Park's Pediatric Cardiology for Practitioners, 6th Ed.

Primary Myocardial Disease

Cardiomyopathies are structural or functional abnormalities of the myocardium not secondary to congenital, valvular, hypertensive, pulmonary, or coronary heart diseases. Cardiomyopathy has been classified into three types based on anatomic and functional features; hypertrophic, dilated, and restrictive (Fig. 18-1).

1. In hypertrophic cardiomyopathy (HCM), there is massive ventricular hypertrophy with a smaller than normal ventricular cavity. Contractile function of the ventricle is enhanced, but ventricular filling is impaired by relaxation abnormalities.

2. Dilated cardiomyopathy (DCM) is characterized by decreased contractile function of the ventricle associated with ventricular dilatation. Endocardial fibroelastosis (seen in infancy) and doxorubicin cardiomyopathy (seen in children who have received chemotherapy for malignancies) have clinical features similar to those of DCM.

3. Restrictive cardiomyopathy denotes a restriction of diastolic filling of the ventricles (usually infiltrative disease). Contractile function of the ventricle may be normal, but there is marked dilatation of both atria.

Recently, two new ones have been added to the classification, arrhythmogenic cardiomyopathy and left ventricular (LV) noncompaction. The two new types of cardiomyopathies are presented later in this chapter. The original three types of cardiomyopathies are functionally different from one another, and demands of therapy also are different. Table 18-1 summarizes clinical characteristics and treatment of the original three types of cardiomyopathies.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is a heterogeneous, usually familial disorder of heart muscle. In about 50% of cases, HCM is inherited as a Mendelian autosomal dominant trait and is caused by mutations in one of 10 genes encoding protein components of the cardiac sarcomere (e.g., β-myosin heavy chain, myosin binding protein C, and cardiac troponin-T). The remainder of the cases occurs sporadically. HCM usually is seen in adolescents and young adults, with equal gender distribution. It is the most common cause of sudden cardiac death in teens and young adults, especially among athletes. It may be seen in children with LEOPARD syndrome (see Table 2-1). A usually transient form of HCM occurs in infants of mothers with diabetes, which will be presented under a separate heading in this chapter.

Pathology and Pathophysiology

1. The most characteristic abnormality is the hypertrophied LV, with the ventricular cavity usually small or normal in size. Although asymmetrical septal hypertrophy, a condition formerly known as idiopathic hypertrophic subaortic stenosis (Fig. 18-2), is most common, the hypertrophy may be concentric or localized to a small segment of the septum (Fig. 18-3). Microscopically, an extensive disarray of hypertrophied myocardial cells, myocardial scarring, and abnormalities of the small intramural coronary arteries are present.

2. In some patients, an intracavitary pressure gradient develops during systole, either at subaortic or rarely at mid-cavity. This subset is called hypertrophic obstructive cardiomyopathy (HOCM).

a. The subaortic obstruction is commonly caused by systolic anterior motion (SAM) of the mitral valve against the hypertrophied septum (see Fig. 18-2). The SAM probably is created by the high outflow velocities and Venturi forces with frequent association of mitral regurgitation (MR).

b. Midcavity obstruction is caused by anomalous insertion of anterolateral papillary muscle into the anterior mitral leaflet.

c. In so-called apical HCM, hypertrophy is confined to the LV apex without intracavitary obstruction (and with giant negative T waves on the electrocardiogram (ECG). This subtype is present in about 25% of patients in Japan and fewer than 10% in other parts of the world.

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FIGURE 18-1 Diagram of the 50-degree left anterior oblique view of the heart in different types of cardiomyopathies at end-systole and end-diastole. “Congestive” corresponds to “dilated” cardiomyopathy as used in the text. (From Goldman MR, Boucher CA: Values of radionuclide imaging techniques in assessing cardiomyopathy. Am J Cardiol 46:1232–1236, 1980.)

3. The myocardium itself has an enhanced contractile state, but diastolic ventricular filling is impaired by abnormal stiffness of the LV, which may lead to left atrial enlargement and pulmonary venous congestion, producing congestive symptoms (exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea).

4. A unique aspect of HOCM is the variability of the degree of obstruction from moment to moment; the intensity of the heart murmur varies from time to time. Because the obstruction of the LVOT results from SAM of the mitral valve against the hypertrophied ventricular septum, any influence that reduces the LV systolic volume (e.g., positive inotropic agents, reduced blood volume, or lowering of the systemic vascular resistance) increases the obstruction. On the other hand, any influence that increases the LV systolic volume (e.g., negative inotropic agents, leg raising, blood transfusion, or increasing systemic vascular resistance) lessens the obstruction.

5. A large portion of the stroke volume (≈80%) is ejected during the early part of systole when there is little or no obstruction, producing a sharp upstroke in the arterial pulse, a characteristic finding of HOCM. The obstruction occurs late in systole, producing a late systolic murmur.

6. Patients with severe hypertrophy and obstruction may experience anginal chest pain, lightheadedness, near syncope, or syncope. Patients also are prone to develop arrhythmias, which may lead to sudden death (presumably from ventricular tachycardia or fibrillation). Nearly 30% of children with HCM have myocardial bridging (seen on coronary angiograms) with narrowing of the anterior descending coronary artery, which may have a key role in the development of ventricular arrhythmias. These patients may be more prone to sudden death. (Normally, the large epicardial coronary arteries run on the surface of the heart, with only their terminal branches penetrating the myocardium. When parts of the epicardial artery dip beneath the epicardial muscle so that there is a muscle bridge over the artery, they are called myocardial bridges.)

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FIGURE 18-2 Systolic anterior motion of the mitral valve. A, Diagram of systolic anterior motion in the presence of an asymmetrical septal hypertrophy. The Venturi effect may be important in the production of systolic anterior motion. B, M-mode echocardiography of the mitral valve in a patient with hypertrophic cardiomyopathy. Systolic anterior motion of the anterior leaflet of the mitral valve is indicated by arrows. AO, aorta; IVS, interventricular septum; LA, left atrium; LV, left ventricle; LVPW, LV posterior wall; mv, mitral valve; RV, right ventricle.

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FIGURE 18-3 Morphologic variability in hypertrophic cardiomyopathy seen on parasternal short-axis view of two-dimensional echo. In type I hypertrophy, relatively mild left ventricular hypertrophy confined to the anterior portion of the ventricular septum (VS) is present. In type II, hypertrophy of the anterior and posterior septum is present in the absence of free wall thickening. In type III, there is diffuse hypertrophy of substantial portions of both the ventricular septum and the anterolateral free wall (ALFW). In type IV, the M-mode echocardiography beam (M) does not traverse the thickened portions of the left ventricle (LV) in the posterior septum and anterolateral free wall. A or ANT, anterior; AML, anterior mitral leaflet; L, left; LVFW, left ventricular free wall; P or POST, posterior; PML, posterior mitral leaflet; R, right. (From Maron BJ: Asymmetry in hypertrophic cardiomyopathy: The septal to free wall thickness ratio revisited [editorial]. Am J Cardiol 55: 835-838, 1985.)

TABLE 18-1

SUMMARY OF CLINICAL CHARACTERISTICS OF CARDIOMYOPATHIES

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AD, autosomal dominant; ASH, asymmetrical septal hypertrophy; HOCM, hypertrophic obstructive cardiomyopathy; LV, left ventricle; LVDD, left ventricular diastolic dimension; LVEDP, left ventricular end-diastolic pressure; LVSD, left ventricular systolic dimension; RV, right ventricle.

Clinical Manifestations

History

1. Easy fatigability, dyspnea, palpitation, dizziness, syncope, or anginal pain may be present.

2. Family history is positive for the disease in 30% to 60% of patients.

Physical Examination

1. A sharp upstroke of the arterial pulse is characteristic (in contrast to a slow upstroke seen with fixed aortic stenosis [AS]). An LV lift and a systolic thrill at the apex or along the lower left sternal border may be present.

2. The S2 is normal, and an ejection click is generally absent. A grade 1 to 3 of 6 ejection systolic murmur of medium pitch is most audible at the mid-and lower left sternal borders or at the apex. A soft holosystolic murmur of MR is often present. The intensity and even the presence of the murmur vary from examination to examination.

Electrocardiography

The ECG is abnormal in the majority of patients. Common ECG abnormalities include left ventricular hypertrophy (LVH), ST-T changes, and abnormally deep Q waves (owing to septal hypertrophy) with diminished or absent R waves in the left precordial leads (Fig. 18-4). Occasionally, “giant” negative T waves are seen in the left precordial leads, which may suggest apical HCM. Other ECG abnormalities may include cardiac arrhythmias and first-degree AV block.

Radiography

Mild LV enlargement with a globular-shaped heart may be present. The pulmonary vascularity usually is normal.

Echocardiography

1. Echocardiography is diagnostic. Two-dimensional echocardiography demonstrates the wide morphologic spectrum of the disease; including concentric hypertrophy (Fig. 18-5), localized segmental hypertrophy, and asymmetrical septal hypertrophy (see Fig. 18-3). Apical HCM may be missed by two-dimensional echocardiography. (If apical HCM is suspected, a cardiac MRI should be obtained.)

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FIGURE 18-4 Tracing from a 17-year-old girl with hypertrophic obstructive cardiomyopathy with marked septal hypertrophy. Note the prominent Q waves with absent R waves in V5 and V6.

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FIGURE 18-5 Parasternal short-axis view of a 14-year-old boy with hypertrophic cardiomyopathy. Marked hypertrophy of the interventricular septum (IVS) as well as the posterior wall of the left ventricle (LVPW) is present. The left ventricle (LV) cavity is small. The IVS is approximately 39 mm, and the LV posterior wall is 26 mm thick. The thickness of both structures does not exceed 10 mm in normal persons.

2. The diastolic LV wall thickness 15 mm or larger (or on occasion, 13 or 14 mm), usually with LV dimension smaller than 45 mm, is accepted for the clinical diagnosis of HCM in adults. For children, z-score of 2 or more relative to body surface area is theoretically compatible with the diagnosis.

The heart of some highly trained athletes may show hypertrophy of the LV wall, making the differentiation between the physiologic hypertrophy and HCM difficult. An LV wall thickness of 13 mm or larger is very uncommon in highly trained athletes, and it is always associated with an enlarged LV cavity (with LV diastolic dimension >54 mm, with ranges 55 to 63 mm). Therefore, athletes with LV wall thickness greater than 16 mm and a nondilated LV cavity are likely to have HCM (Pelliccia et al, 1991).

3. M-mode echocardiography may demonstrate an asymmetrical septal hypertrophy of the interventricular septum (with the septal thickness 1.4 times greater than the posterior LV wall) and occasionally SAM of the anterior mitral valve leaflet in the obstructive type (see Fig. 18-2).

4. Mitral inflow Doppler tracing demonstrates diastolic dysfunction with decreased E-wave velocity, increased deceleration time, and decreased E/A ratio of the mitral valve (usually <0.8) (Fig. 18-6). LV systolic function is normal or supernormal.

5. Doppler peak gradient in the LVOT of 30 mm Hg or greater indicates an obstructive type.

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FIGURE 18-6 Examples of diastolic dysfunction seen in various forms of cardiomyopathy. (See Chapter 5 for further discussion.) A, A-wave velocity (the velocity of a second wave that coincides with atrial contraction); AFF, atrial filling fraction; DT, deceleration time; E, E-wave velocity (the velocity of an early peak); E/A, ratio of E-wave to A-wave velocity; IVRT, isovolumic relaxation time.

Natural History

1. The obstruction may be absent, stable, or slowly progressive. Genetically predisposed individuals often show striking increases in wall thickness during childhood.

2. Death is often sudden and unexpected and typically is associated with sports or vigorous exertion. Sudden death may occur most commonly in patients between 10 and 35 years of age. The incidence of sudden death may be as high as 4% to 6% a year in children and adolescents and 2% to 4% a year in adults. Ventricular fibrillation is the cause of death in the majority of sudden deaths. Even brief episodes of asymptomatic ventricular tachycardia on ambulatory ECG may be a risk factor for sudden death. Patients with myocardial bridging (occurring in about 30%) may be at risk for sudden death.

3. Atrial fibrillation (AF) may cause stroke or heart failure. AF results from left atrium (LA) enlargement with loss of the atrial “kick” needed for filling the thick LV.

4. In a minority of patients, heart failure with cardiac dilatation (“burned-out” phase of the disease) may develop later in life.

Management

The goal of treatment is to reduce ventricular contractility, increase ventricular volume, increase ventricular compliance, and increase LV outflow tract (LVOT) dimensions. In the obstructive form of the condition, reduction of the LVOT pressure gradient is important. However, unfortunately, most of therapeutic modalities used do not appear to significantly reduce the mortality rate. Surgical implantation of an automatic defibrillator may prove to be a very important modality to reduce sudden death.

Medical

1. General management

a. Moderate restriction of physical activity is recommended. Patients with the diagnosis of HCM should avoid strenuous exercise and competitive sports, regardless of age, gender, symptoms, LVOT obstruction, or treatment.

b. Digitalis is contraindicated because it increases the degree of obstruction. Other cardiotonic drugs and vasodilators should be avoided because they tend to increase the pressure gradient. Diuretics usually are ineffective and can be harmful. However, judicious use can help improve congestive symptoms (e.g., exertional dyspnea, orthopnea) by reducing LV filling pressure.

c. Clinical screening of first-degree relatives and other family members should be encouraged.

d. Annual evaluation of adolescence (12–18 years of age) is recommended, regardless of symptoms, with physical examination, ECG, and two-dimensional echocardiography studies.

2. Patients with symptoms (dyspnea, chest discomfort, disability)

Exertional dyspnea and disability are caused by diastolic dysfunction with impaired filling caused by increased LV stiffness. Chest pain is probably caused by myocardial ischemia of severely hypertrophied LV. Beta-blockers and calcium channel blockers are effective therapies in children with HCM. These agents reduce hypercontractile systolic function and improve diastolic filling.

a. A β-adrenergic blocker (e.g., propranolol, atenolol, or metoprolol) appears to be a preferred drug for symptomatic patients with outflow gradient, which develops only with exertion. Beta-blockers reduce the degree of outflow tract obstruction, decrease the incidence of anginal pain, and have antiarrhythmic effects.

In small children, propranolol is the drug of choice because of liquid formulation and low side effect profile. The dosage is 2 to 5 mg/kg/day given in three divided doses, with the heart rate goal of 80 to 100 beats/min. In older children, atenolol is typically used. In patients with excessive LVH and severe LVOT obstruction, a combination therapy with atenolol and verapamil may be considered.

b. Calcium channel blockers (principally verapamil) may be equally effective in both the nonobstructive and obstructive forms. Adverse hemodynamic effects may occur presumably as the result of vasodilating properties predominating over negative inotropic effects.

3. Asymptomatic patients. Prophylactic therapy with either β-adrenergic blockers or the calcium channel blocker verapamil is controversial in asymptomatic patients without LV obstruction. Some favor prophylactic administration of these drugs to prevent sudden death or to delay progression of the disease process; others limit prophylactic drug therapy to young patients with a family history of premature sudden death and those with particularly marked LVH. The efficacy of empiric prophylactic drug treatment with the above agents is unresolved.

4. Drug-refractory patients with obstruction. When standard pharmacologic therapy fails, there are limited options. In small children with persistent LVOT obstruction, the Morrow’s myectomy is the only option. In adults, alcohol septal ablation has been used but not in children. In patients with syncope, ventricular arrhythmias, or other high-risk factors, implantable cardioverter-defibrillator (ICD) implantation should be considered.

a. Morrow’s myotomy–myectomy. Transaortic LV septal myotomy-–myectomy (the Morrow operation) is the procedure of choice for drug-refractory patients with LVOT obstruction. This operation is performed through an aortotomy without the benefit of complete direct visualization. Two vertical and parallel incisions are made (≈1 cm apart, 1–1.5 cm deep) into the hypertrophied ventricular septum. A third transverse incision connects the two incisions at their distal extent, and the bar of rectangular septal muscle is excised. Indications for the procedure is the presence of a resting pressure gradient of greater than 50 mm Hg by continuous wave Doppler study in patients who are symptomatic despite medical management.

The mortality rate, including children, is 1% to 3%. Partial or complete left bundle branch block (LBBB) always results. Symptoms improve in most patients, but patients may later die of congestive symptoms and arrhythmias caused by the cardiomyopathy. Serious complications of the surgery such as complete heart block requiring permanent pacemaker and surgically induced ventricular septal defect have become uncommon (1%–2%).

b. Percutaneous alcohol septal ablation. For adult patients with persistent LVOT obstruction, the introduction of absolute alcohol into a target septal perforator branch of the left anterior descending coronary artery produces myocardial infarction within the proximal ventricular septum. This is analogous to surgical myomectomy. A decrease in pressure gradient occurs after 6 to 12 months. A large proportion of patients demonstrate subjective improvement in symptoms and in quality of life. The increasing popularity of the procedure is probably unjustifiable. This procedure should not be considered a routine invasive procedure because selection of the appropriate perforator branch is crucially important.

The procedure-related mortality rate is 1% to 4%. Permanent pacemaker implantation occurs in 1% to 4%. This procedure commonly results in right bundle branch block (RBBB) rather than LBBB seen with surgical myotomy.

c. Pacemaker implantation. Dual-chamber pacing was shown in earlier studies to reduce symptoms and the pressure gradient across the LVOT, but more recent studies did not support earlier findings. There are currently no data to support the contention that pacing improves survival or quality of life. Therefore, pacing is not recommended as the primary treatment for most symptomatic patients with obstruction.

5. ICD. Recently, HCM has become one of the most frequent indications for ICD implantation in children with proven efficacy to prevent sudden death from arrhythmias. ICD implantation is warranted when risk for sudden death is judged to be unacceptably high. The following are risk factors for sudden death in HCM.

a. Prior cardiac arrest (ventricular fibrillation)

b. Spontaneous sustained ventricular tachycardia (3 beats/min or more or at least 120 beats/min)

c. Family history of premature sudden death

d. Unexplained syncope, particularly in young patients

e. LV thickness of 30 mm or greater, particularly in adolescents and young adults

f. Abnormal exercise blood pressure (attenuated response or hypotension)

g. Nonsustained ventricular tachycardia

Special consideration may be given to adolescents for ICD implantation because it is the period of life consistently showing the greatest predilection for sudden death.

6. Cardiac arrhythmias

a. Ventricular arrhythmias may be treated with propranolol, amiodarone, and other standard antiarrhythmic agents guided by serial ambulatory ECG monitoring.

b. AF occurs more often in patients with LA enlargement. AF can possibly trigger ventricular arrhythmias in certain patients. For new-onset AF, electrical cardioversion followed by anticoagulation with warfarin (superior to aspirin) is recommended. Amiodarone is generally considered to be the most effective agent for preventing recurrence of AF.

7. In patients with heart failure from either diastolic or systolic dysfunction, therapy is similar to that for DCM, including an angiotensin-converting enzyme (ACE) inhibitor plus beta-blocker with or without diuretic and digoxin. Enalapril plus carvedilol is the most common ACE-inhibitor–β-blocker combination used.

8. Mitral valve replacement. Mitral valve replacement with a low-profile prosthetic valve may be indicated in selected patients with symptomatic mitral regurgitation. The operative mortality rate is about 6%. About 70% of patients show symptomatic improvement, but complications related to the prosthetic valve occur.

Infants of Mothers with Diabetes

Prevalence

At least 1.3% of pregnancies are complicated by diabetes mellitus.

Pathology

1. The teratogenic action of diabetes mellitus is generalized, affecting multiple organ systems. The prevalence of major congenital malformations in infants of mothers with diabetes is as high as 6% to 9% (i.e., three to four times that found in the general population). Neural tube defects (anencephaly, myelomeningocele), congenital heart defects, and sacral dysgenesis or agenesis are common ones. Infants born to mothers with insulin-dependent diabetes are at highest risk for developing congenital malformations; infants born to mothers with non–insulin-dependent, well-controlled diabetes do not appear to have an increased risk of congenital malformations.

2. Infants of mothers with diabetes have a high prevalence of congenital heart defects, cardiomyopathy, and persistent pulmonary hypertension of the newborn (PPHN).

a. The risk of congenital heart defect is three to four times greater than that in the general population, with ventricular septal defect, transposition of the great arteries, truncus arteriosus, tricuspid atresia, and coarctation of the aorta (COA) among the more common defects.

b. HCM with or without obstruction is seen in 10% to 20% of these infants. The weight of the heart is increased by the increased myocardial fiber size and number (rather than by excess glycogen, as once thought); the hypertrophy is thought to be caused by hyperinsulinemia. Although free walls of both ventricles and the ventricular septum are hypertrophied, the ventricular septum characteristically is more hypertrophied than the LV posterior wall (asymmetrical septal hypertrophy) (Fig. 18-7).

c. Infants of mothers with diabetes also have an increased risk of PPHN. They often are affected by conditions that promote the persistence of pulmonary hypertension, such as hypoglycemia, perinatal asphyxia, respiratory distress, and polycythemia.

Clinical Manifestations

The clinical manifestations of only cardiomyopathy are presented in this section. Congenital heart defects and PPHN are discussed under specific headings.

1. The history usually reveals gestational or insulin-dependent diabetes mellitus in the mother. The patient often has a history of progressive respiratory distress with tachypnea (80–100 breaths/min) from birth.

2. These large-for-gestational-age babies often are plethoric and mildly cyanotic and may have tachypnea and tachycardia (>160 beats/min). Signs of CHF with gallop rhythm may be found in 5% to 10% of these babies. The patient may have a systolic murmur along the left sternal border, which may be caused by an outflow tract obstruction or an associated defect.

3. Chest radiography may reveal a varying degree of cardiomegaly. Pulmonary vascular markings are normal or mildly increased due to pulmonary venous congestion.

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FIGURE 18-7 Parasternal long-axis view of 2-D echocardiogram of an infant of a diabetic mother. There is asymmetrical hypertrophy of the interventricular septum (IVS), which is at least two times as thick as the posterior wall of the left ventricle (LV). AO, aorta; LA, left atrium; RV, right ventricle.

4. The ECG usually is nonspecific, but a long QT interval caused by a long ST-segment secondary to hypocalcemia may be found. Occasionally, RVH, LVH, or biventricular hypertrophy (BVH) may be seen.

5. Echocardiography may show the following:

a. The ventricular septum often is disproportionately thicker than the LV free wall, but even free walls are thicker than normal (see Fig. 18-7).

b. Supernormal contractility of the LV and evidence of LVOT obstruction appear in about 50% of infants with cardiomyopathy.

c. Rarely, the LV is dilated, and its contractility is decreased.

Management

1. General supportive measures are provided, such as intravenous fluids, correction of hypoglycemia and hypocalcemia, and ventilatory assistance, if indicated.

2. In most cases, the hypertrophy spontaneously resolves within the first 6 to 12 months of life. β-Adrenergic blockers, such as propranolol, may help the LVOT obstruction, but treatment usually is not necessary. Digitalis and other inotropic agents are contraindicated because they may worsen the obstruction.

3. If the LV is dilated with decreased LV contractility, the usual anticongestive measures (e.g., digoxin, diuretics) are indicated.

Other Rare Forms of Hypertrophic Cardiomyopathies

The following are some examples of HCM that manifest in syndromic forms.

1. Pompe disease (type II glycogen storage disease). In this autosomal recessive inherited disease, deficiency of α-1,4-glucosidase results in massive accumulation of glycogen in various organs, leading to an enlarged tongue, striking hepatomegaly, hypotonia, and HCM and congestive heart failure (CHF). The ECG typically shows gigantic QRS voltages and short PR interval. The disease typically manifests during the first 5 months of life, and patients usually die before their second year of life unless they receive enzyme replacement. Enzyme therapy with Myozyme (alglucosidase alfa) is now possible.

2. Fabry disease. Fabry disease is an X-linked recessive disorder with skin manifestations (angiokeratomas), corneal clouding, peripheral neuropathy, renal failure, and anhidrosis. It is caused by mutations in the gene encoding the enzyme α galactosidase A. Deposits of glycosphingolipids on various tissues, particularly the kidneys and coronary arteries, cause the most important disease manifestations. The diagnosis of the condition is often delayed until the adolescence or adulthood; the average age of first symptoms is 11 years, but the diagnosis is usually further delayed. Primary cardiac manifestations in affected males are HCM and MR. The ECG shows a short PR interval. Replacement enzyme infusion is now approved by the U.S. Food and Drug Administration for treatment of this condition. This treatment resulted in clearance of pathological GL-3 deposits in the kidneys.

Dilated Cardiomyopathy

Cause

1. DCM, previously called congestive cardiomyopathy, is the most common form of cardiomyopathy. The causes of DCM are heterogeneous.

2. The most common cause of DCM is idiopathic (≈50%). About 20% to 35% of patients with idiopathic cardiomyopathy have been shown to have inherited familial DCM (Judge, 2009). Among the familial type, an autosomal dominant inheritance pattern is most frequent (occurring in 30%–50%); X-linked, autosomal recessive, and mitochondrial inheritance patterns are less common. There are at least 35 different genes in which mutation have been reported to cause DCM (Judge, 2009).

3. The most common known causes of DCM are myocarditis (46%) and neuromuscular diseases (≈25%) followed by familial cardiomyopathy, active myocarditis, and other causes. Some cases of idiopathic DCM may be the result of subclinical myocarditis.

4. The most frequently recognized familial form is Duchenne muscular dystrophy.

5. Other rare causes of DCM include infectious causes other than viral infection (bacterial, fungal, protozoan, rickettsial), as well as endocrine–metabolic disorders (hyper- and hypothyroidism, excessive catecholamines, diabetes, hypocalcemia, hypophosphatemia, glycogen storage disease, mucopolysaccharidoses) and nutritional disorders (kwashiorkor, beriberi, carnitine deficiency).

6. Some of the patients with the idiopathic type may have tachycardia-induced cardiomyopathy, which is related to chronic tachycardia (usually atrial or supraventricular tachycardia). (Resolution of ventricular dysfunction in 3 weeks after successful therapy may suggest the diagnosis, but echocardiography improvement may take 3 to 20 weeks.)

7. Cardiotoxic agents such as doxorubicin and systemic diseases such as connective tissue diseases can also cause DCM.

Pathology and Pathophysiology

1. In DCM, a weakening of systolic contraction is associated with dilatation of all four cardiac chambers. Dilatation of the atria is in proportion to ventricular dilatation. The ventricular walls are not thickened, although heart weight is increased.

2. Intracavitary thrombus formation is common in the apical portion of the ventricular cavities and in atrial appendages and may give rise to pulmonary and systemic emboli.

3. Histologic examinations from endomyocardial biopsies show varying degrees of myocyte hypertrophy and fibrosis. Inflammatory cells are usually absent, but a varying incidence of inflammatory myocarditis has been reported.

Clinical Manifestations

History

1. A history of fatigue, weakness, and symptoms of left-sided heart failure (dyspnea on exertion, orthopnea) may be elicited.

2. A history of prior viral illness occasionally is obtained.

Physical Examination

1. Signs of CHF (tachycardia, pulmonary crackles, weak peripheral pulses, distended neck veins, hepatomegaly) are present. The apical impulse usually is displaced to the left and inferiorly.

2. The S2 may be normal or narrowly split with accentuated P2 if pulmonary hypertension develops. A prominent S3 is present with or without gallop rhythm. A soft regurgitant systolic murmur (caused by MR or tricuspid regurgitation [TR]) may be present.

Electrocardiography

1. Sinus tachycardia, LVH, and ST-T changes are the most common findings. Left or right atrial hypertrophy (left atrial hypertrophy [LAH] or right atrial hypertrophy [RAH]) may be present. Rarely, a healed anterior myocardial infarction pattern may be present.

2. Atrial or ventricular arrhythmias and atrioventricular (AV) conduction disturbances may be seen.

Radiography

Generalized cardiomegaly is usually present, with or without signs of pulmonary venous hypertension or pulmonary edema.

Echocardiography

Echocardiography is the most important tool in the diagnosis of the condition and is important in the longitudinal follow-up of patients.

1. Two-dimensional echocardiography shows a marked LV enlargement and poor contractility (Fig. 18-8). The LA may also be enlarged. Occasionally, an intracavitary thrombus may be found, especially in the left atrial appendage and cardiac apex. Pericardial effusion may be seen.

2. On M-mode echocardiography, the end-diastolic and end-systolic dimensions of the LV are increased, with a markedly reduced fractional shortening and ejection fraction of the LV (Fig. 18-9). The M-mode measurement provides a valuable technique for serial assessment of patients with DCM.

3. Mitral inflow Doppler tracing demonstrates a reduced E velocity and a decreased E/A ratio (ratio of E-wave to A-wave velocity) (see Fig. 18-6).

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FIGURE 18-8 Apical four-chamber view of two-dimensional echocardiogram showing a massively dilated left ventricular cavity in a 12-year old child with dilated cardiomyopathy. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Other Laboratory Tests

1. Urine for organic and amino acids; 3-methylglutaconic acid (i.e., Barth syndrome)

2. Blood studies for lactate, calcium, magnesium, carnitine, and acylcarnitine

Cardiac Catheterization

Catheterization can be helpful to (1) exclude anomalous coronary artery; (2) predict etiology and prognosis by obtaining endomyocardial biopsy; and (3) evaluate for cardiac transplantation, including measurement of pulmonary vascular resistance. Endomyocardial biopsy typically shows varying degrees of myocyte hypertrophy and fibrosis without significant lymphocytic infiltration.

Natural History

1. Progressive deterioration is the rule rather than the exception. About two thirds of patients die from intractable heart failure within 4 years after the onset of symptoms of CHF. In one report in children, the 1- and 5-year rates of death or transplantation were 31% and 46%, respectively.

2. Atrial and ventricular arrhythmias develop with time (in ≈50% of patients studied by 24-hour Holter) but are not predictive of outcome.

3. Systemic and pulmonary embolism resulting from dislodgment of intracavitary thrombi occurs in the late stages of the illness.

4. Causes of death are CHF, sudden death resulting from arrhythmias, and massive embolization.

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FIGURE 18-9 M-mode echocardiogram in a child with dilated cardiomyopathy (DCM). A, M-mode echocardiogram from a 9-year-old normal child. The left ventricular (LV) diastolic dimension (d) is 36 mm, and the LV systolic dimension (s) is 24 mm, with resulting fractional shortening of 33%. B, M-mode echocardiogram from an 8-year-old child with DCM with a markedly decreased LV contractile function. The LV diastolic dimension (62 mm) and LV systolic dimension (52 mm) are markedly increased, with a marked decrease in the fractional shortening (16%). IVS, interventricular septum; LVPW, LV posterior wall; RV, right ventricle.

Management

If no identifiable and treatable cause of DCM is found, therapy is supportive and consists of (1) an anticongestive regimen, (2) control of significant arrhythmias, and (3) minimizing the risk of thromboembolic complications.

1. An integral part of medical treatment for underlying heart failure consists of diuretics (furosemide, spironolactone), digoxin, and ACE inhibitors (captopril, enalapril), as well as bed rest or restriction of activity.

2. Antiplatelet agents (aspirin) should be initiated. The propensity for thrombus formation in patients with dilated cardiac chambers and blood stasis may prompt the use of anticoagulation with warfarin. If thrombi are detected, they should be treated aggressively with heparin initially and later switched to long-term warfarin therapy.

3. Patients with arrhythmias may be treated with amiodarone or other antiarrhythmic agents. Amiodarone is effective and relatively safe in children. For symptomatic bradycardia, a cardiac pacemaker may be necessary. An ICD may be considered, but there is limited experience with this device in children.

4. Recently, the use of β-adrenergic blocker therapy in children with chronic heart failure has been shown to improve LV ejection fraction. Carvedilol is a β-adrenergic blocker with additional vasodilating action. The beneficial effects of β-adrenergic blocking agents (somewhat unorthodox, given poor contractility) have been reported in adult patients. Similar beneficial effects of beta-blockers have been reported in children with DCM of various causes. Recent evidence suggests that activation of the sympathetic nervous system may have deleterious cardiac effects (rather than being an important compensatory mechanism, as traditionally thought). β-Adrenergic blockers may exert beneficial effects by a negative chronotropic effect with reduced oxygen demand, reduction in catecholamine toxicity, inhibition of sympathetically mediated vasoconstriction, or reduction of potentially lethal ventricular arrhythmias. Further discussion on the use of β-adrenergic blockers is presented in Chapter 27.

5. If carnitine deficiency is considered as the cause for the cardiomyopathy, carnitine supplementation should be started.

6. After an interesting observation by Fazio and colleagues (1996), several small studies have shown beneficial effects of growth hormone in adult patients with DCM. Some of these studies reported that treatment with growth hormone for 3 to 6 months resulted in increased LV wall thickness, reduction of the chamber size, and improved cardiac output. However, some other studies did not find the same salutary effect of the hormone. A small study involving children (McElhinney et al, 2004) reported that administration of recombinant human growth hormone (0.025–0.04 mg/kg/day for 6 months) showed a trend toward improved LV ejection fraction along with significant acceleration of somatic growth. Whether growth hormone treatment will finally find a place in the treatment of congestive cardiomyopathy remains to be established.

7. The utility of immunosuppressive agents, including steroids, cyclosporine, and azathioprine, remains unproved.

8. Children with severe decompensation may require mechanical circulatory support therapy with a ventricular assist device, intraaortic balloon counterpulsation, or extracorporeal membrane oxygenation. In children, mechanical circulatory support commonly is a bridge to transplantation.

9. Many of these children with DCM may become candidates for cardiac transplantation.

Prognosis

Review of the literature in children suggests that approximately one third die, one third recover completely, and one third improve with some residual cardiac dysfunction.

Endocardial Fibroelastosis

Prevalence

The prevalence of the nonfamilial form of endocardial fibroelastosis is extremely rare. The prevalence has declined in the past 3 decades for unknown reasons; in the past, it accounted for 4% of cardiac autopsy cases in children.

Pathology

1. Primary endocardial fibroelastosis is a form of DCM seen in infants. The condition is characterized by diffuse changes in the endocardium with a white, opaque, glistening appearance. The heart chambers, primarily the LA and LV, are notably dilated and hypertrophied. Involvement of the right-sided heart chambers is rare. Deformities and shortening of the papillary muscles and chordae tendineae (resulting in MR) are often present late in the course. Similar pathology appears secondary to severe congenital obstructive lesions of the left heart, such as AS, COA, and hypoplastic left heart syndrome (called secondary fibroelastosis).

2. The cause of primary fibroelastosis is not known. It may be the result of a process of reaction to many different insults, rather than a specific disease. Viral myocarditis and a sequel to interstitial myocarditis have received more attention than other proposed causes, including systemic carnitine deficiency and genetic factors. Several decades ago, mumps virus was considered the possible causal agent for the disease. Recently, the mumps virus genome was found in the myocardium in a significant number of patients with the diagnosis, suggesting that endocardial fibroelastosis is a complication of myocarditis caused by the mumps virus.

Clinical Manifestations

1. Symptoms and signs of CHF (feeding difficulties, tachypnea, sweating, irritability, pallor, failure to thrive) develop in the first 10 months of life.

2. Patients have tachycardia and tachypnea. No heart murmur is audible in the majority of patients, although a gallop rhythm usually is present. Occasionally, a heart murmur of MR is audible. Hepatomegaly frequently is present.

3. The ECG typically shows LVH with “strain.” Occasionally, myocardial infarction patterns, arrhythmias, and varying degrees of AV block may be seen.

4. Chest radiographs show marked generalized cardiomegaly with normal or congested pulmonary vascularity.

5. Echocardiography characteristically shows a markedly dilated and poorly contracting LV in the absence of structural heart defects. The LA also is markedly dilated. Bright endocardial echoes are typical of the condition.

Management

1. Early diagnosis and long-term (for years) treatment with digoxin, diuretics, and afterload-reducing agents are mandatory. Digoxin is continued for a minimum of 2 to 3 years and is then gradually discontinued if symptoms are absent, heart size is normal, and the ECG has reverted to normal.

2. An afterload-reducing agent may be beneficial.

Prognosis

When proper treatment is instituted, about one third of patients deteriorate and die of CHF. Another third survive but experience persistent symptoms. The remaining third exhibit complete recovery. Operative procedures are not available.

Doxorubicin Cardiomyopathy

Prevalence

Anthracyclines remain among the most widely used and effective anticancer agents. Unfortunately, life-threatening anthracycline cardiomyopathy continues to develop among survivors of cancer. Its prevalence is nonlinearly dose related, occurring in 2% to 5% of patients who have received a cumulative dose of 400 to 500 mg/m2 of doxorubicin (Adriamycin) and up to 50% of patients who have received more than 1000 mg/m2 of the drug. It may be seen occasionally in patients who received only 220 mg/m2. When radiation therapy is combined with doxorubicin, the risk of cardiac damage is even greater.

Cause

1. C-13 anthracycline metabolites, which are inhibitors of adenosine triphosphatases of sarcoplasmic reticulum, mitochondria, and sarcolemma, have been implicated in the mechanism of cardiotoxicity causing cardiomyopathy.

2. Risk factors for developing doxorubicin cardiomyopathy may include the following.

a. Cumulative dose of anthracyclines greater than 360 mg/m2 are 40 times more likely to die than those who received less than 240 mg/m2.

b. Age younger than 4 years.

c. A dosing regimen with larger and less frequent doses has been raised as a risk factor but not proved.

d. Concomitant cardiac irradiation.

Pathology and Pathophysiology

1. Dilated LV, decreased contractility, elevated filling pressures of the LV, and reduced cardiac output characterize pathophysiologic features.

2. Microscopically, interstitial edema without evidence of inflammatory changes, loss of myofibrils within the myocyte, vacuolar degeneration, necrosis, and fibrosis are present.

Clinical Manifestations

1. Patients are usually asymptomatic until signs of heart failure develop. Patients have a history of receiving doxorubicin, with the onset of symptoms 2 to 4 months, and rarely years, after completion of therapy. Tachypnea and dyspnea made worse by exertion are the usual presenting complaints. Occasionally, palpitation, cough, and substernal discomfort are complaints.

2. Signs of CHF develop, with hepatomegaly and distended neck veins. Gallop rhythm may be present, with occasional soft murmur of MR or TR.

3. Radiography shows cardiomegaly with or without pulmonary congestion or pleural effusion.

4. The ECG shows sinus tachycardia. T-wave flattening or inversion is nonspecific evidence of cardiac involvement.

5. Echocardiography abnormalities of chronic cardiomyopathy occur within 1 year after doxorubicin treatment and may include the following:

a. The LV size is slightly increased, and the LV wall thickness is slightly decreased.

b. LV contractility (either ejection fraction or fractional shortening) is decreased.

c. Indices of diastolic function may be more sensitive for subclinical cardiac dysfunction.

6. During doxorubicin therapy, acute ECG changes may include a prolonged QT interval occurring in 40% of patients immediately after a single dose. Echocardiography may show reduced LV systolic function (ejection fraction or fractional shortening) during therapy. Stopping therapy based on these changes may not be justified.

Management

1. Attempts to prevent anthracycline cardiotoxicity have been directed toward (a) anthracycline dose limitation, (b) method of drug administration, (c) developing less cardiotoxic analogs, and (d) concurrently administering cardioprotective agents to attenuate the cardiotoxic effects of anthracycline to the heart.

a. Restriction of the total dose is controversial. Limiting the total cumulative dose to 400 to 500 mg/m2 reduces the incidence of CHF to 5%, but this dose may not be effective in treating some malignancies.

b. Continuous slow infusion therapy may reduce cardiac injury by avoiding peak levels. At least one study recommends infusion over 6 hours. However, a more recent study (Lipshultz et al, 2012) has reported no long-term cardioprotection of continuous infusion over bolus infusion.

c. The analog of doxorubicin, such as idarubicin and epirubicin, has similar cardiotoxicity to that of doxorubicin. There is some suggestion of lower rate of clinical and subclinical heart failure in patients treated with liposomal encapsulated doxorubicin preparation.

d. Concurrent administration of the cardioprotective agents, such as dexrazoxane (an iron chelator), carvedilol (a β-receptor antagonist with antioxidant property), and coenzyme Q10, has shown varying levels of protective effects. Among these, dexrazoxane appears to be most cardioprotective, and some authorities recommend dexrazoxane to be included in the pediatric oncology protocol.

2. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Currently, the following medications are used.

a. Digoxin, diuretics, and afterload-reducing agents (ACE inhibitors, e.g., enalapril) are useful. It is unclear whether these agents improve clinical outcome.

b. Beta-blockers have been shown to be beneficial in some children with chemotherapy-induced cardiomyopathy, similar to what has been reported in adults. Carvedilol, a nonselective beta-blocker, also has vasodilator effect and antioxidant activity. Carvedilol (12.5 mg once daily) given for 6 months to patients concurrently receiving Adriamycin or epirubicin was shown to prevent ventricular dilatation and maintain their ejection fraction at approximately 70% (Kalay et al, 2006). Metoprolol (starting at 0.1 mg/kg per dose twice a day and increasing to a maximal dose of 0.9 mg/kg per day) increases LV fractional shortening and ejection fraction and improves symptoms.

3. Cardiac transplantation may be an option for selected patients.

Prognosis

Symptomatic cardiomyopathy carries a high mortality rate. The 2-year survival rate is about 20%, and all patients die by 9 years after the onset of the illness.

Carnitine Deficiency

Carnitine deficiency is a rare cause of cardiomegaly in infants and small children. Carnitine is an essential cofactor for transport of long-chain fatty acids into mitochondria, where oxidation takes place. Carnitine deficiency leads to depressed mitochondrial oxidation of fatty acids, resulting in storage of fat in muscle and functional abnormalities of cardiac and skeletal muscle. It is synthesized predominantly in the liver.

Primary carnitine deficiency is an uncommon inherited disorder. The condition has been classified as either systemic or myopathic.

The systemic form of the disease manifests with low concentrations of carnitine in plasma, muscle, and liver. Symptoms are variable but include muscle weakness, cardiomyopathy, abnormal liver function, encephalopathy, impaired ketogenesis, and hypoglycemia during fasting. In systemic carnitine deficiency, patients may present with acute hepatic hypoglycemia and encephalopathy during the first year of life before the cardiomyopathy becomes symptomatic. Both hypertrophic and dilated cardiomyopathies have been reported with carnitine deficiency.

Myopathic disease is characterized primarily by muscle weakness. Fatty infiltration of muscle fiber is found at biopsy. The most common manifestation of myopathic carnitine deficiency is progressive cardiomyopathy with or without skeletal muscle weakness that begins at 2 to 4 years of age.

The patients with cardiomyopathy may show bizarre T-wave spiking on the ECG. These children may die suddenly presumably from arrhythmias.

Secondary forms of carnitine deficiency have been reported in renal tubular disorders (with excessive excretion of carnitine), chronic renal failure (excessive loss of carnitine from hemodialysis), inborn errors of metabolism with increased concentrations of organic acids, and occasional patients receiving total parenteral nutrition. Diagnosis of the condition is established by extremely low levels of carnitine in plasma and skeletal muscle.

Treatment

1. Treatment with oral carnitine (L-carnitine: 50–100 mg/kg/day orally divided twice or three times a day; maximum daily dose, 3 g) may improve myocardial function, reduce cardiomegaly, and improve muscle weakness.

2. A recent multicenter study has shown that treatment of various forms of cardiomyopathy with L-carnitine, especially those with suggestive evidence of disorders of metabolism, provided clinical benefits.

3. The benefits of carnitine administration have been reported for other conditions with myocardial dysfunction, including prevention of diphtheric myocarditis in children, and potential protective and therapeutic effects on doxorubicin-induced cardiomyopathy in rats.

Other Forms of Dilated Cardiomyopathies

Barth Syndrome

Barth syndrome is a sex-linked cardioskeletal myopathy with abnormal mitochondria and neutropenia. This disorder typically presents in male infants as CHF associated with neutropenia (cyclic) and 3-methylglutaconic acidemia. Echocardiography shows LV dysfunction with LV dilatation, endocardial fibroelastosis, or a dilated hypertrophic LV. Some infants die from CHF, ventricular tachycardia, or sepsis caused by leukocyte dysfunction. Most children survive infancy and do well clinically, although DCM usually persists. Some require cardiac transplantation.

Kearns-Sayre Syndrome

This mitochondrial myopathy is characterized by ptosis, chronic progressive external ophthalmoplegia, abnormal retinal pigmentation, DCM, and cardiac conduction defects. Approximately 20% of patients with Kearns-Sayre syndrome have cardiac involvement, and the majority have conduction defect causing progressive AV block, requiring pacemaker therapy.

Restrictive Cardiomyopathy

Prevalence and Cause

Restrictive cardiomyopathy is an extremely rare form of cardiomyopathy, accounting for 5% of cardiomyopathy cases in children. It may be idiopathic or may be associated with a systemic infiltrative disease (e.g., scleroderma, amyloidosis, and sarcoidosis) or an inborn error of metabolism (mucopolysaccharidosis). Malignancies or radiation therapy may result in restrictive cardiomyopathy.

Pathology and Pathophysiology

1. This condition is characterized by markedly dilated atria and generally normal ventricular dimensions. Ventricular diastolic filling is impaired, resulting from excessively stiff ventricular walls. Contractile function of the ventricle is normal. Therefore, this condition resembles constrictive pericarditis in clinical presentation and hemodynamic abnormalities.

2. There are areas of myocardial fibrosis and hypertrophy of myocytes, or the myocardium may be infiltrated by various materials. Infiltrative restrictive cardiomyopathy may be caused by conditions such as amyloidosis, sarcoidosis, hemochromatosis, glycogen deposit, Fabry’s disease (with deposition of glycosphingolipids), or neoplastic infiltration.

Clinical Manifestations

1. The patients may have a history of exercise intolerance, weakness and dyspnea, or chest pain.

2. Jugular venous distention, hepatomegaly, a loud pulmonary component of S2 (P2), gallop rhythm, and a systolic murmur of AV valve regurgitation may be present.

3. Chest radiography shows cardiomegaly, pulmonary venous congestion, and occasional pleural effusion.

4. The ECG usually shows LAH, RAH, or both. It may show AF and paroxysms of supraventricular tachycardia. AV block may be present in familial restrictive cardiomyopathy.

5. Echocardiography studies reveal:

a. Characteristic biatrial enlargement with normal dimension of the LV and right ventricle (RV) is almost diagnostic.

b. LV systolic function is normal (until the late stage of the disease).

c. Atrial thrombus may be present.

d. Findings of diastolic dysfunction are present (see Fig. 18-6); the mitral inflow Doppler tracing shows an increased E velocity, shortened deceleration time, and increased E/A ratio.

e. Differentiation from constrictive pericarditis can pose difficulties. In constrictive pericarditis, echocardiography shows a thickened pericardium, and Doppler studies show a marked respiratory variation in the filling phase. Doppler studies also show similar findings of diastolic dysfunction as those seen in restrictive pericarditis.

6. Cardiac catheterization should be performed. It shows elevated LV and RV end-diastolic pressures and frequent pulmonary hypertension (with elevated pulmonary vascular resistance). Endomyocardial biopsy reveals myocyte hypertrophy and interstitial fibrosis; it may also reveal a specific cause.

Management

Treatment is nonspecific and directed at alleviating symptoms. In general, medical therapy does not improve survival. The prognosis is poor.

1. Diuretics are beneficial to relieve congestive symptoms, but they should be used judiciously because they can reduce end-diastolic pressure, making symptoms worse. Digoxin is not indicated because systolic function is unimpaired. ACE inhibitors may reduce systemic blood pressure without increasing cardiac output and therefore should probably be avoided.

2. Calcium channel blockers may be used to increase diastolic compliance.

3. Anticoagulants (warfarin) and antiplatelet drugs (aspirin and dipyridamole) may help prevent thrombosis.

4. Corticosteroids and immunosuppressive agents have been suggested.

5. A permanent pacemaker is indicated for complete heart block.

6. Surgical options are limited to cardiac transplantation. Early transplantation is preferable before severe pulmonary hypertension develops. In patients with systemic disease (e.g., sarcoidosis), recurrence is a major concern after transplantation, and it may not be a viable option.

Arrhythmogenic Cardiomyopathy

This cardiomyopathy is also known as arrhythmogenic RV dysplasia, arrhythmogenic RV cardiomyopathy, RV dysplasia, or RV cardiomyopathy.

Cause

1. Most cases appear to be sporadic, although familial occurrences have been reported. Whether the disease is congenital or acquired is unknown, although recent evidence favors an acquired degenerative process.

2. An inflammatory process, possibly infection (by coxsackievirus B3 and adenovirus) has been implicated as a cause.

3. The prevalence of the disease is not known, but it is estimated to range from 1 in 1000 to 1 in 5000 population.

Pathology

1. This is a rare abnormality of unknown cause in which the myocardium of the RV is partially or totally replaced by fibrous or adipose tissue. The RV wall may assume a paper-thin appearance because of the total absence of myocardial tissue, but in others, RV wall thickness is normal or near normal. The LV is also often affected.

2. Histologic sections show a variable reduction in myofibrils and inflammation associated with interstitial infiltration by histocytes and lymphocytes.

Clinical Manifestations

1. The onset is in infancy, childhood, or adulthood (but usually before the age of 20 years) with a history of palpitation, syncopal episodes, or both. Sudden death may be the first sign of the disease.

2. The physical examination is usually normal. An irregular rhythm or signs of heart failure may occasionally be present.

3. The ECG is helpful. Tall P waves in lead II (RA hypertrophy) and decreased RV forces may be present. Inverted T waves in the right precordial leads (V1–V4) may be significant (although this pattern is normally seen in young children). It may show premature ventricular contractions or ventricular tachycardia with LBBB morphology. An incomplete RBBB pattern may be present (in >30% of the cases).

4. Chest radiography usually show no or minimal cardiomegaly. Pulmonary vascular markings are usually normal.

5. Echocardiography shows selective RV enlargement and often systolic bulging or areas of akinesia or dyskinesia.

6. Cardiac MRI can visualize RV enlargement, aneurysm, systolic bulging of the RV free wall, myocardial fibrosis, and inflammation. Cardiac MRI is emerging as a more definite diagnostic tool than endomyocardial biopsy because the ventricular septum may lack the characteristic histologic changes.

7. Cardiac catheterization may show an elevated right atrial “a” wave. An RV angiogram usually shows RV systolic dysfunction. The hallmark of the disease is systolic bulging of the RV free wall. Endomyocardial biopsy of the RV septum shows classic pathologic changes in more than 90% of the patients but with a high false-negative rate.

8. A substantial portion of patients die before 5 years of age from CHF and intractable ventricular tachycardia.

Management

1. Various antiarrhythmic agents may be tried, but they are often unsuccessful in abolishing ventricular tachycardia.

2. Surgical intervention (ventricular incision or complete electrical disarticulation of the RV free wall) may be tried if antiarrhythmic therapy is unsuccessful.

3. An ICD may be indicated in selected cases.

Noncompaction Cardiomyopathy

Noncompaction cardiomyopathy, also known as LV noncompaction, LV hypertrabeculation, or spongy myocardium, results from an intrauterine arrest of normal compaction of the loose interwoven meshwork of the ventricular myocardium (which normally occurs during the first month of fetal life). Mutations in the gene G4.5 on Xq28 may be responsible for noncompaction.

Clinical Manifestations

1. Most of the patients with this disorder are asymptomatic. Occasionally, they may present with signs and symptoms of heart failure during infancy. Familial occurrence has been reported in up to 25% with a less severe form of the disease. Evaluation of all members of the family has been recommended.

2. Physical examination findings may be entirely normal in some patients. Associated dysmorphic facial features may be seen in 14%. Nearly 30% of the patients have neurologic disorders, including seizures, hypotonia, myopathy, or mental or motor retardation. Patients with dysmorphic features or neuromuscular disorders may have associated metabolic disorders. It may coexist with various congenital heart defects. Signs of LV dysfunction may be present when the diagnosis is made; if not, most of them will eventually develop CHF.

3. The ECG may show giant QRS complexes, sometimes with Wolff-Parkinson-White preexcitation. Chest radiography findings are usually normal.

4. Echocardiography findings

a. Characteristic echocardiography findings are segmental thickening of the LV wall consisting of two layers with a thin, compacted epicardial layer and an extremely thickened noncompacted endocardial layer with prominent trabeculations and deep recesses. The apical and midventricular segment of both the inferior and lateral walls are most commonly affected (Fig. 18-10).

b. The LV is uniformly affected, resulting in systolic and diastolic dysfunction and clinical heart failure. The RV is rarely affected, but it is difficult to demonstrate by echocardiographic study. In pediatric patients, LV systolic dysfunction is seen in 35% to 90% at diagnosis and during follow-up.

5. When echocardiography studies are inconclusive, cardiac MRI should be obtained. MRI not only helps establish the diagnosis but can also find RV dysfunction in 16% of patients.

6. The disease is usually progressive with worsening of heart failure despite optimal treatment. Arrhythmias and thromboembolic events are mostly seen in adults, but they may also be seen in children.

Treatment

Treatment should be directed toward its complications. The most common complication of the disease is heart failure. Less common complications are thromboembolic events and ventricular arrhythmias, more frequently seen in adult patients.

1. Anticongestive measures with digoxin, diuretics, and afterload-reducing agents are usually used.

2. In addition to the usual anticongestive measures, the use of carvedilol, a beta-blocker, should be considered in patients with LV dysfunction. Carvedilol has been shown to improve LV dysfunction.

3. All patients should be on an antiplatelet dose of aspirin. If thrombosis is detected, anticoagulation with Coumadin should be started.

4. Appropriate antiarrhythmic therapy is indicated. Implantation of an ICD may be considered for life-threatening ventricular arrhythmias.

5. Patients with dysmorphic features or neurologic manifestations may need detailed metabolic screening (e.g., fatty acid oxidation disorder or mitochondrial disease).

6. Heart transplantation is a possible option for selected patients.

image

FIGURE 18-10 Noncompaction cardiomyopathy. Apical four-chamber view of a two-dimensional echocardiogram showing characteristic increase in trabeculation (T) and deep recesses (arrows) in the left ventricular apical area. (From Connolly HM, Oh JK: Echocardiography. In Bonow RO, Mann DL, Zipes DP, Libby P (eds): Braunwald’s Heart Disease, 9th ed. Saunders, Philadelphia, 2012. Used with permission.)