Chapter 10: The Cardiomyopathies

Intro

Introduction

The cardiomyopathies are a group of heart disorders in which the major structural abnormality is limited to the myocardium. These conditions often result in symptoms of heart failure, and although the underlying cause of myocardial dysfunction can sometimes be identified, the etiology frequently remains unknown. Excluded from the classification of this group of diseases is heart muscle impairment resulting from other defined cardio vascular conditions, such as hypertension, valvular disorders, or coronary artery disease.

Cardiomyopathies can be classified into three types based on the anatomic appearance and abnormal physiology of the left ventricle (LV) ( Fig. 10.1). Dilated cardiomyopathy is characterized by ventricular chamber enlargement with impaired systolic contractile function; hypertrophic cardiomyo pathy, by an abnormally thickened ventricular wall with abnormal diastolic relaxation but usually intact systolic function; and restrictive cardiomyopathy, by an abnormally stiffened myocardium (because of fibrosis or an infiltrative process) leading to impaired diastolic relaxation, but systolic contractile function is normal or near normal.

Figure 10.1. Anatomic appearance of the cardiomyopathies (CMPs).

Anatomic appearance of the cardiomyopathies (CMPs).

A. Normal heart demonstrating left ventricle (LV) and left atrium (LA). B. Dilated CMP is characterized by prominent ventricular enlargement with only mildly increased thickness. C. Hypertrophic CMP demonstrates significant ventricular hypertrophy, often asymmetrically involving the intraventricular septum. D. Restrictive CMP is caused by infiltration or fibrosis of the ventricles, usually without chamber enlargement. LA enlargement is common to all three types of CMP.

Dilated Cardiomyopathy

Etiology

Myocyte damage and cardiac enlargement in dilated cardiomyopathy (DCM) result from a wide spectrum of genetic, inflammatory, toxic, and metabolic causes ( Table 10.1). Although most cases are idiopathic (i.e., the cause is undetermined), examples of defined conditions that are associated with DCM include viral myocarditis, chronic excessive alcohol ingestion, the peripartum state, and specific gene mutations.

Acute viral myocarditis generally afflicts young, previously healthy people. Common responsible infecting organisms include c oxsackievirus group B, parvovirus B19, and adenovirus, among many others. Viral myocarditis is usually a self-limited illness with full recovery, but for unknown reasons, some patients progress to DCM. It is hypothesized that myocardial destruction and fibrosis result from immune-mediated injury triggered by viral constituents. Nonetheless, immunosuppressive drugs have not been shown to improve the prognosis of this condition. Transvenous right ventricular biopsy during acute myocarditis may demonstrate active inflammation, but specific viral genomic sequences have been demonstrated in only a minority of patients.

Table 10.1. Examples of Dilated Cardiomyopathies

Idiopathic

 

  •  Familial (genetic)
  •  Inflammatory
    •  Infectious (especially viral)
    •  Noninfectious
      •  Connective tissue diseases
      •  Peripartum cardiomyopathy
      •  Sarcoidosis
  •  Toxic
    •  Chronic alcohol ingestion
    •  Chemotherapeutic agents (e.g., doxorubicin)
  •  Metabolic
    •  Hypothyroidism
    •  Chronic hypocalcemia or hypophosphatemia
  •  Neuromuscular
    •  Muscular or myotonic dystrophy

 

Alcoholic cardiomyopathy develops in a small number of people who consume alcoholic beverages excessively and chronically. Although the pathophysiology of the condition is unknown, ethanol is thought to impair cellular function by inhibiting mitochondrial oxidative phosphorylation and fatty acid oxidation. Its clinical presentation and histologic features are similar to those of other dilated cardiomyopathies. Alcoholic cardiomyopathy is important to identify because it is potentially reversible; cessation of ethanol consumption can lead to dramatic improvement of ventricular function.

Peripartum cardiomyopathy is a form of DCM that presents with heart failure symptoms between the last month of pregnancy and up to 6 months postpartum. Risk factors include older maternal age, being African American, and having multiple pregnancies. A unifying etiology of this condition has not yet been identified. Ventricular function returns to normal in approximately 50% of affected women in the months following pregnancy, but recurrences of DCM with subsequent pregnancies have been reported. Other potentially reversible causes of DCM include other toxin exposures, metabolic abnormalities (such as hypothyroidism), and some inflammatory etiologies, including sarcoidosis and connective tissue diseases.

Several familial forms of DCM have been identified and are believed to be responsible for 20% to 30% of what were once classified as idiopathic DCM. Autosomal dominant, autosomal recessive, X-linked, and mitochondrial patterns of inheritance have been described, leading to defects in contractile force generation, force transmission, energy production, and myocyte viability. Identified mutations occur in genes that code for cardiac cytoskeletal, myofibrillar, and nuclear membrane proteins ( Table 10.2).

Table 10.2. Familial Forms of Dilated and Hypertrophic Cardiomyopathies

Protein Mutations Identified in Dilated Cardiomyopathy Mutations Identified in Hypertrophic Cardiomyopathy
Cytoskeletal Proteins
Desmin ?
Dystrophin ?
Myosin-binding protein C ? ?
Sarcoglycans ?
Titin ? ?
Myofibrillar Proteins
?-Myosin heavy chain ? ?
Cardiac troponin T ? ?
Cardiac troponin I ? ?
Cardiac troponin C ? ?
?-Tropomyosin ? ?
Essential myosin light chain ?
Cardiac actin ? ?
Nuclear Membrane Protein
Lamin A/C ?

Pathology

Marked enlargement of all four cardiac chambers is typical of DCM ( Fig. 10.2), although sometimes the disease is limited to the left or right side of the heart. The thickness of the ventricular walls may be increased, but chamber dilatation is out of proportion to any concentric hypertrophy. Microscopically, there is evidence of myocyte degeneration with irregular hypertrophy and atrophy of myofibers. Interstitial and perivascular fibrosis is often extensive.

Figure 10.2. Transverse sections of a normal heart (right) and a heart from a patient with dilated cardiomyopathy (DCM).

Transverse sections of a normal heart (right) and a heart from a patient with dilated cardiomyopathy (DCM).

In the DCM specimen, there is biventricular dilatation without a proportional increase in wall thickness. LV, left ventricle; RV, right ventricle.
(Modified from Emmanouilides GC, ed. Moss and Adams’ Heart Disease in Infants, Children, and Adolescents. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1995:86.)

Pathophysiology

The hallmark of DCM is ventricular dilatation with decreased contractile function ( Fig. 10.3). Most often in DCM, both ventricles are impaired, but sometimes dysfunction is limited to the LV and even less commonly to the right ventricle (RV).

Figure 10.3. Pathophysiology of dilated cardiomyopathy.

Pathophysiology of dilated cardiomyopathy.

The reduced ventricular stroke volume results in decreased forward cardiac output and increased ventricular filling pressures. The listed clinical manifestations follow. JVD, jugular venous distention.

As ventricular stroke volume and cardiac output decline because of impaired myocyte contractility, two compensatory effects are activated: (1) the Frank–Starling mechanism, in which the elevated ventricular diastolic volume increases the stretch of the myofibers, thereby increasing the subsequent stroke volume; and (2) neurohormonal activation, initially mediated by the sympathetic nervous system (see Chapter 9). The latter contributes to an increased heart rate and contractility, which help to buffer the fall in cardiac output. These compensations may render the patient asymptomatic during the early stages of ventricular dysfunction; however, as progressive myocyte degeneration and volume overload ensue, clinical symptoms of heart failure develop.

With a persistent reduction of cardiac output, the decline in renal blood flow prompts the kidneys to secrete increased amounts of renin. This activation of the renin-angiotensin-aldosterone axis increases peripheral vascular resistance (mediated through angiotensin II) and intravascular volume (because of increased aldosterone). As described in Chapter 9, these effects are also initially helpful in buffering the fall in cardiac output.

Ultimately, however, the “compensatory” effects of neurohormonal activation prove detrimental. Arteriolar vasoconstriction and increased systemic resistance render it more difficult for the LV to eject blood in the forward direction, and the rise in intravascular volume further burdens the ventricles, resulting in pulmonary and systemic congestion. In addition, chronically elevated levels of angiotensin II and aldosterone directly contribute to pathological myocardial remodeling and fibrosis.

As the cardiomyopathic process causes the ventricles to enlarge over time, the mitral and tricuspid valves may fail to coapt properly in systole, and valvular regurgitation ensues. This regurgitation has three detrimental consequences: (1) excessive volume and pressure loads are placed on the atria, causing them to dilate, often leading to atrial fibrillation; (2) regurgitation of blood into the left atrium further decreases forward stroke volume into the aorta and systemic circulation; and (3) when the regurgitant volume returns to the LV during each diastole, an even greater volume load is presented to the dilated LV.

Clinical Findings

The clinical manifestations of DCM are those of congestive heart failure. The most common symptoms of low forward cardiac output include fatigue, lightheadedness, and exertional dyspnea associated with decreased tissue perfusion. Pulmonary congestion results in dyspnea, orthopnea, and paroxysmal nocturnal dyspnea, whereas chronic systemic venous congestion causes ascites and peripheral edema. Because these symptoms may develop insidiously, the patient may complain only of recent weight gain (because of interstitial edema) and shortness of breath on exertion.

Physical Examination

Signs of decreased cardiac output are often present and include cool extremities (owing to peripheral vasoconstriction), low arterial pressure, and tachycardia. Pulmonary venous congestion results in auscultatory crackles (rales), and basilar chest dullness to percussion may be present because of pleural effusions. Cardiac examination shows an enlarged heart with leftward displacement of a diffuse apical impulse.

On auscultation, a third heart sound (S3) is common as a sign of poor systolic function. The murmur of mitral valve regurgitation is often present as a result of the significant left ventricular dilatation. If right ventricular heart failure has developed, signs of systemic venous congestion may include jugular vein distention, hepatomegaly, ascites, and peripheral edema. Right ventricular enlargement and contractile dysfunction are often accompanied by the murmur of tricuspid valve regurgitation.

Diagnostic Studies

The chest radiograph shows an enlarged cardiac silhouette. If heart failure has developed, then pulmonary vascular redistribution, interstitial and alveolar edema, and pleural effusions are evident (see Fig. 3.5).

The electrocardiogram (ECG) usually demonstrates atrial and ventricular enlargement. Patchy fibrosis of the myofibers results in a wide array of arrhythmias, most importantly atrial fibrillation and ventricular tachycardia. Conduction defects (left or right bundle branch block) occur in most cases. Diffuse repolarization (ST segment and T wave) abnormalities are common. In addition, regions of dense myocardial fibrosis may produce localized Q waves, resembling the pattern of previous myocardial infarction.

Echocardiography is very useful in the diagnosis of DCM. It typically demonstrates four-chamber cardiac enlargement with little hypertrophy and global reduction of systolic contractile function. Mitral and/or tricuspid regurgitation is also frequently visualized.

Cardiac catheterization is often performed to determine whether coexistent coronary artery disease is contributing to the impaired ventricular function. This procedure is most useful diagnostically in patients who have symptoms of angina or evidence of prior myocardial infarction on the ECG. Typically, hemodynamic measurements show elevated right- and left-sided diastolic pressures and diminished cardiac output. In the catheterization laboratory, a transvenous biopsy of the RV is sometimes performed in an attempt to clarify the etiology of the cardiomyopathy.

Cardiac magnetic resonance imaging (described in Chapter 3) is emerging as a promising technique in the evaluation of DCM, particularly for the diagnosis of myocardial inflammation (myocarditis).

Treatment

The goal of therapy in DCM is to relieve symptoms, prevent complications, and improve long-term survival. Thus, in addition to treating any identified underlying cause of DCM, therapeutic considerations include those described in the following sections.

Medical Treatment of Heart Failure

Approaches for the relief of vascular congestion and improvement in forward cardiac output are the same as standard therapies for heart failure (see Chapter 9). Initial therapy typically includes salt restriction and diuretics, vasodilator therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), and a ?-blocker. In patients with advanced heart failure, the potassium-sparing diuretic spironolactone should be considered. These measures have been shown to improve symptoms and reduce mortality in patients with DCM.

Prevention and Treatment of Arrhythmias

Atrial and ventricular arrhythmias are common in advanced DCM, and approximately 40% of deaths in this condition are caused by ventricular tachycardia or fibrillation. It is important to maintain serum electrolytes (notably, potassium and magnesium) within their normal ranges, especially during diuretic therapy, to avoid provoking serious arrhythmias. Studies have shown that available antiarrhythmic drugs do not prevent death from ventricular arrhythmias in DCM. In fact, when used in patients with poor LV function, many antiarrhythmic drugs may worsen the rhythm disturbance.

Amiodarone is the contemporary antiarrhythmic studied most extensively in patients with DCM. Whereas there is no convincing evidence that it reduces mortality from ventricular arrhythmias in DCM, it is the safest antiarrhythmic for treating atrial fibrillation and other supraventricular arrhythmias in this population. In contrast to anti arrhythmic drugs, the placement of an implantable cardioverter-defibrillator (ICD) does reduce arrhythmic deaths in patients with DCM. Therefore, based on large-scale randomized trials, ICD placement is a recommended approach for patients with chronic symptomatic DCM and at least moderately reduced systolic function (e.g., LV ejection fraction ?35%), regardless of the detection of ventricular arrhythmias.

Many patients with DCM have electrical conduction abnormalities that contribute to dyssynchronous ventricular contraction and reduced cardiac output. Electronic pace makers capable of stimulating both ventricles simultaneously have been devised to better coordinate systolic contraction as an adjunct to medical therapy (cardiac resynchronization therapy, as described in Chapter 9). Demonstrated benefits of this approach include improved quality of life and exercise tolerance as well as decreased hospitalizations for heart failure and reduced mortality, particularly in those with pretreatment left bundle branch block or other conduction abnormalities with a markedly prolonged QRS duration.

Prevention of Thromboembolic Events

Patients with DCM are at increased risk of thromboembolic complications for reasons that include: (1) stasis in the ventricles resulting from poor systolic function, (2) stasis in the atria due to chamber enlargement or atrial fibrillation, and (3) venous stasis because of poor circulatory flow. Peripheral venous or right ventricular thrombus may lead to pulmonary emboli, whereas thromboemboli of left ventricular origin may lodge in any systemic artery, resulting in, for example, devastating cerebral, myocardial, or renal infarctions.

The only definite indications for systemic anticoagulation in DCM patients are atrial fibrillation, a previous thromboembolic event, or an intracardiac thrombus visualized by echocardiography. However, chronic oral anticoagulation therapy (i.e., warfarin) is often administered to DCM patients who have severe depression of ventricular function (e.g., LV ejection fraction <30%) to prevent thromboembolism (be aware that prospective studies are lacking to confirm the effectiveness of this approach in DCM patients who are in sinus rhythm).

Cardiac Transplantation

In suitable patients, cardiac transplantation offers a substantially better 5-year prognosis than the standard therapies for DCM previously described. The current 5- and 10-year survival rates after transplantation are 74% and 55%, respectively. However, the scarcity of donor hearts greatly limits the availability of this technique. As a result, other mechanical options have been explored and continue to undergo experimental refinements, including ventricular assist devices and completely implanted artificial hearts.

Prognosis

Up to one third of patients will experience spontaneous improvement of heart function after the diagnosis of DCM is made. However, the prognosis for patients with persistent DCM who do not undergo cardiac transplantation is poor—the average 5-year survival rate is <50%. Methods to reduce progressive LV dysfunction by early intervention in asymptomatic or minimally symptomatic patients, and the prevention of sudden cardiac death, remain major research goals in the management of this disorder.