Cardiomyopathies

Cardiomyopathies WILLIAM D. EDWARDS, MD The cardiomyopathies, or myocardiopathies, may be defined as primary myocardial diseases of undetermined cause.! As such, the term cardiolllJoPathy is not considered synonymous with end stage heart failure. Moreover, the terms ischemic cardiolllJopathJ, hypertensive cardiolllJopathy, and valvular cardiomJopathy are inappropriate because the underlying cause is known. The World Health Organization recognizes three chronic forms of cardiomyopathy-dilated, hypertrophic, and restrictive.!

Autopsy Pathology GrossFeatures

The heart is characterized by biventricular hypertrophy and four-chamber dilatation (figs. IA through IC). Although the heart is enlarged and globular and often attains a weight that is increased 25 to 50 per cent above normal, the ventricular wall thicknesses are generally normal because of the effect of dilatation (figs. IB and IC). Recently, a form of dilated cardiomyopathy has been described in which the degree of dilatation is quite mild.!O Subendocardial and transmural scarring may occur, even in the absence of identifiable thromboembolic obstruction of the coronary arteries l l (fig. ID). Endocardial fibrosis may be prominent, particularly in children; the dilated form of endocardial fibroelastosis probably represents dilated cardiomyopathy in many instances. Mural thrombi may develop in any cardiac chamber and may vary considerably in size (fig. IB).2 Their organization produces focal endocardial fibrosis. Tricuspid insufficiency may occur and is related to annular and right ventricular dilatation. In contrast, mitral regurgitation, when present, is primarily due to left ventricular dilatation and geometric malalignment of the papillary muscles rather than appreciable anular dilatation (fig. lD).

DILATED CARDIOMYOPATHY General Features

Dilated (congestive) cardiomyopathy is a spectrum of disorders that have in common a dilated and failing heart for which no cause can be established. 2- s The diagnosis, therefore, is one of exclusion. Although persons of any age may be affected, most patients are 20 to 50 years old, and men are more often affected than women. 2 •S The clinical course is usually characterized by chronic progressive heart failure, with a markedly reduced ventricular ejection fraction. s However, in some patients, the initial manifestation may be severe acute heart failure, life-threatening arrhythmias, chest pain, or systemic thromboembolic events. S •6 Although global hypokinesis is the rule, some patients may exhibit segmental wall motion abnormalities clinically. The possible role of myocarditis in the pathogenesis of dilated cardiomyopathy has been investigated extensively in the past several years, particularly with the use of transvenous endomyocardial biopsy.7,8 However, because the reported frequency of myocarditis among patients with dilated cardiomyopathy varies so greatly (from 6 to 64 per cent), considerable controversy still exists. 9 The variation in frequencies seems to be related, in part, to differences in histopathologic definitions of myocarditis, the misinterpretation of noninflammatory interstitial cells as lymphocytes, the clinical misinterpretation of acute heart failure as cardiomyopathy, bias in patient selection, and strong pressure from the clinician for the pathologist to render a diagnosis of myocarditis. 8.9

Received from the Section of Medical Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Address reprint requests to Dr. Edwards: Section of Medical Pathology, Mayo Clinic, Rochester, MN 55905. 0046-8177/87 $0.00

+ .25

MicroscopicFeatures

Myocytes generally are hypertrophied and exhibit variable degrees of attenuation (stretching) and sarcoplasmic degeneration (figs. 2A through 2C).2-4 In attenuated cells with normal diameters, enlarged and hyperchromatic nuclei are the best histologic indicator of hypertrophy.3 The myocardial interstitium may be quite cellular (fig. 2D), and care must be taken, in cells cut in cross section, not to misinterpret active stromal elements as inflammatory cells, particularly lymphocytes. 8,9 Interstitial fibrosis is observed commonly and may consist of delicate perivascular. or pericellular collagen or dense patches of replacement fibrosis (figs. 2£ and 2F); its distribution tends to be more extensive in the left ventricular subendocardium than elsewhere. 2 Endocardial fibrosis, when present, is usually mild but may be dense, particularly in areas of mural thrombosis (fig. 2G). In some cases, lymphocytic myocarditis may be present and is characterized by multiple microscopic aggregates of lymphocytes associated with degenerative or necrotic myocardial cells (fig. 2H). The inflammatory lesions tend to be small and sparse. Among patients with idiopathic dilated cardiomyopathy, the light microscopic features are nonspe-

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FIGURE 1. Gross features of idiopathic dilated cardiomyopathy. A, Anterior view shows enlarged and globoid heart. Normal heart at right is for comparison. B, Short-axis view demonstrates biventricular dilatation with normal wall thicknesses. Normal heart at right is for comparison. C Four-chamber view shows dilatation of all chambers and mural thrombus (arrow) in apex of right ventricle. Normal heart at right Is for comparison. D, Short-axis view of cardiac base shows scarring (arrows) of inferior wall of left ventricle. Mitral and tricuspid vaives were both regurgitant clinically. fN, right ventricle; LV, left ventricle.

cific and are often surprisingly mild. In some cases, hypertrophied and attenuated myocytes may be the only apparent abnormality, whereas other cases may be characterized not only by hypertrophy but also by extensive fibrosis. Surgical Pathology

In the setting of dilated cardiomyopathy, surgically excised tissues may include transplantation specimens or incompetent mitral or tricuspid valves. Hearts resected during cardiac transplantation may be dissected tomographically to correspond with clinical cross-sectional imaging techniques such as twodimensional echocardiography or magnetic resonance imaging. Endomyocardial Biopsy

The microscopic features of dilated cardiomyopathy are the same in biopsy tissues as in autopsy spec-

imens 12 - 17 (fig. 2). However, various tissue artifacts, particularly contraction bands, are encountered commonly in biopsy specimens and may produce artifactual sarcoplasmic degeneration. 13 The distinction between true and artifactual sarcoplasmic changes is important because the extent to which contractile elements are lost, as determined by quantitative morphometry, may correlate with prognosis,1s In contrast, the degree of hypertrophy and fibrosis does not seem to correlate with prognosis. Routine stains include hematoxylin-eosin, trichrome, and, in the Mayo Clinic laboratory, sulfated alcian blue. The use of a routine iron stain is considered optional. By transmission elecd'on microscopy, abnormalities within myocytes are the rule, but the changes are variable and nonspecific (fig. 2C).

Dilated cardiomyopathy cannot be diagnosed by examination of biopsy tissue alone because the histopathologic features are so nonspecific. However, the observed abnormalities may be considered consistent

FIGURE 2. Microscopic features of idiopathic dilated cardiomyopathy. A, Hypertrophy with attenuation (compare with cell diameters in B). B, Sarcoplasmic degeneration with loss of contractile elements. C Transmission electron micrograph shows loss of contractile elements. D, Noninflammatory interstitial hypercellularity with early fibrosis. £ Pericellular Interstitial fibrosis. F, Patchy interstitial replacement fibrosis. G, Focal endocardial fibrosis. H, Focal lymphocytic myocarditis (A, B, D, £ G, and H, hematoxylin-eosin stain. Original magnification, x 360. C uranyl acetate and lead citrate stains. Original magnification. x 15.000. F, sulfated alcian blue stain. Original magnification. x 180.)

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CAADIOMYOPATHIES (Edwards)

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FIGURE 3. Gross fealures of hypertrophic cardiomyopathy. A and B. Long-axis views demonstrate disproportionate ventricular septal (VS) hypertrophy associated with sudden death in 13-year-old boy and 54-year-old man. respectively. C. Short-axis view shows markedly hypertrophied ventricular seplum in 65-year-old man. D. Subaortic fibrous endocardial patch (arrows) results from traumatic impaction of anterior mitral leaflet (Ant) against ventricular seplum. Ao. aorta; LA. left atrium; LV. left ventricle; rN. right ventricle; VS. ventricular seplum.

with dilated cardiomyopathy if appreciable ischemic,

hypertensive, valvular, and toxic disorders have been excluded clinically. Accordingly, the rational for endomyocardial biopsy is not to diagnose cardiomyopathy but rather to exclude other disorders that are treatable or have specific histopathologic features, such as myocarditis and hemochromatosis. Differential Diagnosis

Several disorders may mimic idiopathic dilated cardiomyopathy. Patients with ischemic heart disease, particularly diabetics, may present with unexplained heart failure and without an antecedent history of angina pectoris or myocardial infarction. 19 Unless coronary arteriography or other procedures are performed, the ischemic nature of the disease may remain clinically undetected. Hemochromatosis also may mimic dilated cardiom~opathy and may be detected by tissue iron stain. 0 However, iron deposition tends to be more extensive subepicardially than subendocardially and,

thereby, may be prone to sampling error by endomyocardial biopsy. Myocarditis may present as heart failure and clinically may mimic dilated cardiomyopathy. Some cases may be idiopathic or viral and may be important etiolo~ically in the later development of cardiomyop.athy..7 However, other cases may be unrelated to the cardiomyopathies and, instead, may be associated with drug toxicity or hypersensitivity, rheumatic or collagen-vascular diseases, or sarcoidosis. 9 HYPERTROPHIC CARDIOMYOPATHY General Features

628

Hypertrophic cardiomyopathy is characterized by disproportionate septal hypertrophy, systolic anterior motion of the anterior mitral leaflet, and myofiber disarray.2-4.21.22 Each of these disorders may vary considerably in extent. Moreover, the hypertrophied walls are poorly compliant and offer an increased resistance to ventricular filling. Clinically,

CAADIOMYOPATHIES (Edwards)

FIGURE 4. Microscopic features of hypertrophic cardiomyopathy. A, Myocyte hypertrophy shows hyperchromatic nuclei and increased cell diameters. B. Myofiber disarray is characterized by haphazard nonparallel arrangement of myocytes. C. Transmission electron micrograph shows disarray of contractile elements within myocyte. D. Interstitial and endocardial fibrosis is typically present. (A, hematoxylineosin stain. Original magnification, x 360. Band D. hematoxylin-eosin stain. Original magnification. x 180. C. uranyl acetate and lead citrate stains. Original magnification. x 3.000.)

however, the disease has been characterized by its variable obstruction to ventricular emptying rather than by its restrictive features. Accordingly, it may be designated as obstructive or nonobstructive, based on the presence or absence of left ventricular outflow tract obstruction. Less frequently, right ventricular or biventricular outflow tract obstruction may occur. Sudden death and infective endocarditis are relatively common complications. Hypertrophic cardiomyopathy may be diagnosed at any age and is more common in men than women. In general, the younger the patient at diagnosis, the more severe the disease. 23 •24 It is familial in about half of cases, but the patterns of genetic transmission seem to be heterogeneous. 25 •26 In a few instances, hypertrophic cardiomyopathy may be associated with lentiginosis. 27 Autopsy Pathology GrossFeatures

The heart is involved by marked biventricular hypertrophy, and its weight may be increased 100 to 200 per cent above the normal mean value for age, sex, and body size. 2 In most cases, the thickness of the ventricular septum is greater than that of the lat629

eralleft ventricular free wall (figs. 3A to 3C), and the disproportionate hypertrophy often extends for variable distances into the anterior or inferior free wall. 2 - 4 f\loreover, the septal thickening may be quite localized and involve primarily the basal (subaortic) region, the midventricular region, or the apex. 28 ,29 Chronic contact between the anterior mitral leaflet and the ventricular septum produces a thickened mitral leaflet and subaortic endocardial fibrosis (fig. 3D).2-4 The fibrotic patch may attain the mirror-image shape of the anterior mitral leaflet. The ventricular chambers usually are not dilated until heart failure supervenes. However, left atrial dilatation usually is observed. 2 MicroscopicFeatures

Myocardial cells tend to be greatly hypertrophied and are characterized by enlarged and hyperchromatic nuclei (fig. 4A). Myofiber disarray generally occurs to a much greater extent in hypertrophic cardiomyopathy than in other forms of heart disease and is characterized by whorled and intertwined clusters of myocytes and by the nonparallel arrangement of sarcoplasmic contractile elements (figs. 4B and 4C).30.31

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Patchy interstitial fibrosis frequently is observed, and endocardial fibrosis may be prominent, particularly in the subaortic region (fig. 4D).2-4 Subendocardial and transmural fibrosis may occur even in the absence of coronary atherosclerosis. 32 .33 In the ventricular septum, thickened intramural coronary branches have been reported. 32 The severity of each of the aforementioned histopathologic features may vary considerably.

sinophils may be responsible for focal necrosis and subsequent fibrosis. Restrictive features are due to thrombosis and fibrosis of the ventricular inflow tracts. In contrast, fibrosis alone provides the morphologic substrate for decreased ventricular compliance in the noneosinophilic form of restrictive cardiomyopathy.2.39.4o In the United States, restrictive cardiomyopathy frequently seems to be unrelated to peripheral eosinophilia.

Surgical Pathology

Tissues may be obtained during septal myectomy or mitral valve replacement. The extent of myofiber disarray depends in part on the plane of section and tends to be greater in tissues cut perpen~ dicular to the ventricular long axis than in those cut parallel to it. Endomyocardial Biopsy

The microscopic features are similar to those de~. scribed for autopsy specimens (fig. 4). However, because myofiber disarray is often present· only deep within the core of the ventricular septum and beyond the reach of the bioptome, endomyocardial biopsy tissues usually exhibit only hypertrophy and fibrosis.1 3 Although, for biopsy tissues, criteria have been proposed to distinguish hypertrophic cardiomyopathy from other forms of cardiac disease,34,35 there seems to be much overlap, and some investigators have not found the criteria to be particularly useful. 16 Accordingly, the rationale for biopsy is not to diagnose hypertrophic cardiomyopathy but rather to rule out other disorders that may mimic this disease. Differential Diagnosis

Any disorder that produces disproportionate thickening of the ventricular septum may mimic hypertrophic cardiomyopathy. Clinically, the three most important entities are amyloidosis, chronic hypertension, and age-related angulation of the ventricular septum. 16 Additional disorders include aortic stenosis, so-called hypercontractile states, and type II glycogen storage disease. Among infants of diabetic mothers, cardiomegaly ma~ exist and resemble hypertrophic cardiomyopathy. 6 Although it is apparently transient in some cases, it may be progressive and fatal in others.

RESTRICTIVE CARDIOMYOPATHY General Features

Restrictive cardiomyopathy encompasses two groups of idiopathic disorders that are characterized by restriction to ventricular filling. One is associated with peripheral eosinophilia, and the other is not. The spectrum of eosinophilic endomyocardial disease includes the hypereosinophilic syndrome, eosinophilic myocarditis, and, endomyocardial fibrosis.2-4.37-39 Degranulation of endomyocardial eo-

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Autopsy Pathology GrossFeatures

In eosinophilic endomyocardial disease, mural thrombus characteristically lines both ventricular inflow tracts. 2- 4 If extensive, it may obliterate much of the ventricular cavities or entrap the leaflets and chordae tendineae of the atrioventricular valves and thereby produce mitral or tricuspid insufficiency (figs. 5A and 5B). Atrial dilatation is the rule, but ventricular hypertrophy and dilatation seem to be related to the degree of valvular incompetence. In the noneosinophilic form, the heart is characterized by marked atrial dilatation and by nondilated ventricles (figs. 5C and 5D).· Ventricular hypertrophy tends to be mild, such that the heart weight is usually not increased more than 50 per cent above the expected normal. Mural thrombus is not a feature. MicroscopicFeatures

The active form of eosinophilic endomyocardial disease is associated with fresh mural thrombus rich in eosinophils (fig. 6A) or with an eosinophilic endomyocarditis (fig. 6B).2-4.37 During the healing phase, proliferative granulation tissue lines the endocardium (fig. 6C). The inactive form is characterized by dense endocardial fibrosis (fig. 6D) and may be associated with fibrosis of the subjacent myocardium. In contrast, in the noneosinophilic form of restrictive cardiomyopathy, the severity of endocardial fibrosis tends to be less, and eosinophils are not observed. The myocardium is affected primarily by patchy or diffuse interstitial fibrosis. 40 Myocytes may be hypertrophied and may exhibit sarcoplasmic degeneration. Surgical Pathology

In the setting of eosinophilic endomyocardial disease, replacement of regur~itant atrioventricular valves may be performed. 41 - 4 Decortication of the thrombotic and fibrotic endocardium may relieve the ventricular cavity obliteration and the restrictive hemodynamics. 41 .42 Endomyocardial Biopsy

The biopsy findings are similar to the histopathologic features described in autopsy tissues (fig. 6). The lesions of active eosinophilic endomyocardial disease are specific and diagnostic. However, the typ-

CARDIOMYOPATHIES (Edwards)

FIGURE 5. Gross features of restrictive cardiomyopathy. A and B, In patient with peripheral eosinophilia, mitral leaflets are encased in mural thrombus (doffedline in A indicates mitral anulus). C and D, In patient without peripheral eosinophilia. heart is characterized by marked biatrial dilatation and ventricles of normal size (C view from above; D, four-chamber view). Ao, aorta; LA, left atrium; LV. left ventricle; PT, pulmonary trunk; RA. right atrium; R\I. right ventricle.

ical features of inactive disease and of noneosinophilic restrictive cardiomyopathy are nonspecific. Consequently, in the latter setting, an endomyocardial biopsy may be indicated not to diagnose the cardiomyopathic state but rather to rule out the various disorders that may mimic it.

restnctlve hemodynamics. In some patients, even after cardiac catheterization and two-dimensional echocardiography, the distinction between these disorders and restrictive cardiomyopathy may remain unresolved. An endomyocardial biopsy may be indicated to help resolve the issue. Amyloid is detected easily in cardiac biopsy specimens and may be deposited in the interstitium in a pericellular or nodular pattern, in the endocardium, or in myocardial blood vessels44 •15 (figs. 7A and 7B). Because amyloid shows staining variability, a tinc-

Differential Diagnosis

Amyloidosis and constrictive pericarditis may interfere with ventricular filling and thereby produce 631

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FIGURE 6. Microscopic features of restrictive cardiomyopathy. A Mural thrombus shows large numbers of eosinophils. 8, Eosinophilic endomyocarditis shows focal myocyte necrosis (arrow). C, Healing phase is characterized by endocardial granulation tissue. D, Healed phase shows dense endocardial fibrosis. (A, azure eosin stain. Original magnification. x 900. B. hematoxylin-eosin stain. Original magnification. x 360. C through E. hematoxylin-eosin stain. Original magnification. x 180.)

torial battery is recommended, including sulfated alcian blue, methyl violet, and perhaps thioflavine T stains. 16 Congo red stain may not be particularly satisfactory in cardiac biopsy tissues. Immunoperoxidase stains for K and A light chains and for prealbumin may be indicated in selected cases. Chronic constrictive pericarditis is associated with normal or mildly atrophic myocardium, assuming that there is no other coexistent disorder that produces hypertrophy (figs. 7C and 7D). In contrast, the chronic (inactive) forms of restrictive cardiomyopathy are characterized by hypertrophy and fibrosis. Consequently, the observation of normal cardiac biopsy tissue would support the diagnosis of constrictive rather than restrictive disease. However, myocardial abnormalities also may be mild during the early phase of restrictive cardiomyopathy.40 Hypertrophic cardiomyopathy is characterized by interference with ventricular filling and, thereby, may mimic restrictive cardiomyopathy.46 However, because the biopsy features of hypertrophic and restrictive cardiomyopathies are often quite similar, an endomyocardial biopsy is generally not useful for distinguishing the two. Restrictive features also have been associated with hemochromatosis and pseudoxanthoma elasticum. 47 .48

OTHER FORMS OF CARDIOMYOPATHY

Alcoholic Cardiomyopathy

Congestive heart failure, unrelated to thiamine deficiency (beriberi), may develop in chronic alcoholics but rarely occurs in those with alcoholic cirrhosis. 49 Ethanol and its metabolite, acetaldehyde, seem to be toxic to myocytes. 50,51 The gross and microscopic features of the heart are indistinguishable from those of idiopathic dilated cardiomyopathy.2-4 Postpartum Cardiomyopathy During the last month of pregnancy or the first six months after delivery, progressive congestive heart failure may develop. In some cases, the cardiovascular stress of pregnancy apparently unmasks an evolving cardiomyopathy, and in other cases, the pregnancy seems to be causally related to the development of the cardiomyopathic state.52-54 The gross and microscopic lesions are typical of idiopathic dilated cardiomyopathy.53.54 Familial Cardiomyopathy Although hypertrophic cardiomyopathy has the highest frequency of genetic transmission among the cardiomyopathies, the dilated form ma~ also be familial in a small percentage of cases. 25 ,26, 5-57 In most

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CMDIOMYOPATHIES (Edwards)

FIGURE 7. Disorders that may mimic restrictive cardiomyopathy. Amyloidosis produces stiff and poorly compliant ventricles (A) because of interstitial deposition (B). Constrictive pericarditis Interferes with ventricular diastolic filling (C) and is associated with normal or atrophic ventricular myocytes (D). (B and D, hematoxylin-eosln stain. x 360.)

individual families, the type of cardiomyopathy tends to be constant throughout the generations. Arrhythmic Cardiomyopathy

Both the dilated and the hypertrophic forms of cardiomyopathy may be associated with secondary arrhythmias and sudden death. However, certain primary recurrent supraventricular or ventricular arrhythmias may be causally related to the development of confestive heart failure and a cardiomyopathic state.5 In so-called arrhythmogenic right ventricular dysplasia, it is unclear whether the arrhythmia or the cardiomyopath~should be considered the primary abnormality.59- 1

acterized by severe intractable ventricular and supraventricular arrhythmias. The heart is involved grossly by biventricular hypertrophy and dilatation and microscopically by multiple clusters of palestaining myocytes that resemble Purki~e'cells. Keshan Cardiomyopathy

An edemic form of dilated cardiomyopathy has been reported in China. 65 The heart is characterized by biventricular hypertrophy, four-chamber dilatation, multifocal myocyte necrosis, and patchy replacement fibrosis. It may be related to selenium or other nutritional deficiencies. Mitochondrial Cardiomyopathy

Histiocytoid Cardiomyopathy

This disorder generally occurs in ~irls and is fatal during the first two years of life. 62 - It is char-

633

Hypertrophic cardiomyopathy has been described in patients with a rare form of cardiac and skeletal myopathy in which primary structural abnor-

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malities of mitochondria are observed.66 ,67 The disorder may be familial. Friedreich's Ataxia

Patients with Friedreich's ataxia often develop a myopathic heart. In some, the gross and microscopic features are typical of hypertrophic cardiomyopathy, and in others, the appearance is that of dilated cardiomyopathy.68-70 REFERENCES I. Report of the WHOflSFC task force on the definition and classification of cardiomyopathies, Br HeartJ 44:672. 1980 2. Roberts WC, Ferrans VJ: Pathologic anatom)' of the cardiom)'opathies: idiopathic dilated and h)'pertrophic t)'pes, infiltrath'e types. and endocardial disease with and without eosinophilia, HUM PATHOL 6:287. 1975 3. Olsen EGJ: The pathology of cardiomyopathies: a critical analysis, Am Heart J 98:385. 1979 4. Da\'ies MJ: The cardiomyopathies: a review of terminolog)'. pathology, and pathogenesis. Histopathology 8:363. 1984 5. Fuster V. Gersh BJ. Giuliani ER. et al: The natural history of idiopathic dilated cardiom)'opathy. AmJ CardioI47:525. 1981 6. Dec GW Jr, Palacios IF. Fallon JT. et al: Aeti\'e myocarditis in the spectrum of acute dilated cardiomyopathies: clinical features, histologic correlates, and clinical outcome. 1'\ Engl J Mcd 312:885, 1985 7. Kereiakes DJ. Parmley WW: M)'ocarditis and cardiom)·opathy. Am HeartJ 108:1318. 1984 8. Edwards WD: M)'ocarditis and endomyocardial biops)'. Cardiol Clin 2(l'\ov):647. 1984 9, Edwards WD: Current problems in establishing quantitati\'e histopathologic criteria for the diagnosis of lymphocytic myocarditis by endom)'ocardial biops)'. Heart Vessels l(suppl 1):138, 1985 10. Keren A. Billingham ME. Weintraub D. et al: Mildly dilated congesth'e cardiomyopathy. Circulation 72:302. 1985 II. Isner JM. Virmani R. Its,:oitz SB. et al: Left and right \'entricular myocardial infarction in idiopathic dilated cardiomyopathy. Am Heart J 99:235. 1980 12, Lewis AB. I'\eustein HB, Takahashi M, et al: Findings of endomyocardial biopsy in infants and children with dilated cardiom)'opathy. Am J Cardiol 55: 143. 1985 13, Edwards WD: Endomyocardial biopsy and cardiomyopathy, Cardio\asc Rev Rep 4:820, 1983 14, Schwarz F. Mall G, Zebe H, et a1: Quantitati\e morphologic findings of the m)'ocardium in idiopathic dilated cardiomyopathy, AmJ Cardiol 51:501,1983 15. Dick MR. Um'erferth DV. Baba 1'\: The pallern of myocardial degeneration in nonischemic congesti\'e cardiomyopathy. HUM PATHOL 13:740. 1982 16. I'\ippoldt TB, Edwards WD. Holmes DRJr. et al: Right \entricular endomyocardial biopsy: clinicopathologic correlates in 100 consecutive patients. Mayo Clin Proc 57:407. 1982 17. Baandrup U. Olsen EGJ: Critical analpis of endom)'ocardial biopsies from patients suspected of having cardiom)'opathy. I. Morphological and morphometric aspects, Br HeartJ 45:475. 1981 18. Figulla· HR. Rahlf G, I'\ieger M, et al: Spontaneous hemod)'namic impro\ement or stabilization and associated biopsy findings in patients with congestive cardiom)·opathy. Circulation 71: 1095. 1985 19. Pantely GA. Bristow JD: Ischemic cardiom)'opathy, Prog Cardiovasc Dis 27:95, 1984 20. Short EM, Winkle RA, Billingham ME: M)'ocardial in\oh'ement in idiopathic hemochromatosis: morphologic and clinical improvement following venesection. AmJ Med 70:1275,1981 21. Olsen EGJ: The patholog)' of idiopathic h)'pertrophic subaortic stenosis (hypertrophic cardiom)'opath)'): a critical review. Am Heart J 100:553, 1980 22. Maron BJ, Epstein SE: H)'pertrophic cardiom)'opathy: recent obser\ations regarding the specificity of three hallmarks of the disease; as)'mmetric septal h)'pertrophy, septal disorganization and systolic anterior motion of the anterior mitral leaflet. AmJ CardioI45:14I. 1980 23, Maron BJ, Edwards JE. Henry WL, et al: As)'mmetric septal hypertrophy (ASH) in infancy. Circulation 50:809, 1974 24. Maron BJ. upson LC, Roberts WC, et al: "~Iatignant" h)'pertrophic cardiom)'opathy: identification of a subgroup of families with unusually frequent premature death, AmJ CardioI41:1133, 1978 25. Branzi A. Romeo G. Specchia S, el al: Genetic heterogeneity of h)'pertrophic cardiom)'opathy. IntJ Cardiol 7:129. 1985 26. Maron BJ, I'\ichols PF II I, Pickle LW, el al: Patterns of inheritance in

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