Idiopathic cardiomyopathy: clinical features, prognosis and therapy

IDIOPATHIC CARDIOMYOPATHY: CLNCAL FEATURES, PROGNOSIS AND THERAPY JACK P. SEGAL, M.D. JOHN F. STAPLETON,M.D. JOSEPH R. MCCLELLAN, M.D. BRUCE F. WALLER, M.D. W, PROCTOR HARVEY, M.D.

0146-2806/78/0009-0001$05.00 @ 1978 Year Book Medical Publishers,

Inc.

Editorial William de Leon.

Board (clockwise C. Roberts, Robert

EDITOR’S

from A.

top): W. O’Rourke.

Proctor Frank

Harvey, James I. Marcus and

J. Leonard, Antonio C.

PREFACE

Formerly cardiomyopathy was considered rare but now it is known not to be so. It is a great mimicker of other cardiac diseases and is often overlooked or misdiagnosed. Its diagnosis, clinical features, course, management and prognosis are outlined in this .discussion of 115 patients with idiopathic cardiomyopathy. This study is limited specifically to cases of unknown etiology, which are the largest number seen by our group at Georgetown and probably by the majority of others studying the problem. Patients with known causes of cardiomyopathy were excluded, as were the patients with obstructive cardiomyopathy (idiopathic ‘hypertrophic subaortic stenosis, asymmetric septal hypertrophy). My own interest in cardiomyopathy began in the early 1950s when Dr. Thomas Mattingly, then Chief of Cardiology at Walter Reed Army Hospital, presented some of these patients on my teaching rounds at the hospital. Dr. Mattingly, one of the early workers and contributors in this field, quickly convinced me that these patients were seen more commonly than previously recognized. He used the term “primary myocardial disease,” to designate the problem and to emphasize that it was the myocardium that was affected primarily rather than the valves or coro-

nary vessels. We, too, used this terminology because it appeared appropriate. With the passage of time, however, the term “cardiomyopathy” became popular and it has become the term most commonly used throughout the world. Also at the Walter Reed Army Medical Center at the same time as Dr. Mattingly, was the late Dr. William Manion, Chief of Cardiovascular Pathology at the Armed Forces Institute of Pathology. Bill Manion was a world authority on cardiomyopathy and worked closely with Dr. Mattingly. He taught many of us the pathology of this disease and used the term “myocarditis.” I recall once asking him how many cases of myocarditis he had studied. He reflected a few moments and then said, “about 14,000 or 15,000.” We would like to pay tribute to Drs. William Manion and Thomas Mattingly and express appreciation and admiration for their contributions to the understanding and management of this important cardiac disease. It is an interesting coincidence that at about the same time you are reading this issue of CURRENT PROBLEMS IN CARDIOLOGY, Dr. Jack Segal is presenting the manuscript at the World Congress of Cardiology in Tokyo (September 22,1978).

TABLE

OF CONTENTS

EDITOR’S PREFACE SELF-ASSESSMENT

. QUESTIONS

CASE SELECTION

.

COURSE

CLINICAL-PATHOLOGIC

.

THERAPY

.

.

ADDENDUM

4

. . .

5

......

10

.

......

13

.

......

20

......

25

......

30

......

32

......

40

......

41

......

45

......

46

.

CORRELATION

DIAGNOSIS

SUMMARY

......

.

NONOBSTRUCTIVE

CORRELATIONS

DIFFERENTIAL

DISCUSSION.

2

.

.

PROGNOSIS AND CLINICAL

.

. .

CLINICAL FEATURES- IDIOPATHIC CARDIOMYOPATHY CLINICAL

.

......

.

.

.

.

.

.

.

.

. .

. .

.

SELF-ASSESSMENT

QUESTIONS

1. All patients with idiopathic nonobstructive cardiomyopathy present with signs or symptoms of congestive heart failure. a. True. b. False. 2. The murmur most commonly associated with idiopathic cardiomyopathy is: a. Aortic ejection murmur. b. Systolic murmur at the lower left sternal border. c. Apical pansystolic murmur. d. Apical late systolic murmur. 3. List in order of decreasing frequency the following initial electrocardiographic findings: a. Atria1 fibrillation. b. Premature ventricular contractions. c. Premature atria1 contractions. d. Complete heart block. 4. Right axis deviation or right bundle branch block occurs rarely and if present weighs against the diagnosis of cardiomyopathy. a. True. b. False. 5. The initial heart size was normal in more than 30% of the living group who survived more than 5 years. a. True. b. False. 6. Which of the following statements is false? a. Prognosis is unrelated to heart size. b. Prognosis is related to initial functional class. c. Ventricular tachycardia, complex premature ventricular contractions and atria1 fibrillation are associated with a poor prognosis. 7. Congestive heart failure, marked cardiac enlargement and atria1 fibrillation occurred more frequently in those patients who had emboli. a. True. b. False. 8. List the following prognostic factors in order of decreasing importance: a. Left bundle branch block. b. Complex premature ventricular contraction. c. 3 and 4 + cardiomegaly d. Atria1 fibrillation. 5

9. Of the following, which would be the most frequent cause of death: a. Emboli. b. Sudden death. c. Congestive failure, 10. Which of the following was most frequently associated with sudden death: a. Left bundle branch block. b. Atria1 fibrillation. c. Marked cardiac enlargement. d. Emboli. 11. The differential diagnosis between cardiomyopathy and arteriosclerotic heart disease may be difficult. The presence of left bundle branch block would favor which of these diagnoses: a. Arteriosclerotic heart disease. b. Cardiomyopathy. 12. Echocardiography is least helpful in the differential diagnosis of: a. Mitral stenosis. b. The click murmur syndrome. c. Asymmetric septal hypertrophy. d. Coronary artery disease. 13. Digitalis preparations may be helpful in the treatment of congestive heart failure. However, those with more advanced cardiomyopathy may demonstrate digitalis toxicity at lower doses. a. True. b. False. 14. Unless there are specific medical contraindications, anticoagulation is indicated in the majority of patients with idiopathic nonobstructive cardiomyopathy. a. True. b. False. Answers are listed at the end of the article.

6

Left to right:

JACK

Drs.

McClellan,

Wailer,

Segai.

Harvey

and Stapleton

P. SEGAL is Clinical Professor of Medicine at Georgetown University Medical School, Washington. D.C. Dr. Segal received his M.D. from George Washington University, did his internship in internal medicine at Boston City Hospital and did a residency in internal medicine at Boston City Hospital and a residency in diagnostic clinic at Georgetown University Hospital.

JOHN F. STAPLETON is Professor, Department of Medicine and Associate Dean at Georgetown University School of Medicine and Medical Director at Georgetown University Hospital. Dr. Stapleton received his M.D. from Georgetown University Medical School, did his internship at Providence Hospital, Washington, D.C. and did his residency in medicine at Georgetown University Hospita I.

JOSEPH

R. MCCLELLAN is Chief, Cardiology Section, Berkshire Medical Center, Massachusetts. He received his M.D. from Georgetown University School of Medicine, Washington, D.C. and did his internship and residency at Duke University Medical Center, Durham, North Carolina. Dr. McClellan’s scientific and research interests include all aspects of cardiology with special emphasis on cardiomyopathy.

is a Staff Associate in the Pathology Branch of the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. He graduated from the University of Minnesota Medical School and did his postgraduate training at the Mayo Clinic and Mayo Graduate School of Medicine. He recently completed his cardiology fellowship at Georgetown University. Dr. Waller’s academic interests are diabetic heart disease and coronary artery disease.

THE WORLDWIDE PREVALENCE OF CARDIOMYOPATHY has become apparent in recent decades. This disease category represents a pathologic process that predominantly involves heart muscle. A number of terms other than cardiomyopathy have been used to describe this condition and include: primary myocardial disease, cardiopathy, myocardiopathy, myocarditis, myocardosis, diffise myocardial disease, idiopathic cardiac hyper-trophy, idiopathic cardiomegaly, familial cardiomegaly, familial myocardial disease, familial cardiomyopathy and others. As emphasized by Mattingly, clinical features and hemodynamic alterations are specific enough to justify a positive diagnosis.’ Obviously, coronary, syphilitic, hypertensive, rheumatic, pulmonary and congenital heart diseases are excluded. Clinical findings vary according to the extent and location of myocardial involvement and the characteristics of the causative disease. At times there may be significant involvement of the pericardium and endocardium. Some patients present initially with pericarditis, but myocardial features later predominate. Cardiomyopathy may be classified as idiopathic (primary) when the cause is unknown, or secondary (known cause) when the myocardial involvement is part of a systemic disease such as amyloidosis or collagen vascular disease (Table 1). Unfortunately, at the time of the initial examination, no etiologic factor is apparent and usually the patient has had no recent illness. However, at times an acute myocarditis may be evident. Goodwin has classified idiopathic cardiomyopathy into 4 clinical groups: congestive, hypertrophic (asymmetric septal hypertrophy), obliterative and restrictive.2 Congestive cardiomyopathy features left ventricular dilatation with or without myocardial hypertrophy depending on the extent of myocardial involvement. Low cardiac output, various arrhythmias and congestive heart failure result. The obliterative group is characterized by endomyocardial fibrosis that encroaches on the ventricular cavities. The restrictive type consists of an inelastic, rigid myocardium without marked hypertrophy. Clinical features may resemble constrictive pericarditis. Hypertrophic obstructive cardiomyopathy (idiopathic hypertrophic subaortic stenosis, or asymmetric septal hypertrophy) is characterized by excessive ventricular hypertrophy that reduces the systolic volume of the left ventricle. Septal hypertrophy and anterior systolic movement of the anterior mitral valve may narrow the outflow tract causing a systolic gradient between the aorta and left ventricle. Many cases of idiopathic cardiomyopathy do not fit any of the 4 categories described by Goodwin. This presentation reviews the characteristics of idiopathic cardiomyopathy, covering clinical and laboratory features, therapy and clinical course, and emphaSupported

by a grant

from

the McCann

Foundation.

Inc

TABLE

1. -ETIOLOGY

OF

CARDIOMYOPATHY

Idiopathic (unknown) Nonobstructive* - with and without congestive failure Obstructive Obliterative Restrictive Secondary (known) Infectious (viral, bacterial, mycotic, parasitic, protozoal, rickettsial) Connective tissue diseases ana hypersensitivity. Metabolic (hyperthyroidism, hypothyroidism, pheochromocytoma, nutritional, electrolyte imbalance) Toxic (emetine, carbon tetrachloride. bacterial toxins, cobalt) Alcoholic cardiomyopathy Infiltrative (malignancy, sarcoidosis, hemochromatosis, amyloidosis, glycogen storage disease) Neuromuscular disorders (progressive muscular dystrophy, dystrophia tonia, Friedreich’s ataxia, pseudohypertrophic and facioscapulohumeral muscular dystrophy) Pregnancy and postpartum state Congenital or familial myocardial disease *Subject

of this

myo-

study

sizes specific clinical “pearls” that have prognostic and therapeutic importance. In this study, we have excluded cases of the hypertrophic, obliterative and restrictive categories and have included only nonobstructive (dilated or congestive) idiopathic cardiomyopathy. We have divided our nonobstructive cardiomyopathy patients into 2 groups: those with and those without congestive heart failure. In most cases in this group, the patients present with symptoms and signs of congestive heart failure. However, many are first seen because of arrhythmias, systemic or pulmonary emboli, cardiac enlargement or electrocardiographic abnormalities rather than manifestation of congestive failure. CASE

SELECTION

Since 1961 a special cardiomyopathy study unit at Georgetown University Hospital has evaluated more than 600 cases involving.patients referred because of suspected cardiomyopathy (Fig 1). All 115 patients included in this report were followed for a minimum of 5 years or until death, if it occurred in less than 5 years. The median follow-up period was 8 years, and the longest 25 years. Thirty-nine patients were observed for more than 10 years, and 6 for more than 20 years. All cases were evaluated by members of the Division of Cardiology, in many instances by the same observer for more than 15 years. A few individuals were included in the series retrospectively when their autopsy findings indicated cardiomyopathy and the clinical records provided 10

I Other

ldiwathic

Types

FSg l.-Selection cases.

of 115 cases

for this

study

from

600

cardiomyopathy

clinic

a complete clinical background. In addition to a complete history and physical examination, evaluation commonly included echocardiography, stress testing and cardiac catheterization. The series includes only those whose diagnosis was established by postmortem examination or by careful evaluation of clinical data. Patients with significant coronary risk factors such as hypertension, diabetes or hypercholesterolemia were excluded from the study. Some classifications of cardiomyopathy have included coronary artery disease as one of the etiologic factors, but we believe this creates semantic confusion, and we have eliminated this group from the study. Although many patients were seen before the use of coronary arteriography became common, we felt that exclusion of ischemic heart disease was possible in most cases on clinical grounds, an impression confirmed by following many individuals to autopsy. This was the largest group of patients eliminated from the study. Since the study deals only with the idiopathic (unknown) cases, patients with a history of excessive alcoholic intake also were excluded. In addition, those having uremia were excluded. As previously noted, those with asymmetric septal hypertrophy and mitral valve prolapse (Barlow’s syndrome) were excluded. Many patients were referred because of unexplained arrhythmias; in the absence of cardiac enlargement, gallop rhythm, electrocardiographic abnormalities or other features of cardiomyopathy, these individuals were excluded from the study. Figure 2 shows the number of patients in each cardiomyopathy group that was initially evaluated. There were 198 patients, 123 of whom died. In order to further “purify” our idio11

1OOr

I

q

Fig 2.-Classification of 198 cardiomyopathy of cardiomyopathy included collagen vascular amyloidosis. sarcoidosis and malignancy. The pathy are evaluated in this study.

Living (75 Patients) Dead (123 Patients)

patients. Miscellaneous causes diseases, hemachromatosis. 115 with idiopathic cardiomyo-

pathic group, we eliminated 4 subgroups including postinfectious (viral), myopericarditis, peripartal and a miscellaneous group. Idiopathic postinfectious cardiomyopathy was defined as beginning several days or weeks after a respiratory infection (24 patients). Idiopathic peripartal cardiomyopathy began during the latter part of pregnancy or early postpartum period (8 patients). The myopericarditis group comprised 7 patients whose illness started with a well-documented episode of acute pericarditis, during the course of which the myocardium was involved. Some of these, of course, can also be classified as postinfectious. A miscellaneous group, including patients with collagen vascular disease, amyloidosis, hemochromatosis and sarcoidosis, was also excluded. The majority of cardiomyopathy patients (115) had no such distinguishing etiologic characteristics at the onset of their disease and, therefore, were classified as idiopathic cardiomyopathy. The following statistics and discussion are limited to these 115 patients with idiopathic cardiomyopathy with or without congestive features. (As previously mentioned, the hypertrophic, obliterative and restrictive types of cardiomyopathies were not included.) The various clinical and laboratory features are tabulated and analyzed at the beginning and again later in the course of the cardiomyopathy. “Onset” or “initial” indicates that a specific finding was present within the first year of the disease. “Late” indicates the presence of a specific feature 5 years after the onset, or at the time of death if this occurred before 5 years. 12

TABLE CARDIOMYOPATHY

2. -SURVIVAL PATIENTS

Male White Black Total Female White Black Total Total white Total black Total of both

OF

IDIOPATHIC BY SEX AND

17 -

sexes

and

races

RACE

ai;

33 16 49

50 21 71

11 5 16 28 10 38

17 11 28 50 27 77

28 16 44 78 37 115

Of the 115 patients with idiopathic cardiomyopathy, 77 were dead and 38 alive at the conclusion of this study (Table 2). There were 78 white and 37 black patients. Of the 50 white males, 33 died; of the 28 white females, 17 died; of the 21 black males, 16 died; and of the 16 black females, 11 died. That a larger number of white patients were studied has no significance for this evaluation. CLINICAL FEATURESCARDIOMYOPATHY

IDIOPATHIC

NONOBSTRUCTIVE

Figure 3 shows the distribution of patients’ ages at the onset of idiopathic cardiomyopathy, for both those who were alive and Fig %-Patient age at onset of idiopathic cardiomyopathy. patients who survived, onset occurred most frequently peaking at age 30. Onset occurred slightly later, peaking tients who died.

Age

iv~ars)

In the group of from age 10 to 50, at age 40, for pa-

those who were dead at the conclusion of this study. The average age of onset was 31 for the patients who lived and 40 for those who died. Below the age of 40, a higher percent were living, and after the age of 40, a higher percent were dead. SYMPTOMS Figure 4 shows the mode of onset of idiopathic cardiomyopathy for the 115 patients in this study, and compares these initial features in the 2 groups of patients, those who lived, and those who died. The disease often began insidiously without known precipitating factors. An abnormal ECG or unexplained cardiomegaly was commonly the first evidence of disease in asymptomatic individuals. Initial symptoms were usually due to congestive heart failure or arrhythmia. Left-sided congestive heart failure was more frequent than right-sided failure. The most common arrhythmias were premature ventricular contractions and atria1 fibrillation. Occasionally, either systemic or pulmonary emboli were the first indication of disease. Less common presenting symptoms were syncope (usually related to arrhythmias) or chest pain, sometimes suggesting coronary insufficiency. Although chest discomfort may follow effort, suggesting coronary insufficiency, it can differ by lasting longer (hours instead of minutes) and/or not responding to nitroglycerin. Congestive heart failure, emboli, syncope and chest pain were more common among patients who died than among those who lived. Cardiomegaly or an electrocardiographic abnormality Fig 4.-Initial features of idiopathic cardiomyopathy. Congestive heart failure occurred at the onset (within 1 year) in 35% of those who lived and over 70% of those who died. Arrhythmias occurred at the onset of 55% of those who lived and 38% of those who died. Less frequent initial features were emboli, chest pain, syncope and infection. 80

m

70

q

Living t 38 Patients I Dead I77 Patients I

60

Congestive Failure

Arrhythmia

Fmboll

Chest Paln Symptoms

14

Other

Infection

was a more common initial those who died.

finding among survivors

than among

b FRANK I. MARCUS: During the past 2 years I have seen 2 patients whose first manifestations of cardiomyopathy were cerebral emboli. One patient had a history of heavy alcoholic intake and was in atria1 fibrillation. The other patient had idiopathic cardiomyopathy. He did not have an alcoholic history and he was not in atria1 fibrillation. He had repeated systemic emboli despite adequate anticoagulation with warfarin. Autopsy showed clots in the left ventricle, and histology showed diffuse myocardial fibrosis. Both patients were below the age of 55. Thus my index of suspicion has been heightened to search for emboli in middle-aged patients who present with cerebrovascular accidents. --.____

PHYSICAL

EXAMINATION

Figure 5 shows the initial physical findings. Blood pressure was usually normal, but a few patients with advanced decompensation had lowered systohc pressure. However, in some, blood pressure was initially elevated during congestive heart failure, returning to normal with compensation. Asymptomatic patients commonly had an abnormally displaced and sustained Fig C.-Initial physical findings for 115 idiopathic cardiomyopathy patisnts. At the onset of the disease, signs of left ventricular dysfunction such as ventricular gallop (third heart sound) atrial gallop (fourth heart sound), left ventricular lift and mitral insufficiency were common. Evidence of right ventricular disease or failure was less common initially but appeared later in the course of the disease. 50

r

r

Atria1 Gallop

t.v. Lift

R.V. ill,

Mitral l~rufftiency

Tricuspid Insufficiency

VOBOUS Dirtcntion

nevatomegaly

Edema

Fig &-Data on a 24-year-old woman with 2-year history of progressive congestive heart failure, cardiomegaly and frequent multifocal premature ventricular beats. A systolic murmur was present at the apex, and both atrial and ventricular diastolic gallops were heard. The patient died suddenly, and autopsy revealed diffuse and extensive myocardial fibrosis and cardiac dilatation. (From Segal, J. P., Harvey, W. P., and Stapleton, J. F.: Clinical Features and Natural History of Cardiomyopathy, in Fowler, N. 0. (ed.): Myocardial Disease (New York: Grune &Stratton, Inc.. 1973). Used by permission.)

apical systolic impulse when examined in the supine position. A presystolic apical impulse also was detected frequently. The jugular venous pressure was normal until significant decompensation had occurred; at times jugular venous distention was accompanied by the systolic pulsation of functional tricuspid regurgitation. Pulsus alternans and ventricular (third heart sound) gallop rhythm also were consistent findings in patients with cardiac decompensation. Fifty percent of patients had atria1 and/or ventricular gallop sounds at the onset of illness; almost all patients had gallop rhythm at some time during the 16

course. In fact, gallop rhythm is a “hallmark” of these patients and occurs in the majority. The second heart sound (S,) was often accentuated over the pulmonic area, due to cardiac decompensation and pulmonary hypertension. Paradoxical splitting of the S, was heard with left bundle branch block. Those with right bundle branch block had wide splitting of the S, sound. Twenty percent of our patients had holosystolic murmurs due to the the mitral incompetence of left ventricular dilatation. Signs of left ventricular failure occur earlier and more frequently than signs of right-sided congestive failure. A left ventricular precordial impulse was a frequent finding, indicating predominant left-sided involvement, and was more common than a right ventricular parasternal lift. In comparing the initial physical findings for the 2 groups of patients, it is not surprising that a persistent ventricular diastolic gallop and signs of right ventricular failure were more common in the group of patients who died than in the group of those who survived. Typical data are shown in Figure 6. This 24-year-old woman had a 2-year history of slowly progressive congestive heart failure, cardiomegaly and frequent ventricular premature beats. Both atria1 and ventricular diastolic gallops and an apical systolic murmur were present. In spite of all therapy including bed rest, digitalis, diuretics and antiarrhythmics, she remained in advanced cardiac decompensation and died suddenly. Autopsy revealed cardiac enlargement, left ventricular hypertrophy and diffuse myocardial fibrosis. ELECTROCARDIOGRAPHIC FINDINGS-

INITIAL (FIG 7, A AND B)

Only 3 of 115 patients with idiopathic congestive cardiomyopathy had a normal ECG. The most common abnormality consistFig ‘I.-initial electrocardiographic findings in idiopathic cardiomyopathy patients. A, premature ventricular contractions occurred in 35% of the group who lived and 40% of the group who died during the lstyearof their illness. Atrial fibrillation was relatively common. ST-T wave changes were present in almost 20%, frequently associated with left ventricular hypertrophy. 6, although lstdegree heart block occurred in about lo%, 2d- and Bd-degree blocks were uncommon. Left bundle branch block occurred in 10% of the group who lived and 15% of the group who died. and left axis deviation without left bundle branch block was present in 12% of the group who died. Right bundle branch block and right axis deviation occurred infrequently

ed of ventricular extrasystoles. Next in frequency was atria1 fibrillation. Left bundle branch block and/or left axis deviation were common, whereas right bundle branch block and/or right axis deviation were unusual. Left ventricular hypertrophy with or without ST-T changes occurred in about 35% of the patients. Four percent of the individuals who died had the pattern of myocardial infarction. Ten percent of all patients had first-degree atrioventricular block. A comparison of those who died with those who survived reveals no significant difference in electrocardiographic features except for a higher incidence of myocardial infarction patterns, left axis deviation and ventricular tachycardia among those who died. report Loogen and Kuhn confirmed the high incidence of left bundle branch block in patients with congestive cardiomyopathy. Forty percent of 80 patients had this finding. Of particular interest was the observation that 9 of these patients with typical left bundle branch block at the onset of symptoms had prior ECGs that showed that left bundle branch block was present previously. In one patient the ECG showed left bundle branch block 22 years before the onset of clinical symptoms. This observation, if confirmed, suggests that patients who have left bundle branch block, and who have no other evidence of disease, may have a cardiomyopathy which is in the latent phase. These patients may develop the clinical symptoms later. (Loogen, F., and Kuhn, H., in Myocardial Failure. (Berlin, Springer-Verlag 1977), p. 232.) b FRANK I. MARCUS: In a recent

) Abnormal P waves indicative of left atria1 enlargement or biatrial enlargement may be found in up to one third of patients with idiopathic myocardial disease. McMartin and Flowers observed that these

findings were present more frequently in patients with mitral regurgitation than in those without it. They performed cardiac catheterization in 30 patients with idiopathic myocardial disease and found that 73% had an increase in mean PA pressure, 80% had an ejection fraction less than 30%, and 87% had an ejection of less than 50%. Mitral regurgitation was present in 37%. Most patients with idiopathic myocardial disease have a decreased ejection-fraction. (McMartin, D. E., and Flowers, N, C.: Clinical-electrocardiographic correlations in diseases ofthe myocardium, Cardiovasc. Clin. 3:191, 1977.) CHEST

X-RAY

Chest x-ray films were reviewed by a cardiologist and a radiologist, and heart size was graded as follows: 0, normal; I+, minimal enlargement; 2+, mild enlargement; 3+, moderate enlargement; and 4+, marked enlargement. A comparison of the initial heart size in the 2 groups reveals that only 31% of the group who lived had 2+ or greater cardiac enlargement (Fig 8). Of those,who lived, 34% had no initial cardiac enlargement, whereas only 5% those who died had no initial cardiac enlargement. 18

ILiving

138 Patients)

Ezi Dead I65 Patbents I

No Enlargement

I+

2s

Enlarqement

fnlargement

3+ Enlargement

4+ Enlargement

Size

Heart

Fig K-Comparison of initial heart size of idiopathic cardiomyopathy patients. Significant cardiac enlargement was characteristic of the group who died. Initially, 34% of the group who lived had no cardiac enlargement, but only 5% of the group who died had no cardiac enlargement. Fig Q.-Comparison of important clinical patients who died. As anticipated, signs of significantly more common among patients onset of the disease and during the entire tients who died had congestive heart failure, lar beats and mitral insufficiency. Cardiomegaly 50%. The common occurrence of left bundle emboli is again emphasized

60

50

Living - % 40 30 20 10

features, patients who lived versus advanced myocardial disease were who died. This was true both at the clinical course. The majority of pagallop rhythm, premature ventricuof 3 or 4+ was present in almost branch block, atrial fibrillation and

CLINICAL FEATURES 0

0 Congestive

Failure

Ventricular

Gallop

10

20

30

Dead - Ri 40 50 60

70

80

90

PVC’S Mitral

Insufficiency

31 or 4+ Cardiomegaly Lee!! Atrlal

Fib~~llall~n illb”,,

Anytime

During

IlInes:

19

CLINICAL

COURSE

Figure 9 compares the important clinical features of the 2 groups. Each bar represents the incidence of a specific feature present at the onset and during the entire course of the disease. For example, in the group of patients who died, congestive heart failure was present at the onset in 72%, and at some time during the clinical course in 89%. In the group of patients who lived, congestive failure was present in 35% initially and at some time in the clinical course in 38%. Similar comparisons are made for ventricular gallop, mitral insufficiency, atria1 fibrillation, left bundle branch block, premature ventricular contractions and 3 or 4+ cardiomegaly. Not surprisingly, these features were more common, both during the initial phase of the disease and during its course, among those who eventually died. As one would expect, congestive heart failures and arrhythmias were more common among those who died by the end of the study. HEART

SIZE

Figure 10 charts the change in heart size of those who lived and of those who died. It is at once apparent that the heart size of many surviving patients decreased or remained stable over the years. In contrast, none of the patients who died had a decrease in heart size. In the surviving group, heart size decreased in 5, remained the same in 19 and increased in 11. In the group who died, heart size increased in 20 and remained the same in 27 (including 5 who had 4+ cardiomegaly at initial presentationl. ELECTROCARDIOGRAPHIC

FINDINGS

The progression of the initial electrocardiographic findings (see Fig 7, A and B) are tabulated for the 38 patients who lived and the 77 who died (Table 3). The initial and total percentages are recorded for each feature. Premature ventricular contractions, atria1 fibrillation and left bundle branch block were more common among those who died. The pattern compatible with anterior- myocardial infarction was uncommon but occurred more frequently among those who died. Left bundle branch block occurred in 13% of those who lived and 39% of those who died. The incidence of left bundle branch block did not correlate with cardiomegaly. Of 29 patients with left bundle branch block who died, 2 had no cardiomegaly , 8 had 1 + ,9 had 2+, 5 had 3+ and 5 had 4+ cardiac enlargement. This distribution of heart size did not differ significantly from those without left bundle branch block. Right bundle branch block was present in none of 20

Fig lo.-Heart size change 1st year (onset), the average who lived. In most, the heart the heart size often increased decrease. TABLE

in idiopathic cardiomyopathy heart size was significantly size decreased or remained in those who died, and

3. -PROGRESSION OF IDIOPATHIC

patients. Within the smaller in the group the same; in contrast, in no instance did it

ELECTROCARDIOGRAPHIC CARDIOMYOPATHY

FINDINGS-

:i* PATIENTS WHO LlYED _ ,srr:41 ‘Z KmAI. o/r Myocardial infarct pattern Ventricular tachycardia Premature ventricular contractions Atria1 fibrillation Left ventricular hypertrophy and strain Left ventricular hypertrophy ST-T changes First-degree atrioventricular block Second-degree atrioventricular block Third-degree atrioventricular block Right bundle branch block Left bundle branch block Right axis deviation Left axis deviation

0 3 34 16 13 -: I! ri ,l 0 1:; 0 t.)

3 5 50 26 18 16 18 13 5 3 0 13 0 11

7: PATIENTG WHO DIED ..---.-INlTlAL c/c TOTAL ‘r, 4 8 40 21 11 11

13 12 0 1 1 15 3 13

8 14 69 30 13 20 23 21 0 3 5 39 4 27 21

Living (38 patients) Onset

Dead 162 patients) -Final

o”retnFi”a’

Fig Il.-Change in functional class-idiopathic cardiomyopathy. The functional class was better initially in those who lived. The functional class improved in 37% of those who lived and in none of those who died. Deterioration occurred in 21% of those who lived and in 63% of those who died.

the group who lived and in only 5% of the group who died. Left axis deviation was more frequent than right axis deviation. Figure 11 records the changes in functional status of the patient groups classified according to the criteria of the New York State Heart Association. The functional status at onset did not improve in any patients who died, but did improve in 14 of the 38 patients who lived, in some instances by 2 grades. Functional status deteriorated in 8 of 38 patients (21%) who lived, whereas it worsened in 39 of 62 patients who died (63%). Poor initial cardiac function or deterioration of functional therefore, poor prognostic signs. Conversely,

functional nosis. MITRAL

classification

commonly

indicates

classification

are,

improvement in a favorable prog-

INSUFFICIENCY

The murmur of mitral insufficiency was common, and usually intensified as heart size increased further. The average murmur loudness of patients with 2+ cardiac enlargement was grade 2 (based on 6 grades), while that of patients with 3+ cardiomegaly was closer to grade 3, and that of patients with 4+ enlargement was grade 3 or louder. Most of the surviving patients had grade 22

1 or grade 2 murmurs, while among those who died grade 3 and grade 4 murmurs were commonplace, particularly with larger hearts. A decrease in heart size often led to decreased murmur intensity. Cardiac enlargement was also related to atria1 fibrillation in that all patients who died with atria1 fibrillation had cardiomegaly; 21% were fibrillating at the onset of their illness, The frequency of left bundle branch block, premature ventricular contraction, atria1 fibrillation and heart size were correlated. Of 29 patients with left bundle branch block who died, 19 (66%) had premature ventricular contractions, of whom 6 had multifocal extrasystoles. Thus, premature ventricular contractions are no more common in patients with left bundle branch block than in the entire group who died. As previously noted, 21% of the group who died had atria1 fibrillation during the initial phase of their illness and had some degree of cardiac enlargement. EMBOLI

Eighteen percent of the surviving patients and 22% of those who died had either arterial or pulmonary emboli diagnosed on clinical grounds or autopsy. As noted in Figure 12, by clinical Fig 12.-Embolic episodes in rdropathic cardiomyopathy patients. Either arterial or pulmonary emboli were found at autopsy in 22% of those who died and clinically in 18% of the living. In the group who lived, 71% of the emboli were arterial and 29%. pulmonary; in the group who died 90% were arterial and 10% pulmonary. All patients had congestive heart failure and the majority had premature ventricular contractions. The incidence of 3 and 4+ cardiac enlargement and arterial fibrillation was increased in those with emboli 100 -

Living fzi3a patients] Dead 121177 patients)

80 -

Arterial I’nbUii

PVC’S

31 or 4+ Catdlac i ~iargement

Atrial fib.

Mural Thrombi

23

NO.

fibrillation. in 3 patients

*Atrial TX-ray available.

0

27 not

2

11

Totals Atria1 fibrillation Without atria1 fibrillation 2

3

0 0 1 1 2

4t

1"

0 2 2 0 5

0

SYSTEMI(‘

9

PlKMONARY

LIVED

EMBOLl

11 9 8 1 38

OF

WHO

SYSTEMlC

0

0

0 0 0 0 0

wLM,^"

*ND

OF ARTERIAL FIBRILLATION

1+ 2+ 31

PATIENTS

PATIENTS

4. -CORRELATION ATRIAL

0

SIZE

HEART

TABLE

_

AND AND

NO.

52

22

3 7 18 27 19 74:

PATlENTS

--

OF P”LMONAKI

PULMONARY HEART SIZE

2

3

0 0 0 4 1 5

PATIENTS

__---

EMBOLl

SYSTEM,,‘

WHO

EMBOLI

6

3

1 0 3 2 3 9

(AUTOPSY1

DIED

WITH

1

1

0 0 0 1 1 2

SYSTEMIC

PULXONABY AND

diagnosis, 90% of emboli of patients who died were arterial, and 10% were pulmonary. Among the patients who died, 100% who suffered emboli had congestive heart failure compared with 72% of all of those who died; 43% of those with emboli had advanced cardiac enlargement (3+ to 4+) compared with 18% in the entire group who died; 63% had premature ventricular contractions and 33% atrial fibrillation (approximately the same frequency as in the entire group who died). In Table 4 heart size and atria1 fibrillation are correlated with the frequency of emboli. Of all patients from both groups with no or lf cardiac enlargement, 2 of 12 had systemic emboli (17%). With 2+, 3+ or 4+ cardiac enlargement, 21 of our 82 patients (26%) had emboli: 12 systemic, 7 pulmonary, and 2 both pulmonary and systemic. Of the 33 patients from both groups with atrial fibrillation, 12 (36%) had emboli: 6 systemic, 5 pulmonary and 1 both pulmonary and systemic. This contrasts with a 14% frequency of emboli in 80 patients without atria1 fibrillation. Of the arterial emboli, almost 50% went to the brain. Congestive heart failure, marked cardiac enlargement and atria1 fibrillation occurred, therefore, more common2.y among those who had emboli.

Of the patients who underwent autopsy, 40% had pathologically verified pulmonary emboli, only 10% of which were diagnosed clinically, confirming again the observation that pulmonary emboli are frequently overlooked during life. PROGNOSIS

AND

CLINICAL

CORRELATIONS

Figure 13 graphically illustrates how various unfavorable prognostic factors influence survival. Advanced cardiomegaly is the most ominous sign. Other findings of grave significance include poor functional status (New York Heart Association classification), atria1 fibrillation frequent or multifocal premature ventricular contractions or ventricular tachycardia. Infrequent, unifocal premature ventricular contractions had no prognostic significance. Of all patients who died by the end of the study, 50% died within 6 years. But of those with 4+ cardiac enlargement, 50% died within 2 years. Those who had ventricular tachycardia died within 3 years (Fig 14). Figure 15 illustrates the relationship of mortality to heart size. The Syear-survival rate ranges from only 11% for patients with 4% cardiac enlargement to 89% for those with 1+ enlargement. As previously mentioned, arrhythmias are important prognostic indicators. As illustrated in Figure 16, atria1 fibrillation is associated with a &year-survival rate of 40% and complex premature ventricular contractions with a 5-year-survival rate of 25

6

Age

Under 40

Total Croup

LBEB

Age

Over 40

Complex Pv c I

functtonsl Class ln or

Ventr~rular TlCh

AtrIal Fib

3+ an* 4+ Cardiomqaly

m

Fig 13.-Survival time of Idiopathic cardiomyopathy patients correlated various factors, Poor survival is associated with 3 or 4+ cardiomegaly, fibrillation, ventricular tachycardia and functional class 3 or 4.

with atrial

Fig 14.-Effect of onset of ventricular tachycardia and 4+ cardiac enlargement on survival time. Fifty percent of patients with 4+ cardiac enlargement are dead within 2 years, and 50% of those with an episode of ventricular tachycardia are dead within 3 years.

20 -

0

e+ Y -

Onset

Total group Ventricular Tachycardia 4+ Cardiac Enlargement I I I 2 3 1 Survival-Years

26

I 4

I 5

80 .-F

2 J

v) z 2 -z a

2+ 60

40

z 2s 20

0

**Total D--O o-u -

Onset

groua Enlargement Enlargement Enlargement Enlargement

No 1+ 2+ 3+

1

3+

4+

?

3

4

5

Survival-Years

Fig 15.-Effect of initial heart size on survival. Patients with 4+ cardiac enlargement had a poor survival rate. The 5-year-survival rate ranges from 11% in those with 4+ cardiac enlargement to 89% in those with 1+ enlargement. Fig 16.-Effect of atrial fibrillation and premature ventricular contractions on survival. Simple premature ventricular contractions do not affect survival. The 5-year survival rate for the entire group is 65% compared to 54% in those with complex oremature ventricular contractions and 40% in those with atrial fibrillation

80

60

*-OTTotat Atrial w

Simple

group fib. PVC’s

(living and dead) (any time during (any

time

during

illness) illness)

Survival-Years

27

Sudden Death

Fig 17.-Rate of deaths from the various Congestive failure was the primary cause 29% of the cases.

causes of idiopathic cardiomyopathy. of death in 48% and sudden death

54%. On the other hand, 70% of patients with simple premature ventricular contractions were alive after 5 years. This compares with 5-year-survival rate of 65% for all patients. The frequency of extrasystoles was probably underestimated, since Holter monitoring was not performed (this procedure was not utilized until recent years), and the type and frequency of premature Fig l&-Comparison of various factors in patients who died suddenly versus all patients who died. Significant cardiac enlargement and an episode of ventricular tachycardia occurred more commonly in those who died suddenly. There was no correlation of sudden death with the presence of congestive heart failure, premature ventricular contractions, left bundle branch block, atrial fibrillation or emboli. m

Total Group (Dead Patients)

q

Pattents

V-tach

28

With Sudden Death

3+ or 4* Cardiac Enlargement

LBBB

Atria! Fibrillation

in

Fig 18B.-Heart in a patient with idiopathic dilated cardiomyopathy. A, both atria are dilated. B, opened left exterior of heart. Both ventricles an ventricle and aorta. A large thrombus is present in the apical portion of left ventricle. C, opened left atrium and left ventricle. D, opened right atrium and right ventricle showing thrombus in both chambers. (Courtesy of Dr. William Roberts.)

ventricular contractions were determined by standard 12-lead ECGs and clinical assessment. Figure 17 shows the proportions of deaths from the various causes. Congestive heart failure was the cause of death in 48%, while arrhythmias caused death in 10% and embolic episodes in 3%. In 29%, the deaths were sudden. Arrhythmic deaths were defined as those due to an arrhythmia that was documented by electrocardiography at the time the death occurred. Many had concurrent congestive heart failure. Sudden deaths were instantaneous and unobserved (usually not in a hospital) and presumably due to arrhythmia. In 10% of the patients, death was due to unrelated causes. Features associated with sudden death are tabulated in Figure 18. Only 3+ and 4+ cardiomegaly (590/o) and ventricular tachycardia (1890) were significantly more common among those who died suddenly than arn,on,Af the entire group of patients who 29

died. In the total

group who died, ventricular tachycardia occurred in 10% and 3+ and 4+ cardiomegaly in 18%. Among those who died, 17 complained of chest discomfort during some part of their illness, in some instances suggestive of coronary insufficiency. (Significant coronary atherosclerosis was excluded in all cases by coronary arteriography at autopsy). Only one of these had the electrocardiographic pattern of myocardial infarction, and this patient had normal coronary arteries at autopsy. Of the 17, 88% had congestive heart failure and 35% arrhythmias. The degree of cardiomegaly in patients with chest pain was no greater than those without chest pain. However, left ventricular hypertrophy was twice as frequent in those who suffered chest pain.

CLINICAL-PATHOLOGIC

CORRELATION

Of the 77 patients who died, 48 were autopsied. Table 5 summarizes the pathologic findings of these 48 autopsied patients. Average heart weight was 560 gm, ranging from 200 to 850 gm. Hypertrophy was present in 73%. Fibrosis was present in 76%, being focal in 38% and diffuse in 38%. Acute inflammation was rare (40/o).. but chronic inflammation was found in 23% of patients. MURAL

THROMBI

AND EMBOLI

Mural thrombi were present in 17 autopsied patients (35%) of whom 10 suffered emboli (5 pulmonary, 3 systemic and 2 combined). One of these embolic episodes followed cardioversion. Of the group who died, 21 patients had emboli clinically diagnosed; 90% of these were arterial (50% to the brain). Advanced cardiomegaly was present in 76% of patients who had mural thrombi and in 58% with emboli. All of the 21 patients with emboli had pathologic evidence of congestive failure, including all 8 autopsied patients who had atria1 fibrillation. Approximately a third of patients who died and who had clinically detectable emboli, had mural thrombi at autopsy (Fig 18B). Of those with emboli at autopsy,- 58% had associated mural thrombi. The average heart weight for patients with emboli was 608 gm, compared to 560 gm for patients without emboli. Myocardial fibrosis was found in 76% of autopsies (38% focal, 38% diffuse). However, the incidence of diffuse myocardial fibrosis increased (82%) among those patients with mural thrombi, and was even more common in those with 3-t or 4+ cardiac enlargement. b

FRANK

30

At autopsy the hearts of patients with idiopathic are always increased in weight. This is consistent with

I. MARCUS:

cardiomyopathy

White. White, Black, Black, Totals 57

male female male female

TABLE

20 12 7 9 48

:i, OF i’AliL.vlt

5

588 411 700 542 560

M>Al 200 200 500 430200

- 800 - 820 - 850 700 - 850

ILANGe 16 5 7 7 35 73

8 3 2 5 18 38

7 i 3 18 38

F‘RROSIS A.. illFPUBF

I %)(‘*I.

CARDIOMYOPATHY

HYI’EHTKOI’HI’

-IDIOPATHIC

,II;XKI ‘i.lil(i,FT tgmi

PATHOLOGY

1 0 1 0 2 4

*CUTE

4 3 1 3 11 23

CHRLNIC

INFLAYMAT,OK

148 PATIENTS)

6 3 5 3 17 35

ML HA,. IHHU,IIH:

the hypothesis that left ventricular hypertrophy is an invariable concomitant of dilatation. The left ventricular free wall thickness and ventricular septum, however, always measure less than 1.5 cm. (Roberts, W. C.: Cardiomyopathy and myocarditis - morphological features, Adv. Cardiol. 22:184,197&L) ____PATHOLOGIC-ELECTROCARDIOGRAPHIC

CORRELATION

Table 6 presents electrocardiographic-pathologic correlations. Of autopsied patients, 76% had focal or diffuse myocardial fibrosis. This figure was approximately the same for those with premature ventricular contractions, ventricular tachycardia, left ventricular hypertrophy with or without strain and nonspecific ST-T changes. However, myocardial fibrosis was present in 96% of patients with atria1 fibrillation and 94% of those with left bundle branch block (as compared to 65% of those without left bundle branch block). The average heart weight was increased in patients with electrocardiographic left ventricular hypertrophy, left bundle branch block, left axis deviation and ST-T changes. Left ventricular wall thickness was increased in the group of patients with electrocardiographic left ventricular hypertrophy or left bundle branch block or atria1 fibrillation. The average heart weight of patients with electrocardiographic left ventricular hypertrophy was 634 gm compared to 478 gm in those without electrocardiographic evidence of left ventricular hypertrophy. In 4 cases there was electrocardiographic evidence of anterior myocardial infarction; at autopsy there was no evidence for infarction, and the coronary arteries were normal. For these 4 patients, the average heart weight was 502 gm and all had left ventricular hypertrophy; 2 had diffuse myocardial fibrosis. DIFFERENTIAL

DIAGNOSIS

Idiopathic cardiomyopathy heart disease. It is commonly agnosed. It can be especially emit heart disease. ARTERIOSCLEROTIC

HEART

frequently mimics other types of overlooked, and commonly misdidifficult to distinguish from isch-

DISEASE

Confusion of idiopathic cardiomyopathy with ischemic heart disease commonly occurs, particularly in men between the ages of 30 and 50. Table 7 summarizes features that may help to differentiate congestive cardiomyopathy from ischemic heart disease. Coronary risk factors, especially in men over 40, strongly support the diagnosis of ischemic heart disease. The physician 32

560 565 690 634 627 645 630 600 300x 565 564 502 484 613

14 16 17 10 12 2 7 13 4 15 29

.A”ERACE HRAHT WEIGH7 (gml

OF ECG IDIOPATHIC

48 33 7

NO. OF PATlENTS

6. --CORRELATION

60 52

71 75 24 30 42 100 100 69 100

73 52 57

1IYI’~NTK”PNY (91

AUTOPSY

27 38

‘7 ;0 35 39 42 0 29 46 0

38 30 29

40 38

21 44 41 40 50 100 71 46 50

38 46 57

Fl-dR”SlS rsi ~~___ FOCAL DIFFUSE

FEATURES WITH CARDIOMYOPATHY

FINDINGS

27 41

14 0 0 0 8 0 0 15 0

4 6 0

7 3

50 38 41 70 50 50 29 38 25

35 42 43

MURAL YHKOM”! (%I

LVH = left ventricular = atrioventricular block;

33 17

29 25 18 10 8 0 29 15 0

23 21 29

lNFLAMMATlON cvrt ---ACUTE CHRONIC

PVCs = premature ventricular contractions; Vent. tach. = ventricular tachycardia; hypertrophy; LBBB = left bundle branch block; LAD = left axis deviation; AVB PACs = premature atria1 contractions; Atria1 fib. = atria1 fibrillation. *One child, age 5.

Total group PVCS Vent. tach. LVH and strain or LVH LBBB ST-T changes LAD First-degree AVB Third-degree AVB PACs Atria1 fib. Myocardial infarction Heart size 0, 1 and 2t 3 and 4+

TABLE

commonly sees a male patient without angina pectoris, over age 40, who has unexplained cardiac enlargement, signs of congestive failure or an electrocardiographic abnormality such as left bundle branch block. In this clinical situation, the presence of any coronary risk factor supports the diagnosis of ischemic heart disease. A normal or slightly enlarged heart would favor the diagnosis of ischemic heart disease. Differentiation is further complicated by the fact that some patients with ischemic heart disease do not have chest pain, while some patients with idiopathic cardiomyopathy can have chest discomfort resembling that of coronary insufficiency. Chest discomfort in cardiomyopathy is more likely to occur in those with moderate or marked cardiac enlargement and congestive heart failure; it usually lasts longer than the pain of typical angina pectoris, and significant relief with nitroglycerin is less common. In contrast, angina pectoris commonly occurs in patients with normal-sized hearts, with or without cardiac decompensation, and usually responds promptly to nitroglycerin. Some patients with cardiomyopathy may have Q-waves on their ECG, suggesting old myocardial infarction, usually anterior. Usually this occurs with extensive myocardial fibrosis and cardiac hypertrophy. The diagnosis of cardiomyopathy is supported by factors such as: young age, female sex, the presence of left bundle TABLE 7. -FEATURES BETWEEN IDIOPATHIC ARTERIOSCLEROTIC

DIFFERENTIATING CARDIOMYOPATHY HEART DISEASE

ARTERlOSCl.EROTIC HEART DlSEASE

FEATURE

Age

Sex Angina pectoris Angina pectoris without congestive heart failure Electrocardiographic - _ infarction pattern Infarction pattern with normal or slightly enlarged heart Elevation of blood sugar, cholesterol and blood pressure and clinical gout

Equal Occasional Rare

Over 40 Men predominate Common Common

Occasional

Common

Rare

Common

Unusual

Common

Any

From Segal, J. P., Harvey, W. P., Clinical Features and Natural History in Fowler, N. 0. (ed.1: Myocardial Grune & Stratton, Inc., 1973). Used by 34

AND

and Stapleton, J. F.: of Cardiomyopathy, Disease (New York: permission.

Fig lg.-Data on a cardiomyopathy patient with a misdiagnosis of ischemic heart disease, a 38-year-old man with no chest discomfort. Note the left ventricular hypertrophy, left bundle branch block and premature ventricular extrasvstoles. Postmortem examination showed normal coronary arteries, althouoh previous coronary arteriogram reportedly showed coronary artery disease. (From Seaal, J. P., Harvev. W. P., and Stapleton, J. F.: Clinical Features and Natural Hktory of Cardiomyopathy. in Fowier, N. 0. (ed.): Myocardial Disease (New York: Grune - Stratton. Inc.. 1973). Used by permission.)

branch block, the absence of coronary risk factors, the absence of coronary insufficiency type of chest discomfort and the absence of a significant electrocardiographic Q deflection. The echocardiogram of cardiomyopathy usually indicates diffuse left ventricular dysfunction; the echocardiogram of ischemic heart disease commonly displays a localized segmental defect or aneurysm of the left ventricle. Radioisotopic techniques, such as thallium scanning, may also similarly differentiate the diffuse nature of cardiomyopathy from the localized abnormalities of ischemic heart disease. Rarely, however, cardiomyopathy may be associated with a segmental rather than a diffuse myocardial defect, and cardiac catheterization and coronary angiography are necessary to establish this differential diagnosis. Figure 19 shows data on a patient referred for evaluation with a diagnosis of ischemit heart disease based on misinterpreted clinical coronary angiographic findings, disproved at autopsy. Clinical features of cardiomyopathy such as left bundle branch block, premature ventricular extrasystoles, and the absence of chest pain suggested the diagnosis of cardiomyopathy. 35

ASYMMETRIC SEPTAL HYPERTROPHY

Asymmetric septal hypertrophy may resemble idiopathic cardiomyopathy. Obstructive asymmetric septal hypertrophy (ASH) commonly presents as a quickly rising arterial pulse, a prominent fourth heart sound, a systolic murmur at the lower left sternal border and apex that diminishes with squatting, and occasionally, as abnormal electrocardiographic Q deflections. In nonobstructive ASH, the murmur may be absent. Echocardiography and isotope myocardial scanning can be used to identify asymmetric septal hypertrophy before typical clinical findings have developed. MITRAL VALVE PROLAPSE (BARLOW’S SYNDROME, CLICKMURMUR SYNDROME, FLOPPY-VALVE SYNDROME)

Usually diagnosed by using a stethoscope and by making a total clinical examination, this syndrome is characterized by a midsystolic click or clicks and, usually, a late systolic murmur at the apex. It is oRen associated with chest discomfort, extrasystoles and electrocardiographic T-wave changes. Echocardiography usually confirms the diagnosis. The apical systolic murmur and frequent premature ventricular extrasystoles may suggest a diagnosis of myocarditis or cardiomyopathy. In fact, the premature ventricular beats were first observed in a few patients after upper respiratory viral infection, and the diagnosis of myocarditis was made with resulting treatment that included rest for several months. Chest deformity, such as pectus excavatum, “straightback,” may be misdiagnosed as cardiac enlargement in some patients, particularly if a lateral x-ray film is not reviewed, Since the prolapsing mitral-valve-leaflet syndrome commonly occurs in patients with chest wall abnormalities, further confusion may result. Shortness of breath and hyperventilation may be present in some patients with this syndrome and suggest congestive failure. However, unless such complications as rupture of a chordae tendineae occur, resulting in severe mitral insufficiency with cardiac decompensation, ventricular gallop, pulsus alternans, true cardiomegaly and congestive failure do not occur in isolated mitral valve prolapse. CONGENITAL HEART DISEASE

Although idiopathic cardiomyopathy usually involves the left ventricle, some patients have right ventricular hypertrophy with isolated right heart failure. The findings in these cases can simulate atria1 septal defect, particularly if the congenital defect has atypical features. This occurred in a patient referred to our 36

Fig 20.-Data on a 17-year-old boy referred for cardiomyopathy but who proved to have an atrial septal defect. Note the atrial and ventricular diastolic gallops and right interventricular conduction defect. A pulmonic ejection systolic murmur was heard. (From Segal, J. P., Harvey, W. P., and Stapleton, J. F.: Clinical Features and Natural History of Cardiomyopathy, in Fowler, N. 0. (ed.): Myocardial Disease (New York: Grune & Stratton. Inc.. 1973). Used by permission.)

clinic. His grade II, short, pulmonic ejection murmur and normal chest x-ray (Fig 20) were diagnosed as cardiomyopathy. However, the ECG revealed incomplete right bundle branch block, a pattern not usually associated with cardiomyopathy. This finding prompted us to perform a cardiac catheterization, thus discovering an atria1 septal defect. Another patient in our clinic had been seen over a number of years with the diagnosis of alcoholic cardiomyopathy. However, he subsequently had right heart catheterization and an atria1 septal defect was detected. Patients with congestive cardiomyopathy seldom have right axis deviation or right intraventricular conduction defects; these findings should alert the physician to consider another possible diagnosis. RHEUMATIC

HEART

DISEASE

Long-standing calcific mitral stenoses lead, although uncommonly, to valve immobility with loss of the characteristic loud first heart sound and opening snap. Occasionally, when cardiac output is depressed and pulmonary hypertension is severe, the typical diastolic rumble is absent. These instances of severe but 37

Fig 21.-Data on a 59-year-old man initially thought to have cardiomyopathy but proved to have tight mitral stenosis. Note right ventricular hypertrophy, cardiac enlargement and significant mitral diastolic pressure gradient (shaded area). (From Segal, J. P., Harvey, W. P., and Stapleton, J. F.: Clinical Features and Natural History of Cardiomyopathy, in Fowler, N. 0. (ed.): Myocardial Disease (New York: Grune 8 Stratton. Inc 1973). Used by permission.)

“silent” mitral stenosis can be mistaken for cardiomyopathy. The apical diastolic rumble of mitral stenosis is often subtle, requiring careful listening over the apical impulse with the patient in the left lateral position. Figure 21 presents data on a patient with tight mitral stenosis in whom neither an opening snap nor an apical diastolic murmur were detected. The ECG presented broad notched P-waves, right axis deviation and right ventricular hypertrophy. Not common features of cardiomyopathy, they suggested the possibility of mitral stenosis, and this was confirmed by left heart catheterization. Careful search for roentgenographic evidence of mitral calcification can be helpful in such cases. Rheumatic valvular disease also may be simulated when ventricular dilatation and papillary muscle dysfunction causes mitral and tricuspid regurgitation. An apical holosystolic murmur, grade 3 and occasionally grade 4 (grading on basis of l-61, on initial examination may suggest rheumatic regurgitation. In addition, the occurrence of emboli, particularly in association with atria1 fibrillation, may further increase the resemblance of cardiomyopathy to rheumatic mitral valve disease. Effective therapy, by reducing heart size, can promptly diminish or eliminate these murmurs. 38

w FRANK I. MARCUS: I, too, have been impressed that an occasional patient with idiopathic myocardial disease may present with severe mitral regurgitation that suggests a rheumatic etiology. One clue to the differential diagnosis is that patients with idiopathic myocardial disease do not have aortic valve involvement. The differential diagnosis may be clarified by cardiac catheterization since patients with idiopathic myocardial disease and mitral regurgitation invariably have poor left ventricular function, but this does not necessarily exclude a rheumatic etiology.

PULMONARY

HYPERTENSION

Figure 22 shows data on a patient with congestive cardiomyopathy and progressive left ventricular failure who then developed pulmonary hypertension over a 4-year period. The later clinical findings were consistent with primary pulmonary hypertension. Had she been seen for the first time at this stage, a diagnosis of primary pulmonary hypertension might well have been made. It is of interest that this patient on initial admission to the hospital had a diastolic rumble caused by both atria1 (fourth heart sound) and ventricular (third heart sound) gallops occurring in close proximity, leading one physician to diagnosis mitral stenosis. Occasionally, cardiomyopathy may be confused with such Fig 22.-Data on a 50-year-old woman with mild left heart failure, atria1 and ventricular gallop sounds and slight cardiac enlargement. Pulmonary hypertension developed within the next 4 years, characterized by dominant right ventricular failure and right ventricular hyper-trophy on the ECG. Note the atrial and ventricular diastolic gallops and cardiac enlargement. (From Segal, J. P.. Harvey, N. P., and Stapleton. J. F.: Clinical Features and Natural History of Cardiomyopathy, in Fowler, N. 0. (ed.): Myocardial Disease (New York: Grune & Stratton, Inc., 1973). Used by permission j

other conditions as infective endocarditis, pneumonia, pulmonary emboli, brain tumor, cerebral thrombosis and even aortic dissection. Pulmonary or systemic emboli commonly complicate congestive cardiomyopathy, producing a confusing clinical picture. Emboli are easily overlooked, and require a high degree of suspicion for diagnosis. Although hydropericardium related to congestive heart failure can occur in advanced cardiomyopathy, echocardiography can usually differentiate between the large dilated heart of cardiomyopathy and pericardial effusion. THERAPY Digitalis toxicity was observed in one of the patients who survived and in 9 (13%) of the 70 who died who were receiving digitalis. Six of the 9 had 3+ or 4+ cardiomegaly, and 8 of the 9 were on diuretics at the time they received digitalis. Those not on diuretics had 2+ cardiomegaly. Thus, it appears that those with more advanced cardiomyopathy, having advanced cardiomegaly, are more sensitive to digitalis preparations and may demonstrate toxicity at lower doses. Control of progressive congestive heart failure and disabling arrhythmias may require prolonged periods of rest, usually for a number of months. Burch et al. have emphasized the importance of early diagnosis and prompt institution of prolonged periods of bed rest.” Patients who improved had a shorter average duration of heart disease before treatment with bed rest was instituted .3, 4 For most individuals, practical considerations necessitated moderate or marked restriction of activities, rather than strict bed rest, Favorable clinical features are: slowing of the heart rate, decrease in heart size, fewer arrhythmias and lessening of congestive heart failure. Steroids were given to 4 surviving patients, 2 of whom appeared to respond. Both had ventricular irritability (ventricular extrasystoles) as the predominant manifestation of their disease. Steroids were administered to 27 who died, one third of whom appeared to have improved, temporarily. Average survival (5.8 years) was approximately the same whether or not steroids were used. In some patients the signs and symptoms of congestive heart failure diminished, heart size decreased and arrhythmias disappeared or were better controlled. The duration of improvement was variable, but usually encompassed several months, at the end of which time progressive deterioration recurred. The initial dose was usually lo- 15 mg of prednisone orally every 4-6 hours. If the patient did not respond within several days, steroids were promptly tapered off and discontinued. However, if the patient did respond favorably, the dose was gradually titrated downward until the lowest dose capable of maintaining a clinical improvement was reached. Those receiving steroids gen40

erally had advanced degrees of cardiomyopathy characterized by serious arrhythmias and congestive heart failure. The responses of these patients cannot be predicted. Autopsies were performed on 20 patients who received steroids. The average heart weight in those responding to steroids (562 gm) did not differ significantly from that of those who did not respond (597 gm). The incidence of fibrosis, inflammation, hypertrophy and mural thrombi was the same in the responders and nonresponders. Of the entire series of 115 patients, 28 (24%) suffered identifiable emboli. The presence of congestive heart failure, 3 and 4+ cardiac enlargement and atria1 fibrillation increased the likelihood of emboli (see Fig 12). Thirty-six percent of patients with atria1 fibrillation and emboli, and 26% with enlarged hearts (2+ to 4+) had emboli. According to our evidence, anticoagulants are indicated for most patients with idiopathic cardiomyopathy, particularly those with atria1 fibrillation, cardiac enlargement and congestive failure, unless there is a specific medical contraindication. b FRANK I. MARCUS: In my personal experience I can recall tients with idiopathic cardiomyopathy who have had beneficial to corticosteroids. As mentioned by the authors, the response is completely unpredictable, but when present can be dramatic.

only 2 paresponses to steroids

DISCUSSION Idiopathic cardiomyopathy is a distinct clinical entity of unknown etiology involving principally the myocardium. Although most previous studies dealing with cardiomyopathy have included patients with secondary types of cardiomyopathy, excessive chronic alcohol intake and pregnancy,4-*2 we have excluded secondary cardiomyopathies, the prolapsing mitral valve syndrome and asymmetric septal hypertrophy in this essay. In several publications since 1964, however, our group at Georgetown University Medical Center has reviewed the clinical features, prognosis, and therapy of cardiomyopathies,13-20 including secondary cardiomyopathies, and long-term follow-up data were not available at that time for analysis. There is general agreement on the clinical features of cardiomyopathy, but the frequency of specific findings may vary according to the etiologic makeup of the group discussed. For example, in a series of 50 patients, 60% of whom were alcoholic, Massumi et al. found edema in 78%.” Hypoproteinemia and other nutritional deficiencies may have contributed to this high frequency of edema. In most series of primary and secondary cardiomyopathies, left bundle branch block occurs in from 10 to 20% of patients.“, 10-lR,21 Stapleton et al. have emphasized the predominance of left bundle branch, left axis deviation and left 41

ventricular conduction disturbances.‘*

disturbances

over right

bundle

branch

b FRANK I. MARCUS: Cardiomyopathy is not limited to the human species. I would like to quote from the summary of an article titled Cardiomyopathy in the Dog by Tilley, and Si-Kwang, (in Roy, P. E., and Rona, G. teds.): Recent Advances in Studies on Cardiac Structure and Metabolism, Vol. 10, The Metabolism of Contraction (Baltimore: University Park Press, 1975), p. 671). “Congestive myopathy was the most common form of the disease, affecting 15 out of 17 dogs. The dogs were predominately large breeds that ranged in age from 2 to 8 years. Clinical findings included right and left congestive heart failure presenting as pulmonary congestion and edema, pleural effusion, hepatomegaly and ascites. Thoracic radiographs showed moderate to severe enlargement of all cardiac chambers and evidence of congestive heart failure. Atria1 fibrillation was the predominant rhythm; ventricular premature contractions and left ventricular hypertrophy were sometimes noted. At necropsy, biventricular dilatation including dilation of atria1 ventricular annular rings and accompanying massive atria1 dilatation was observed. Myocardial contractility was poor and resulted in dilation of the heart chambers with minimal hypertrophic responses. The atrioventricular valve, leaflets and chorda tendineae were usually near normal. Medical treatment included rest, digoxin, and diuretics. Medical or electrical cardioversion of atria1 fibrillation to normal sinus rhythm was also attempted. Prognosis for congestive cardiomyopathy is very poor. The average survival time after onset of signs is 6- 12 months; one dog in our study survived for 20 months.” The authors also mention that the hypertrophic form is rare in dogs. -

Hatle et al. in a series of 106 patients (54% idiopathic) followed from 2 to 12 years noted that 40% of the 50 deaths were due to congestive heart failures; 8 of these patients died suddenly. In agreement with our findings an increased mortality was associated with advanced functional class, significant cardiac enlargement and early onset of congestive heart failure. But, contrary to our findings, left bundle branch block and low voltage on the ECG were also associated with increased mortality. Spodick and Littman found that 65% of patients with idiopathic myocardial hypertrophy were dead in 2 years, and sudden death occurred in 26%.*’ Dye et al., in a series of 32 male patients (21 with excessive alcoholic intake), emphasized poor prognosis with persistent cardiac enlargement, bundle branch block, intraventricular block, frequent premature ventricular contractions, gallop rhythm associated with cardiac enlargement and repeated episodes of congestive heart failure.** Of their 32 patients, 12 died, and the average duration of life, after the onset of symptoms, was 3.7 years. Greenwood et al. analyzed the clinical course of primary myocardial disease in 161 infants and children followed over a 30-year period.23 All had increased heart size and 42% had congestive heart failure. Of the 161, 57 patients died, and the prognosis was not affected by congestive 42

heart failure, arrhythmias or left ventricular hypertrophy. A poor prognosis was, however, associated with increased pulmonary vascular congestion. The series of Greenwood et al. comprised infants and children, probably a different etiologic group from our adult population with idiopathic cardiomyopathy. Goodwin noted a 5year mortality of over 50% in a series of patients with congestive cardiomyopathy.H Many authors have commented on the high frequency of emboli, both systemic and pulmonary, in patients with cardiomyopathy.4, R,‘O-l3In the literature generally the clinical frequency of emboli is 15-20%, although Spodick and Littman report a 50% incidence of emboli in 36 autopsied cases.” Goodwin has emphasized the high incidence of systemic emboli due to mural thrombi that form in a dilated, poorly contracting left ventricle, and also pulmonary emboli originating in the lower extremities secondary to congestive heart failure. He recommends anticoagulation in patients with cardiomyopathy who have severe heart failure and are confined to bed.x Our data would indicate the advisability of anticoagulation in most patients with idiopathic cardiomyopathy, particularly those with congestive heart failure, significant cardiac enlargement and atria1 fibrillation, unless there are specific medical contraindications. In a series of 6 patients, Hatle et al. have emphasized the poor prognosis in those with a diminished cardiac output.24 This was also pointed out by Hamby et al. in a series of 50 patients, stressing the poor prognosis in those with left ventricular dilatation associated with an increased left ventricular end-diastolic pressure and decreased ejection fraction2” In their experience, patients pass from an asymptomatic stage through a symptomatic hypertrophic stage and finally to the stage of irreversible dilatation.25 Figure 23 shows our concept of the clinical course of patients with cardiomyopathy.“” The outcome is sometimes unpredictable, but in general the prognosis is worse in those patients with marked cardiac enlargement, congestive heart failure and serious rhythm disturbances, such as multifocal or frequent premature ventricular contractions and ventricular tachycardia. b FRANK I. MARCUS: The least likely medication that one would consider in the treatment of a patient with idiopathic cardiomyopathy, especially with cardiac congestion, is propranolol. Surprisingly, Waagstein and colleagues noted a beneficial clinical response in some patients with congestive cardiomyopathy. One of the common features in the patients who improved was a marked tachycardia which appeared to be out of proportion to the degree of congestive heart failure. These comments are meant only to provoke the reader to note that the use of propranolol undoubtedly will be studied further in selected patients and is not recommended for treatment of patients with idiopathic cardiomyopathy. (Waagstein, et al.: Effective chronic beta adrenergic receptor 4 3

;I ONSET

ACUTf Myocardilis Perimyocardilis

INSIDIOUS

PRtSfNTAIION’

COURSE’ I

COMPLICAIIONS I

l

I

Fig 23.-Diagram of various clinical courses that cardiomyopathy can follow, ranging from benign asymptomatic illness to progressive fatal disease. (From Stapleton, J. F., Segal, J. P., and Harvey, W. P.: Clinical pathways of cardiomyopathy, Circulation 35:168, 1974. Used by permission of the American Heart Association. Inc.)

blockade in congestive cardiomyopathy, Br. Heart J. 37:1022, 1975. Oakley, C. M.: Beta blockers in myocardial failure. in Ricker, G., Weber, A. and Goodwin, G. (eds.): Myocardial Failure (Berlin: SpringerVerlag, 1977), p. 344.)

Spodick and Littman reported sudden death in 26% of their patients,‘” a frequency which agrees with the 29% incidence in our series. Sudden death did not correlate with heart size, atria1 fibrillation, unifocal premature ventricular contractions, left axis deviation, left bundle branch block or prior embolic episodes. However, there was a higher incidence of sudden death (64%) in patients with a prior episode of ventricular tachycardia. w FRANK I. MARCUS: Cardiac transplantation should be considered in patients who have idiopathic cardiomyopathy and who are incapacitated because of their heart disease and are clearly approaching the terminal phase of the disease. The group from Stanford has recently reported survival rates of 66, 63 and 58%, one, two and three years after transplantation, with 90% of the patients ha+g been rehabilitated. Obviously this is a desperate measure but should not be overlooked for appropriate patients. (Baumgartner, W. A., et al.: J. Thoracic Cardiovasc. Surg. 75:525,197&L)

Previous publications have emphasized difficulties in the diagnosis of *cardiomyopathy.‘3, 15-20,26,27 In a previous study by our group, cardiomyopathy was diagnosed initially in 99 patients but this diagnosis was confirmed in only 78%.‘* It is apparent that the early diagnosis of cardiomyopathy requires strong suspicion.

Conversely,

the diagnosis

may not be established

until

later in the course. Overdiagnosis and underdiagnosis are common. Levisman has emphasized the value of echocardiography in the diagnosis of mitral regurgitation due to congestive cardio44

myopathy.28 Diagnostic echocardiographic features are a dilated left ventricle, normal left ventricular thickness, decreased left ventricular posterior wall motion, decreased or absent systolic thickening of the intraventricular septum and decreased motion of the intraventricular septum. Corya et al. have emphasized the echocardiographic features in patients with congestive cardiomyopathy.2g Congestive cardiomyopathy was characterized by “diffuse involvement of the left ventricle with diminished motion of the septum and the posterior left ventricular wall.” In patients with coronary artery disease, left ventricular involvement was more segemental. The echocardiogram may also aid in detecting systemic infiltrative disease involving the heart before clinically evident heart disease develops.3o

SUMMARY Patients with idiopathic cardiomyopathy usually present with congestive heart failure, arrhythmias or emboli. In this study, the 77 patients who eventually died survived for an average of 6.2 years from time of diagnosis. The causes of death were: congestive heart failure 480/c, sudden death 29%, arrhythmias lo%, embolic phenomena 3% and other causes 10%. Moderate or marked initial heart size was associated with 2.1 years average survival. An initial cardiac functional classification of class IV was associated with 3.4 years survival. No patient who died improved heart size or functional class prior to death. Patients with atria1 fibrillation, paroxysmal ventricular tachycardia or multifocal premature ventricular contractions had decreased average survival (Table 8). Left axis deviation, left bundle branch block or unifocal premature ventricular contractions did not affect survival. Sudden death occurred in 29% of the patients; this mode of death did not relate to heart size, atria1 fibrillation, unifocal premature ventricular contractions, left axis deviation, left bundle branch block or prior emboli. But paTABLE

8. -INDICATORS OF PROGNOSIS AND SUDDEN DEATH: IDIOPATHIC CARDIOMYOPATHY

Prognosis correlates with Initial heart size Initial functional class Ventricular tachyrardia Complex premature ventricular Atria1 fibrillation Sudden death correlates with Marked cardiomegaly Ventricular tachycardia

contractions

45

tients with paroxysmal ventricular tachycardia were more likely to die suddenly. Of the 77 patients who died, 48 were autopsied. One third of those autopsied had mural thrombi; two thirds of these individuals had advanced cardiomegaly. All patients with systemic or pulmonary emboli had congestive heart failure. Of patients with thromboembolism, 64% had premature ventricular contractions and 33% suffered atria1 fibrillation. Myocardial fibrosis was present in 76% of all hearts (38% focal, 38% diffuse), in 96% of patients with atria1 fibrillation and 94% of those with left bundle branch block. Hearts with mural thrombi also showed a high percentage of diffuse myocardial fibrosis (82%). Acute inflammatory changes in the myocardium were unusual (4%), but chronic inflammatory changes were present in 23%. Although 16% of patients who died had a history of chest pain and 4% had electrocardiographic evidence of anterior infarction, significant coronary narrowing or myocardial infarction was found in none. Of those who died, 27 had been treated with steroids; one third of these appeared to have improved. The pathology did not differ between the steroid responders and the nonresponders in terms of heart weight, myocardial fibrosis, hypertrophy, the presence of mural thrombi or inflammatory changes. It is our clinical impression that early diagnosis, prompt restriction of activity and appropriate drug therapy can slow down, arrest and even reverse the myocardial damage, thereby preventing or minimizing congestive failure and serious arrhythmias. The duration of restricted activity depends on careful clinical evaluation. Digitalization is indicated for treatment of congestive heart failure; but because of increased sensitivity to digitalis in some individuals, a low dose is usually given. Anticoagulation should be instituted in most cases of cardiomyopathy, particularly those where marked cardiac enlargement, congestive failure and atria1 fibrillation are present. Idiopathic cardiomyopathy may follow many different.+ often unpredictable, clinical pathways (see Fig 23). Great variability exists in the mode of onset, clinical features, clinical course and final outcome. The sequence of events may vary from rapid improvement to fulminating deterioration, ending in congestive failure, serious arrhythmia and sudden death. In some, the clinical course is stable and in others relapsing. Early diagnosis and prompt therapy can favorably influence prognosis.

ADDENDUM Statistical evaluation: 1. Frequency of left bundle 46

branch

block compared

to right

bundle branch block in living patients: P < 0.01; in dead patients, P < 0.00001. 2. Comparison of &year survival in patients with and without ventricular tachycardia: P CC 0.01. 3. Comparison of &year survival in patients with 4+ cardiac enlargement and those with lesser degrees of enlargement; P < 0.0001. 4. Comparison of &year survival in patients with and without atria1 fibrillation: P < 0.005. 5. Comparison of &year survival in patients with and without complex premature ventricular contractions: P < 0.2. 6. Comparison of the frequency of 3 and 4+ cardiac enlargement in the dead and living groups: P c 0.05. 7. Comparison of clinical features between living and dead idiopathic groups. Congestive failure: P < 0.0001; ventricular gallop: P < 0.001; premature ventricular contractions: P < 0.02, mitral insufficiency: P < 0.01; 3 and 4+ cardiomegaly: P < 0.001; left bundle branch block: P < 0.005; atria1 fibrillation: P < 0.25: emboli, P < 0.04. 8. Comparison of the following features in patients with atria1 and/or pulmonary emboli. Incidence of 3 and 4+ cardiac enlargement in living versus dead patients: P < 0.15; incidence of 0, 1 and 2+ heart size in living versus dead patients: P < 0.35; incidence of atria1 fibrillation in Iiving versus dead patients: P < 0.25; incidence of absence of atria1 fibrillation in living versus dead patients, P --I 0.15.

ACKNOWLEDGMENTS Appreciation is expressed to Ruth A. Weinmann, research assistant in cardiology; Bernard Salb, medical photographer, Department of Medical Illustration; and Sharon Federation, secretary, for technical assistance in the preparation of this manuscript. REFERENCES 1. Mattingly, T. W.: The clinical concept of primary myocardial disease, Circulation 32845, 1965. 2. Goodwin, J. F.: Prospects and predictions for the cardiomyopathies, Circulation 50:210, 1974. 3. Burch, G. E., Walsh, J. J., and Block, W. C.: Value of prolonged bed rest in management of cardiomegaly, J.A.M.A. 183:81,1963. 4. McDonald, C. D., Burch, A. L., and Walsh, J. J.: Alcoholic cardiomyopathy managed with prolonged bed rest, Ann. Intern. Med. 74:681, 1971. 5. Hatle, L., Orjavik, O., and Storstein, 0.: Chronic myocardial disease. I: clinical picture related to long-term prognosis, Acta Med. Stand. 199:399, 1976. 47

Alexander, C. S.: Idiopathic heart disease, Am. J. Med. 41:213, 1966. Levander-Lindgren, M.: Studies in myocarditis. IV: Late prognosis, Cardiologia 47:18,1965. Goodwin, J. F.: Treatment of the cardiomyopathies, Am. J. Cardiol. 32:341, 1973. Shugoll, G. I., Bowen, P. J., Moore, J. P. and Lenkin, M. L.: Follow-up observations and prognosis in primary myocardial disease, Arch. Intern. Med. 129:67, 1972. 10. Hamby, R. L.: Primary myocardial disease, Medicine 4955, 1970. 11. Spodick, D. H., and Littman, D.: Idiopathic myocardial hypertrophy, Am. J. Cardiol. 1:610, 1958. 12. Massumi, R. A., Rios, J. C., Coach, A. S., Nutter, D., Devita, V. T., and Datlow, D. W.: Primary myocardial disease, Circulation 31:19, 1965. 13. Harvey, W. P., Segal, J. P., and Gurel, T.: The clinical spectrum of primary myocardial disease, Prog. Cardiovasc. Dis. 7:17, 1964. 14. Stapleton, J. F., Segal, J. P., and Harvey, W. P.: The electrocardiogram of myocardopathy, Prog. Cardiovasc. Dis. 13:217, 1970. 15. Segal, J. P., Harvey, W. P., and Gurel, T.: Diagnosis and treatment of primary myocardial disease, Circulation 32:837, 1965. 16. Harvey, W. P.: Symposium: clinical recognition and treatment of primary myocardial disease, Circulation 32:828, 1965. 17. Harvey, W. P., and Segal, J P.: Primary myocardial disease, Postgrad. Med. 42:145. 1967. 18. Segal, J. P., Harvey, W. P., and Stapleton, J. F.: Clinical Features and Natural History of Cardiomyopathy, in Fowler, N. O., (ed.): Myocardial Disease (New York: Grune & Stratton, Inc., 1973). 19. Stapleton, J. F., Harvey, W. P., and Segal, J. P.: Cardiomyopathy, Am. Fam. Physician 8:84, 1973. 20. Stapleton, J. F., Segal, J. P., and Harvey, W. P.: Clinical pathways of cardiomyopathy, Circ. Res. 35 (Suppl. 11):168, 1974. 21. Marriott, H. J.: Echocardiographic abnormalities, coronary disorders and “arrhythmias in primary myocardial disease, Prog. Cardiovasc. Dis. 7:99, 1964. 22. Dye, C L., Rosenbaum, D., Lowe, J. C., Behulu, R. H., and Genovese, P. D.: Primary myocardial disease. I: clinical features, Ann. Intern. Med. 58:426, 1963. 23. Greenwood, R. D., Nadas, A. S., and Fyler, D. C.: The clinical course of primary myocardial disease in infants and children, Am. Heart J. 92:549, 1974. 24. Hatle, L., Stahe, C., and Storstein, 0.: Chronic myocardial disease. II: hemodynamic findings related to long-term prognosis, Acta Med. Stand. 199: 407,1976. 25. Hamby, R. I., Catangay, P., Apiado, P., and Khan, A. K.: Primary myocardial disease, Am. J. Cardiol. 25:625, 1970. 26. Fowler. N.: Differential diagnosis of cardiomyopathies, Prog. Cardiovasc. Dis. 14:113, 1971. 27. Forrester, J. S., Kemp, H. G., and Gorlin, R.: Primary myocardial disease: distitiction from coronary heart disease. Circulation 39(Suppl. III):Bl, 1969. 28. Levisman, J. A.: Echocardiographic diagnosis of mitral regurgitation in congestive cardiomyopathy, Am. Heart J. 93:33, 1977. 29. Corya, B., Feigenbaum, H., Rasmussen, S., and Black, M.: Echocardiographic features of congestive cardiomyopathy compared with normal subjects and patients with coronary artery disease, Circulation 49:1153,1974. 30. Borei, J. S., Henry, W. L., and Epstein, S. E.: Echocardiographic observations in patients with systemic infiltrative disease involving the heart, Am. J. Cardiol. 39:184, 1977. 48