hence its name), it is secreted
from cardiac ventricles in response to volume or pressure overload. As a result, BNP levels are elevated in
patients with CHF. BNP causes vasodilation and natriuresis.
Counterregulatory responses to neurohormonal activation involve increased release of prostaglandins and
bradykinins. These do not significantly counteract the previously described compensatory mechanisms.
The body's compensatory mechanisms for a failing heart are evidently shortsighted. Compensation for
decreased cardiac output cannot be sustained without inducing further decompensation. The rationale for the
most successful medical treatment modalities for cardiomyopathies is therefore based on altering these
neurohormonal responses.

Circulating cytokines as mediators of myocardial injury


Tissue necrosis factor-alpha (TNF-alpha) is involved in all forms of cardiac injury. In cardiomyopathies, TNFalpha has been implicated in the progressive worsening of ventricular function, but the complete mechanism of
its actions is poorly understood. Progressive deterioration of LV function and cell death (TNF plays a role in
apoptosis) are implicated as some of the mechanisms of TNF-alpha. It also directly depresses myocardial
function in a synergistic manner with other interleukins.
Elevated levels of several interleukins have been found in patients with left ventricular dysfunction. Interleukin
(IL)1b has been shown to depress myocardial function. One theory is that elevated levels of IL-2R in patients
with class IV CHF suggest that T-lymphocytes play a role in advanced stages of heart failure.
IL-6 stimulates hepatic production of C-reactive protein, which serves as a marker of inflammation. IL-6 has
also been implicated in the development of myocyte hypertrophy, and elevated levels have been found in
patients with CHF. IL-6 has been found to correlate with hemodynamic measures in persons with left ventricular
dysfunction.