HCM is addressed in detail in Chapter 29. Since the modern description by Teare in 1958 (13), HCM has been known by a confusing array of names that largely reflect its clinical heterogeneity, relatively uncommon occurrence in cardiologic practice, and the skewed experience of early investigators. This problem in nomenclature has been an obstacle to the general recognition of the disease within the medical and nonmedical communities. Hypertrophic cardiomyopathy (or HCM) is now widely accepted as the preferred term (14) because it describes the overall disease spectrum without introducing misleading inferences that LV outflow tract obstruction is an invariable feature of the disease, such as is the case with hypertrophic obstructive cardiomyopathy, muscular subaortic stenosis, or idiopathic hypertrophic subaortic stenosis. Indeed, most patients with HCM do not demonstrate outflow obstruction under resting (basal) conditions, although many may develop dynamic subaortic gradients of varying magnitude with provocative maneuvers or agents (14). The contemporary definition of HCM focuses on the fact that this disorder is characterized by disproportionate and remarkable left, and sometimes right, ventricular hypertrophy (14,15). Typically, the septum is more involved than the free LV wall, although on occasion the hypertrophy can be completely concentric in nature (Fig. 89.3). HCM, which may develop at any age, is associated with marked LV volume reduction, and systolic LV outflow tract gradients are common. Up to 70% of cases have a familial pattern of occurrence, with autosomal-dominant inheritance. Clinically, the diagnosis of HCM is most reliably made by two-dimensional echocardiography showing left ventricular
hypertrophy (LVH) with asymmetric distribution. This LVH is associated with a nondilated and hyperdynamic chamber, which often shows systolic LV cavity obliteration in the absence of another cardiac or systemic disease such as hypertension or aortic stenosis. Although the usual clinical diagnostic criteria for HCM is a maximal LV wall thickness greater than or equal to 15 mm, genotype–phenotype correlations have shown that virtually any wall thickness is compatible with the presence of a HCM mutant gene (14,15).

The morphologic hallmark of HCM is asymmetric septal hypertrophy (see Figure 89.3) with myocyte and myofibril disarray (16). Some reports have emphasized that variable degrees of myocyte ultrastructural, myofibrillar, and muscle bundle disorganization can be detected, often with substantial degrees of interstitial fibrosis (16). Mutations in sarcomeric protein encoding genes have been described in HCM, but other conditions can mimic the phenotype such as Noonan syndrome, Friedreich ataxia, Fabry disease, and Hunter and Hurler syndromes.

Recently, a proposal for screening patients with familial HCM suggests the use of echocardiography from the age of 12 until full growth and maturation is achieved (18–21 years). If echocardiographic abnormalities are not demonstrated, then a strong reassurance to the family can be made regarding the absence of cardiomyopathy (17). The medical therapy of HCM is discussed in Chapter 29. Other modalities of therapy for patients with outflow tract obstruction include ethanol ablation (via catheterization) and surgical resection of the outflow tract hypertrophied muscle (myectomy). This last procedure is better in terms of outcome (18).

Endomyocardial fibrosis, also known as tropical eosinophilic endomyocardial fibrosis, is common in South and Central America and tropical and subtropical Africa. Surprisingly, it accounts for 15% to 25% of the cardiac deaths in equatorial Africa (20). Endomyocardial fibrosis is characterized by thickening and scarring of the endocardium, which can be so extensive that the ventricular cavity is obliterated. Thrombi may overlie these lesions, increasing the risk of thromboembolism. Frequently, the subendocardial myocardium is also affected. In 50% of cases, the left and the right ventricles are involved, whereas another 40% of cases have lesions isolated to the left ventricle. The mitral and tricuspid valves may become fibrotic as well, leading to valvular regurgitation. Many believe that this disease is a form of, if not the same as, Löeffler endocardial fibrosis, perhaps at a different stage (20,21). Although the overall prognosis is poor, palliative treatment with surgical endocardial resection and valvular repair/replacement may alleviate some symptoms.

Löeffler endocardial fibrosis is also associated with eosinophilia, giving it its other names, eosinophilic cardiomyopathy and nontropical eosinophilic endomyocardial fibrosis. The severity of cardiac dysfunction seems to parallel the degree and duration of the eosinophilia, leading to the belief that the eosinophil itself is responsible for the dysfunction. The contents of the intracytoplasmic granules of the eosinophils can cause direct myocardial necrosis. It has also been observed that the eosinophils bind immunoglobulin G and increase peroxidase, which can have further direct toxic effects. The cardiac manifestations of this eosinophilic disorder are similar, if not identical to, those produced by eosinophilic leukemia and the eosinophilia–myalgia syndrome, which has been associated with tryptophan. Treatment with corticosteroids and cytotoxic agents (hydroxyurea) can improve symptoms and survival (22).

ARVC, also commonly known as arrhythmogenic right ventricular dysplasia (ARVD), is a rare disorder that occurs in adolescence and young adulthood. It has a male : female ratio of approximately 2 to 3 : 1 (23). The true incidence of ARVC
remains unknown, partly because of difficulties with its diagnosis, as described below.

The abnormalities of ARVC affect primarily the right ventricle, although in rare instances, the left ventricle is involved (24,25). Grossly, the ventricle is mildly dilated and thinned (Fig. 89.6). The characteristic feature is the segmental, progressive, noninflammatory loss of myocytes and their replacement by adipose tissue and fibrosis (26). This is in contrast to the nonfibrotic adipose tissue infiltration that normally occurs in the right ventricle and increases as a function of age (27). In ARVC/D, the fibroadipose infiltration is transmural in nature and can be confirmed either at autopsy or with surgical biopsy. Endomyocardial biopsies are sometimes helpful, but have limitations (28). Despite this, finding extensive fibrofatty replacement of myocytes in the right ventricle is concerning. But when interpreted by an experienced team including cardiologists, pathologists, and radiologists, the diagnosis of ARVD can be accurately established (29). Cinemagnetic resonance imaging has the potential to aid diagnosis by being able to differentiate normal myocardium from adipose tissue, assess morphologic alterations, and detect areas of regional and global ventricular dysfunction (30). In fact, a good correlation between imaging and tissue characterization of ARVD has been demonstrated (31).

Genetic studies from several sources have identified at least 7 loci (ARVD1-ARVD7) by linkage analysis. Furthermore, mutations in three desmosomal proteins (desmoplakin, plakoglobin with specific phenotype or Naxos disease [palm plantar keratoderma and wooly hair], and plakophilin) (32,33) have been associated with ARVC. Also, mutations in the cardiac ryanodine receptor (hRYR2), are associated with effort-induced polymorphic ventricular tachycardia and juvenile sudden death (ARVD2) (33). Last, mutations in the transforming growth factor-β3 have been associated with an autosomal dominant inheritance (ARVD1).

Because of the difficulties and risks of obtaining tissue to confirm the diagnosis of ARVC, as well as inaccuracies in assessing right ventricular structure and function with many of the noninvasive tests, a task force from the European Society of Cardiology and the International Society and Federation of Cardiology met and released criteria to assist in this process. The diagnosis can be made by meeting any of the following: two major criteria, one major plus two minor, or four minor criteria (Table 89.2) (34). A recent report of electrocardiographic (ECG) changes evaluated over time shows usefulness of the ECG in assessing progression of ARVC/D (35).

To assess the natural history of ARVC/D, a recent study of 130 patients showed a cardiovascular mortality of 16% (n = 24). Risk stratification showed that the most ominous risk factors presence of right or left ventricular dysfunction and ventricular tachycardia. However, when cause of death in these 24 patients was analyzed, 59% of the patients died of heart failure and 29% of sudden death (36).

This entity shows marked thinning of the right ventricular wall with virtual apposition of the epicardium to the endocardium
without myocardium in between (37). This anomaly has been compared to ARVC/D. However, it is distinct in that it occurs in infancy and early childhood, is incessant, and results in complete destruction of the right ventricle. Furthermore, it does not show fatty infiltration of the wall (38).

Endocardial fibroelastosis is an abnormal thickening of the endocardium of the left ventricle and aortic and mitral valves. It occurs in infancy and early childhood. The fibrosis leads to decreased compliance of the myocardium and diastolic dysfunction. Typically, a DCM occurs frequently with significant mitral regurgitation, but a restrictive cardiomyopathy (see Fig. 89.4) can also occur. A genetic defect has not been identified; autosomal-recessive, autosomal-dominant, and X-linked recessive patterns of inheritance have been reported. The X-linked forms demonstrate mitochondrial abnormalities that are similar to those of Barth syndrome. Endocardial fibroelastosis has also been associated with tissue carnitine deficiency (39), and there is evidence that it may be related to a defect in the plasma membrane carnitine transporter (40). The ECG frequently shows features of LVH, with occasional pseudoinfarction patterns and atrioventricular block. The echocardiogram is remarkable for dense echoes along the LV endocardium. Pathologic examination shows a uniform thickening of the encodardium of the left ventricle, which is composed of a mixture of collagen and elastic fibers.

Left ventricular noncompaction (LVNC) is a rare form of cardiomyopathy believed to be a result of an arrest in cardiac
development (Fig. 89.7). It affects adults and children. In adults, it is often limited to patients without associated cardiac defects, and is thus called isolated LVNC. In children, it is associated with other heart defects in up to 14% of patients. In children, there are two phenotypes: (a) progressive systolic dysfunction that results in early death; and (b) an undulating type, with periods of deterioration and recovery that allow survival into adulthood. Other terms for persistent noncompacted myocardium include spongy myocardium and persistence of myocardial sinusoids; however, the intramyocardial vessels that communicate with the cardiac chambers are invaginations rather than sinusoids (41,42). There are associations of LVNC with mutation in the gene G4.5, which encodes tafazzin. This gene has also been associated with other myopathies and with Barth syndrome (43,44).

Mitochondrial cardiomyopathy is defined as ventricular dysfunction caused by mitochondrial DNA mutations, which are maternally inherited. These mutations are not limited to the heart mitochondria and may also be demonstrated throughout the liver, kidney, pancreas, central nervous system, skeletal muscles, and thyroid gland. The mitochondria are typically irregular, vary in size, and have a very abnormal cristae structure (Fig. 89.8). The myocardial changes can mimic HCM. Mitochondrial cardiomyopathy may also present with signs, symptoms, and features of DCM. Progressive hypertrophy and dilation of the heart with cardiac dysrhythmias are characteristics of these mitochondrial abnormalities. DNA defects frequently result in cytochrome c oxidase deficiency and abnormalities in the mitochondrial respiratory chain. Research is active in identifying these mutations by endomyocardial biopsy (45). Several systemic diseases are associated with mitochondrial dysfunction. For example, the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) is complicated by cardiomyopathy and generalized microangiopathic occlusive disease (46). The wide spectrum of mitochondrial diseases is not limited to the heart; in fact, they are commonly accompanied by manifestations in other organ systems (47,48).

Ischemic cardiomyopathy, defined as an ejection fraction of less than 40%, with multifocal wall motion abnormalities owing to coronary artery diseases, is the most common DCM in the United States (Fig. 89.9). It carries with it significant disability and mortality. In the past, a 5-year survival rate of only approximately 40% has been reported (49). Adequate perfusion of the myocardium is essential for appropriate cellular aerobic respiration, and heart failure due to ischemic cardiomyopathy is caused by at least four distinct mechanisms. Stunned and hibernating myocardial tissue are viable, with potential for improvement in functioning with better perfusion. Differentiation of ischemia, scar, and hibernating myocardial tissue is discussed in Chapters 50 and 55, and includes methods such as positron emission tomography, dobutamine and myocardial contrast echocardiography, and rest-redistribution thallium-201 scintigraphy (50). Diffuse small-vessel atherosclerosis can also produce ischemia-related malfunction of the cardiac
myocyte. Indeed, small vessel disease is involved in the pathogenesis of the cardiomyopathy of diabetes mellitus. Thus, diabetic cardiomyopathy may be due, in part, to epicardial vessel disease as well as diffuse small-vessel subendocardial atherosclerosis. Systemic lupus erythematosus and other autoimmune chronic inflammatory disease states occasionally produce similar findings.

Differentiation of ischemic cardiomyopathy from nonischemic processes is extraordinarily important. Patients with ischemic cardiomyopathy frequently, but not always, have histories of chest discomfort, myocardial infarctions, or abnormal ECGs, suggesting previous infarction. Restoring adequate perfusion to the heart is key to reversing the progression of a clinical heart failure state. Coronary angiography is key, although often lesions are seen that are not producing ischemia, and, on the other hand, diffuse small-vessel disease may not be well appreciated. Relating angiographic findings to perfusion, viability, and functional studies of the heart differentiates contributions of ischemia, scar, hibernation, and periinfarction stunning to the pathologic remodeling process of heart failure.

Valvular cardiomyopathy is produced by valvular defects of numerous etiologies, discussed in Chapters 22,23,24. Typically, defects that produce volume-overloaded states (regurgitation) are more likely to cause cardiomyopathy than are lesions associated with pressure overload (valvular stenosis). Frequently, the issue of corrective valvular surgery in the setting of severe myocardial dysfunction is raised, with the hope of promoting myocardial recovery if the lesion is fixed. For instance, attempts at reducing mitral regurgitation have been performed in patients with severe cardiomyopathy, either as an isolated surgery or in conjunction with partial left ventriculectomy, with some symptomatic success and at least early improvement in certain cases (51,52).

Hypertensive cardiomyopathy is discussed in detail in Chapter 7. Occasionally, patients with hypertensive cardiomyopathy can present with heart failure and a dilated heart. However, most patients show marked symmetric hypertrophy of the left ventricle (Fig. 89.10).