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Table of Contents

Reviewed
December 29, 2003

James O.
O'Neill, MD

Department of
Cardiovascular
Medicine

Corinne Bott-Silverman, MD

Department of
Cardiovascular
Medicine

Print Chapter

Cardiomyopathies are diseases of the myocardium associated with cardiac dysfunction.¹

Table 1 lists the five types of cardiomyopathy: dilated, hypertrophic, restrictive, arrhythmogenic right ventricular, and unclassified cardiomyopathy. Many conditions present as one form of cardiomyopathy and progress to another. For example, hypertensive heart disease may begin with a hypertrophic pattern and subsequently become a dilated cardiomyopathy. Some diseases may have features of more than one type of cardiomyopathy, eg, sarcoidosis may have features of restrictive and dilated cardiomyopathy at different times in the course of the disease.

Cardiomyopathy frequently results in the heart failure syndrome, with multiple systemic manifestations. On the other hand, many systemic conditions have cardiac involvement and may present primarily as heart failure.

In this chapter, discussion will be confined to definition, prevalence, signs and symptoms, and diagnosis of cardiomyopathies, with the exclusion of hypertrophic cardiomyopathy. Management is covered in the chapter on heart failure.

Etiology of
Cardiomyopathies

DILATED CARDIOMYOPATHY

     Definition

     Prevalence

     Pathophysiology

     Definition

     Prevalence

     Pathophysiology

Diagnosis of
Cardiomyopathies

Therapies and
Outcomes of
Cardiomyopathies

References

The cardiomyopathies represent a diverse group of conditions whose final, common pathway is myocardial dysfunction. With few exceptions, histologic findings are nonspecific, with myocyte hypertrophy, cellular necrosis, and fibrosis.

There are multiple known causes of cardiomyopathy. Many systemic diseases have myocardial involvement, which can range from mild to severe (Table 2). The most common cause in developed countries is ischemic cardiomyopathy. In other areas, eg, Equatorial Africa, infiltrative disease is the leading cause.

This condition may be defined as an ejection fraction <40% in the presence of increased left ventricular dimensions (left ventricular end-diastolic size >115% of that calculated for age and body surface area). Increased left ventricular dimensions in the presence of preserved systolic function may be a precursor to the development of systolic dysfunction in certain individuals. Whether pharmacologic intervention with angiotensin-converting enzyme inhibitors and beta-blockers prevents this progression remains to be resolved.

It is difficult to accurately assess the prevalence of cardiomyopathy. Many patients with this condition go undiagnosed and may present with sudden cardiac death. Strict diagnostic criteria are lacking. There are approximately 5 million Americans with symptomatic heart failure, but it is estimated that 50 million Americans fulfill American Heart Association/American College of Cardiology definitions of class A and B heart failure² (Table 3), who are either at risk for or have established structural heart disease in the absence of heart failure symptoms. It is unclear how many people fall into stages B, C, and D combined (those with structural heart disease, with or without heart failure symptoms); most of these people have cardiomyopathies (See AHA/ACC guidelines on heart failure 2002).

It has been estimated that the prevalence of idiopathic dilated cardiomyopathy is 0.4 per 1,000 of the general population. However, in the future, as more etiologies are elucidated and more patients are diagnosed with genetic or familial cardiomyopathy, the number of patients with idiopathic disease (a diagnosis of exclusion) will decrease.

Dilated cardiomyopathy represents the final common morphologic outcome of a variety of biological insults. It is a combination of myocyte apoptosis and necrosis with increased myocardial fibrosis, producing reduced mechanical function. Many causes are a result of direct toxicity (eg, alcohol) or mechanical insults (eg, chronic volume overload in mitral valvular regurgitation). With myocyte failure and cytoskeletal uncoupling, the chambers become dilated. By Laplace's law, increased diameter increases wall stress and causes further mechanical disadvantage. Thus, myocardial dysfunction begets myocardial dysfunction in a process labeled "adverse ventricular remodeling," now an important therapeutic target.³

Specific Cardiomyopathies:

Ischemic cardiomyopathy (ICM) is the most commonly identified specific cause of dilated cardiomyopathy, accounting for more than 60% of patients with symptomatic heart failure and many more with asymptomatic left ventricular dysfunction. There are several mechanisms by which coronary artery disease can result in ICM.

Myocardial infarction causes localized myocyte necrosis with resultant scar formation and loss of contractile function in the ventricular segment perfused by the culprit artery. In addition, myocytes distal to the area of infarction undergo increased wall stress, adverse remodeling, and chamber dilatation, so that a cardiomyopathic process occurs in adjacent nonischemic areas.

Another mechanism for myocardial dysfunction is that areas of myocardium are chronically underperfused and metabolically less active, ie, in hibernation, whereby they remain generally metabolically intact but do not contribute to the mechanical activity of the heart. Identification of these areas and restoration of their perfusion through revascularization may improve ejection fraction and long-term prognosis.

Additional features of ICM include the development of mitral valvular regurgitation, which may be due to papillary muscle dysfunction or functional factors such as failure of mitral valve leaflets to coapt in a dilated ventricle. This further increases the volume overload state, increasing myocardial energy demands, and causing a vicious cycle of worsening systolic dysfunction.

Atrial and ventricular arrhythmias occur commonly in ICM and include atrial fibrillation, which may further compromise contractile function. The development of atrioventricular conduction delays with the necessity for permanent pacemaker insertion can also cause a pacing-induced cardiomyopathic element when pacing is performed from the right ventricular apex alone.

ICM is generally ascribed to epicardial coronary atherosclerosis, but it may also occur in any vasculitic process (eg, Takayasu's arteritis), congenital abnormalities (including aberrant coronary arteries), embolic conditions (atrial fibrillation, endocarditis, thrombophilic states), cardiac allograft vasculopathy, and microvascular ischemia.

Idiopathic Dilated Cardiomyopathy
The term "idiopathic cardiomyopathy" is applied to the majority of patients with nonischemic cardiomyopathy. With progress in the field of gene analysis, it is likely that many patients with previously termed "idiopathic" cardiomyopathy will receive a specific molecular or genetic diagnosis in the future.

Acute myocarditis may be a more common prelude to dilated cardiomyopathy than was once thought.⁴ The natural history of acute myocarditis is largely unknown because it is rarely symptomatic. It is most commonly caused by coxsackie group B viruses. Overall, approximately 50% of patients who receive a diagnosis of acute viral myocarditis will develop dilated cardiomyopathy. Up to 76% of patients with nonischemic dilated cardiomyopathy who had a clinically recognized episode of myocarditis had genomic viral DNA persistence in myocardial samples. Despite this, endomyocardial biopsy (EMB) rarely shows myocarditis in patients with new-onset cardiomyopathy. Most have nonspecific histologic findings. There is significant interobserver variability in the pathologic diagnosis of myocarditis.

There is no specific genetic abnormality for dilated cardiomyopathy. Multiple abnormalities have been found. There are many putative mechanisms in the development of familial cardiomyopathy beyond the scope of this chapter (for a review of the concepts involved, see reference 5). All forms of mendelian inheritance have been observed, including autosomal dominant, recessive, X-linked, and mitochondrial (matrilinear).⁵

Hypertensive heart disease may initially present as left ventricular hypertrophy with isolated diastolic dysfunction and preserved systolic function, as assessed by conventional echocardiographic techniques. As remodeling occurs over time, the hypertrophy may progress to a dilated cardiomyopathy with systolic dysfunction. Atrial fibrillation is a common manifestation of hypertensive heart disease. Hypertensive heart disease is the leading identifiable cause of heart failure in elderly women.

Valvular Heart Disease
Hemodynamically significant valvular lesions such as aortic stenosis, aortic regurgitation, and mitral regurgitation can produce pressure and volume overload states that can result in adverse ventricular remodeling and the development of systolic, diastolic, and combined myocardial dysfunction. In valvular disease, excess hemodynamic demands result in myocyte hypertrophy, eventual chamber enlargement, and myocardial fibrosis. Chamber dilatation then creates or exacerbates existing mitral and/or tricuspid valvular regurgitation. With further chamber dilatation, subendocardial ischemia and localized myocyte necrosis develop. In addition, concomitant coronary artery disease (especially in degenerative aortic stenosis) and atrial fibrillation (especially in mitral regurgitation) can cause further deterioration. (Specific valvular lesions are discussed in the chapter on valvular heart disease).

Toxic Cardiomyopathies
Alcoholic cardiomyopathy may account for approximately 4% of all cardiomyopathies, and men have a significantly worse prognosis when the diagnosis is made.⁶ The average duration of heavy drinking (>90 g/day) in most cohorts is 15 years. Diastolic dysfunction usually precedes any evidence of systolic dysfunction. Left ventricular dilatation is an early finding. Hypertension, atrial fibrillation ("holiday heart"), and coronary disease are more common in heavy drinkers. Identification of alcohol as a potential etiology of cardiomyopathy is vital; abstinence can result in an improved ejection fraction in one-half the patients medically treated for heart failure, and continued drinking can result in further deterioration of cardiac function. The mechanism of alcohol-induced cardiomyopathy is unclear but may involve disturbances in intracellular calcium transients, mitochondrial disruption, decreased myofibrillary proteins, and myocyte apoptosis. Histologic findings are nonspecific.

Cocaine and amphetamines (including 3,4-methylenedioxymethamphetamine, or "ecstasy") can result in dilated cardiomyopathy with both single and chronic use.⁷ The etiology is multifactorial, and includes direct myocyte toxicity, tachycardia-induced injury, hypertension, and infarction.

Doxorubicin can cause cardiomyopathy with characteristic histopathologic features. Trastuzumab, used in the treatment of metastatic breast cancer, can cause a cardiomyopathy. Unlike anthracycline-induced toxicity, it usually responds to standard treatment or the discontinuation of trastuzumab.⁸ Brain-type natriuretic peptide (BNP) is proving useful in monitoring cardiac function in patients receiving cardiotoxic chemotherapy, as elevation of BNP occurs at an early stage in the condition. Hydroxychloroquine can cause skeletal and cardiac myopathies.

Peripartum cardiomyopathy is dilated cardiomyopathy arising in the last month of pregnancy or within 5 months postpartum.⁹ Seventy-five percent of cases occur in the first 2 months after delivery. Risk factors include age >30 years, multiparity, twin pregnancy, African descent, and a family history of peripartum cardiomyopathy.¹⁰ Its etiology is unknown but may be related to reduced suppressor T-cell activity, which occurs during pregnancy, and may result in an autoimmune type of myocardial inflammation or activation of myocarditis. Recovery, usually within 6 months, occurs in 50% of patients. Patients should be advised not to have further children. (See Pregnancy and Heart Disease chapter).

Infective Cardiomyopathies
In addition to the acute (often presumed viral) myocarditis discussed above, a variety of other viral agents have been implicated in the development of cardiomyopathy, including human immunodeficiency virus (HIV) and hepatitis C.

Trypanosoma cruzi (a protozoan) has infected 20 million people in South and Central America. Infection causes Chagas' disease, a dilated cardiomyopathy (either global or with characteristic apical aneurysm formation) in 20% to 30% of patients, either acutely or over many years. Other parasitic infestations that can cause cardiomyopathy in the immunocompetent as well as the immunocompromised patient include Toxoplasma gondii and Trichinella spiralis. Plasmodium falciparum infection (malaria) can cause parasitic coronary artery occlusion.

Tachycardia-Induced Cardiomyopathy
Prolonged exposure to rapid heart rates can induce myocardial dysfunction. Persistent or permanent atrial fibrillation induces electrical and structural remodeling of the atria. When rapidly conducted, it may cause adverse ventricular remodeling and a dilated cardiomyopathy. The diagnosis is one of exclusion, and rate control or restoration of sinus rhythm may restore systolic function. Sometimes cause and effect can be difficult to determine.

Metabolic Conditions
Malnutrition as well as selenium, carnitine, phosphate, calcium, and vitamin B deficiencies can all result in dilated cardiomyopathy. Endocrine etiologies include adrenocortical insufficiency, thyrotoxicosis, hypothyroidism, acromegaly, and pheochromocytoma.

Restrictive cardiomyopathy is a disease of the myocardium that is characterized by restrictive filling and reduced diastolic volume of either or both ventricles with normal or near-normal systolic function.¹

These conditions represent a very small proportion (<5%) of cardiomyopathies in the Western World,¹¹ but are more common in certain populations—eg, endomyocardial fibrosis is a relatively common cause of heart failure in Equatorial Africa (while ischemic heart disease is not).

Restrictive cardiomyopathies can be classified as primary (endomyocardial fibrosis, Löffler's endocarditis, idiopathic restrictive cardiomyopathy) or secondary. Causes of secondary restrictive cardiomyopathy include infiltrative diseases (amyloidosis, sarcoidosis, radiation carditis) and storage diseases (hemochromatosis, glycogen storage disorders, Fabry's disease). Fabry's disease, though very rare, has assumed a new importance recently as effective treatment has become available.¹²

Amyloid heart disease is classified as primary, secondary, familial, or senile. Primary amyloid heart disease is caused by overproduction of light-chain immunoglobulin from a monoclonal population of plasma cells, usually associated with multiple myeloma.¹⁰ Secondary amyloid is associated with chronic inflammatory conditions such as Crohn's disease, rheumatoid arthritis, tuberculosis, and familial Mediterranean fever. Familial and senile amyloid are related to overproduction of transthyretin. Myocardial amyloid is confirmed by EMB. The presence of near-normal left ventricular dimensions combined with increased myocardial wall thickness (particularly biventricular thickening) should arouse suspicion of an infiltrative cardiomyopathy, especially if accompanied by low-voltage QRS complexes on the ECG. Unfortunately, there is no proven treatment for amyloid heart disease, and the prognosis is very poor.

Hemochromatosis ("bronze diabetes") is a disease that results in iron overload and deposition of iron in the sarcoplasmic reticulum of many organs, including the heart. It generally follows an autosomal recessive pattern of mendelian inheritance. The use of serum ferritin levels as a screen for this condition is reasonable.² Hemochromatosis may result in a restrictive or dilated cardiomyopathy with characteristic histologic features. Treatment is by repeated phlebotomy. Family screening is advised.

Sarcoidosis is a systemic disease that results in the formation of noncaseating granulomas that can infiltrate the myocardium. It is associated with restrictive cardiomyopathy in 5% of patients, and may later progress to dilated cardiomyopathy. It is difficult to diagnose unless there is other organ involvement (usually pulmonary). It may be suspected in patients with cardiomyopathy and lymphadenopathy, skin rashes, or splenomegaly. Cardiac sarcoid is associated with ventricular tachycardia and conduction abnormalities (especially complete heart block) that can cause syncope and sudden cardiac death. EMB may show findings that are specific for sarcoidosis, but because of the patchy nature of the disease, biopsy may miss characteristic lesions, resulting in a low overall sensitivity. Cardiac granulomas may occasionally respond to steroids but turn to scar tissue. Sudden death is not prevented by steroids. Regular Holter monitoring is recommended to look for evidence of atrioventricular block, which should be treated with permanent pacemaker insertion.

ARVC is a rare but increasingly recognized condition characterized morphologically by apparent patchy apoptosis of the right and, to a lesser extent, left ventricles. It is sometimes called "fat cardiomyopathy" because of fatty infiltration of the right ventricle. It is familial in more than 50% of patients, generally with an autosomal dominant mode of inheritance.¹³

Presentation is usually in early adulthood, with symptoms consistent with supraventricular and ventricular arrhythmias or with right-sided heart failure. It may be discovered during family screening. Often, sudden death is the first sign of ARVC, with the diagnosis made postmortem. EMB is associated with an increased risk of perforation and tamponade.

Diagnostic features are summarized in Table 4.

Managing these patients is difficult and controversial. Control and prevention of potentially lethal ventricular arrhythmias is of paramount importance and has been approached with anti-arrhythmic medications, radiofrequency ablation and, inevitably, implantable cardioverter-defibrillators. Control of right heart failure is difficult and sometimes impossible by conventional therapy. Cardiac transplantation provides effective therapy in selected cases.

Systolic dysfunction with minimal dilatation, as its name suggests, is characterized by systolic dysfunction, an ejection fraction <30% (with no evidence of restrictive physiology by definition), and preserved left ventricular dimensions. Histologically, there is little myofibrillar loss. It carries a poor prognosis. Patients are treated with conventional approaches. A family history of dilated cardiomyopathy is not uncommon.

Mitochondrial cardiomyopathy, arising from mutations in mitochondrial DNA with resultant impaired oxidative phosphorylation, is transmitted through the maternal line. The resultant cardiomyopathy is characterized by progressive hypertrophy, dilatation, and arrhythmias. Mitochondrial diseases generally are systemic, in tissues with high metabolic activity, and give rise to syndromes. The MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome) can manifest as cardiomyopathy. When a mitochondrial myopathy is suspected, electron microscopy of EMB specimens may reveal giant mitochondria, concentric crystae, and intramitochondrial inclusions. However, skeletal muscle biopsy should be considered first, as it is a safer alternative.

Endocardial fibroelastosis is a rare condition that usually presents in infancy or early childhood. It is characterized by thickening of the left ventricle and left-sided cardiac valves. Multiple modes of inheritance have been described. Dilated or restrictive cardiomyopathy can result.

A careful history is essential, with particular emphasis on family history. A family tree should be constructed to ascertain whether a pedigree consistent with familial cardiomyopathy exists. This may necessitate requesting autopsy reports and medical records, as high suspicion is required. Additional features in the history should focus on exposure to cardiotoxins such as alcohol or cocaine. Specific interrogation about a protracted "flu-like illness" or respiratory tract infection may suggest previous myocarditis.

Five important factors to consider in patients with known or suspected cardiomyopathy are as follows:

• Establish onset and severity of symptoms of dyspnea, fatigue, fluid retention, effect on activities of daily living.
• Conventional risk factors for vascular disease (smoking, hypertension, diabetes, hyperlipidemia) or prior cardiac events (myocardial infarction, coronary artery bypass graft).
• Family history of heart disease, especially sudden death.
• Alcohol, amphetamine, cocaine use.
• Any past or current major medical illness.

The use of genetic screening in the management of cardiomyopathy is currently under evaluation in many centers, but has not yet proven to be clinically useful.

Screening first-degree relatives of patients with known or suspected familial cardiomyopathy is currently best achieved by physical examination, ECG, and echocardiography. The age at which screening should commence and how often it should be continued are unclear.

Examination should focus on whether the heart is palpably dilated, the presence of murmurs, and additional heart sounds (gallops). It is important to look beyond the cardiovascular system to consider a possible systemic disorder that may be contributory or causal, eg, hemochromatosis, thyrotoxicosis.

Five most useful clinical signs to establish presence and severity of cardiomyopathy are as follows:

• General appearance; cachexia, dyspnea at rest indicate severe impairment.
• Hypotension
• Tachycardia
• Elevated jugular venous pressure
• Displaced LV point of maximal impulse (PMI) rhythm.

Basic investigations should include a chest radiograph, an ECG, and an echocardiogram. Screening laboratory investigations include a complete blood cell count and renal, glucose, lipid, liver, and thyroid panels. It is reasonable to measure ferritin levels if hemochromatosis is suspected. The utility of viral titers has not been proven, although it may be reasonable to perform specific viral serology, eg, for HIV, if indicated by the history.

BNP has been identified as a useful marker in the diagnosis, severity, and prognosis in patients with heart failure. BNP levels correlate with functional class but not with ejection fraction.

The five most common abnormalities seen on ECG in cardiomyopathy are:

• Q waves (from previous myocardial infarction)
• Diffuse ST-segment abnormalities
• Left bundle branch block (or any intraventricular conduction delay)
• Atrial fibrillation
• Abnormal P waves (biphasic in leads V₁ and V₂, "left atrial overload).

Figure 2 shows intraventricular delay and diffuse ST-segment abnormalities in ECG from a patient with dilated cardiomyopathy.

Figure 3 shows atrial fibrillation, poor R-wave progression, and diffuse ST-segment abnormalities in ECG from a patient with ischemic cardiomyopathy.

The five most common abnormalities seen on chest radiograph in cardiomyopathy are:

• Cardiomegaly
• Interstitial edema
• Pleural effusion(s)
• Evidence of previous sternotomy (sternal wires)
• May be normal, particularly in heart failure resulting from distolic dysfunction.

The five most common abnormalities seen on echocardiogram in cardiomyopathy are:

• Increased chamber dimensions
• Reduced fractional shortening/ejection fraction
• Functional mitral and tricuspid valvular regurgitation
• Regional wall motion abnormalities
• Myocardial thickening (hypertrophy or infiltration).

Figure 4: Apical four chamber view of dilated cardiomyopathy showing marked chamber enlargement and severely impaired left ventricular systolic function.

The five most common abnormalities seen on Holter monitoring in cardiomyopathy are:

• Premature ventricular complexes
• Premature atrial complexes
• Atrial fibrillation (either sustained or paroxysmal)
• Nonsustained ventricular tachycardia
• First- or second-degree atrioventricular block.

It is important to rule out ischemia as a cause of ventricular dysfunction with the use of noninvasive modalities (eg, dobutamine stress echocardiography, positron emission tomography, magnetic resonance imaging) or coronary arteriography, depending on the clinical setting and the availability of resources.

Role of Endomyocardial Biopsy in
the Diagnosis of Cardiomyopathy:

EMB is not indicated in the routine evaluation of cardiomyopathy² and has a complication rate of less than 1%.¹⁴ Most histologic specimens demonstrate nonspecific changes-myocyte hypertrophy, cell loss, and fibrosis (Figure 5) and do not affect medical management. Histologically specific changes do occur in sarcoid (albeit they are patchy, reducing sensitivity), amyloid, hemochromatosis (Figure 6), endocardial fibroelastosis, Löffler's endocarditis, and ARVC (Figure 7). These conditions may be diagnosed with other less-invasive tests. In addition, there are no data proving that treatment improves outcome in cardiac sarcoid or amyloid although some would support the use of EMB in suspected cases of the latter, to establish the diagnosis and predict a poor prognosis (mean survival 6 to 12 months). Because of recurrent disease, cardiac amyloid generally renders the patient ineligible for cardiac transplantation.

Histologic specimen of arrhythmogenic right ventricular cardiomyopathy (Masson's trichrome stain), showing marked fatty infiltration (40X magnification). Reproduced with permission of N.G. Mahon, MD.

Figure 7

The use of EMB in acute myocarditis is not useful because aggressive immunosuppressive regimens, once thought to be efficacious, do not appear to improve outcome. However, the one exception is that giant cell myocarditis, suggested by a rapidly progressive and downhill course, may benefit from aggressive therapy (intensive hemodynamically guided heart failure therapy, immunosuppression, left-ventricular assist device, or transplantation).

Aside from potential giant cell myocarditis, EMB, combined with cardiac imaging techniques, may be used to document anthracycline toxicity, although BNP levels may be a more sensitive marker.

EMB is useful in distinguishing constrictive from restrictive pathology (the latter being associated with infiltration on EMB).¹⁵ However, this distinction can generally be made with the use of multiple imaging techniques including echocardiography (with diastology studies see chapter on Pericardial Disease), magnetic resonance imaging, computed tomography, and cardiac catheterization.

In the absence of a specific remediable etiology (eg, in peripartum cardiomyopathy, alcoholic cardiomyopathy, ischemic hibernating revascularizable myocardium), the overall outcome is poor in patients with cardiomyopathy. The 5-year survival rate of patients diagnosed with heart failure is 50%.¹⁶ This is paralleled by a high morbidity, punctuated by polypharmacy and multiple hospital admissions. Several clinical and laboratory features imply poor prognosis (Table 5).^10,17,18

Metabolic stress testing is useful to objectively gauge effort tolerance, and a peak VO2 uptake of less than 14 mL/kg/minute is generally accepted as a criterion for heart transplantation. Heart transplantation provides a median 10-year survival and is effective palliation in appropriately selected individuals.

"Who should I refer to a cardiologist?"
Because of the poor prognosis in most cases of cardiomyopathy, any patient for whom active treatment is contemplated should be referred to ascertain the etiology and to commence an aggressive, tailored treatment plan. In short—all patients.

Return to Medicine Index

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