Cardiomyopathies of obscure origin in Cali, Colombia

ardiomyopathies in Cali, Clinical,

Colombia etiologic,

and

~~b~r~t

Jorge Arazijo, M.D.* Gilberto Sa’nchez, M.D.“” Javier Gutikrrez, M.D.“” Fernando Pe/rez, M.D.‘** Cali, Colombia

I

n the city of Cali, Colombia (Soutll America), heart diseases of unknown etiology are second to arterial hypertension as a cause of death resulting from cardiac disease’; they are followed by rheumatic heart disease, myocardial infarction, car pulmonale, bacterial endocarditis, and a number of other less frequent entities. Previously Correa and associates’ have defined their pathologic characteristics and proposed a classification based on histologic findings. It is the purpose of this report to make a clinical and pathologic correlation that might shed light on the etiology of these obscure disorders and to describe electrocardiographic, radiologic, laboratory, and hemodynamic characteristics that could make feasible a diagnosis during life. Material

und

methods

The findings on 41 subjects, ranging in age from 16 to 80 years with a mean of 44 From

at the time of death, constitute the basis of this report. Twenty-one were male and 20 female. Most were Kegroes and Mestizos; their selection reflected the racial characteristics of the area. They were studied between 1961 and 1966. In all of them a complete autopsy was performed. Blocks were cut from different sites of the heart and slices were stained with hematoxylin and eosin and Mallory trichrome, and for reticulum and elastic. Every subject had a physical examination and a complete clinical history was recorded for each. l\lost of the subjects were given routine laboratory tests which included: white and red blood cell counts, platelet count, hemoglobin, hematocrit,, crythrocyte sedimentation rate, blood urea nitrogen, serum albumin and globulins, serum bilirubin, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, cephalin flocculation test, prothrombin time, serum alkaline phos-

the Department of Medicine and Pathology, Facultad de Medic&., South America. Received for publication Aug. 25, 1969. Reprint requests to: Gilbert0 SQnchez, M.D., Universidad de1 Valle Facuitad Interna, Apartados, Aero 2188, National 439, Cali. Colombia. *Professor of Medicine. **Associate Professor of Medicine. ***Assistant Professor of Pathology.

162

American

Heart Journal

Lniversidad

de Medicina,

de1 Valie,

Deparramento

Cali,

Colombia,

de Medicina

Cuvdiomyopathies

phatase, serum cholesterol, tests from the Venereal Disease Research Laboratories, urinalysis, fecal examination for ova and parasites, and fasting blood sugar. Special procedures were performed in a number of patients which included 1311uptake, serum protein electrophoresis, hemoglobin electrophoresis, sickle cell preparation, and tests for Chagas’ disease (xenodiagnosis, complement fixation test, and thick smear). Twelve-lead electrocardiograms were recorded in 38 patients and posteroanterior, oblique, and lateral x-ray films of the heart were obtained in 32 patients. Right heart cardiac catheterization was performed in six. Results Pathologic j&dings. The pathologic characteristics of the different groups of heart diseases observed in this study were similar to those reported by Correa and associates.i GROUP I. This group was composed of 33 subjects whose main pathologic findings were: (a) global enlargement of the heart, especially of the left ventricle; (b) thinning of the apex; (c) mural thrombosis, usually in relation to areas of patchy endocardial fibrosis; (d) foci of myocytolysis and scattered areas of myocardial fibrosis; (e) absence of inflammatory reaction; and (f) frequent pulmonary and systemic embolization. In 12 cases there was clinical and/or pathologic evidence of pyelonephritis (1 patient), nephrosclerosis (1 patient), hyperthyroidism (2 patients), alcoholism (3 patients), postpartum state (2 patients), and the sickle cell trait (3 patients). GROUP II. This group is composed of 4 subjects who showed prominent endocardial fibrosis similar to the lesion described as endomyocardial fibrosis (EXIF) by Davies and Ball2 in Uganda. GROUP III. This group includes 4 subjects with cardiac enlargement associated with signs of myocarditis. Epidemiological and dietary findings. Although the subjects were born in different localities of Colombia, they lived mostly in the Department of Valle de1 Cauca where Cali is located. All belonged to low socioeconomic classes. The nutritional state was poor in most of them as judged by

in Colombia

163

case history, body weight, and low serum albumin and cholesterol levels. Their diet tended to be below normal in total caloric intake and was very low in proteins and of poor biological value. The main components were plantain, rice, potatoes, and yucca. Three subjects gave a history of heavy alcoholic intake. Clinical findings. Clinical characteristics are shown in Table I. GROUP I. Twenty-eight subjects presented with congestive heart failure. This usually began with progressive dyspnea, in many cases reaching the point of orthopnea. There was pulmonary congestion, hepatic enlargement, peripheral edema, and frequently anasarca. The blood pressure was normal in all cases after treatment of congestive heart failure. The point of maximum impulse was always displaced to the left; it occupied an ample area and it was not as strong as in patients with left ventricular hypertrophy due to aortic valvular disease. Gallop rhythm, usually protodiastolic, was found in 5.5 per cent of the cases. About half of them presented with apical systolic murmurs which were pansystolic, high to medium-pitched, and Grade l/4 to Grade 3/4 in intensity. They usually radiated to the axilla. Since abnormalities of the mitral valve leaflets were not demonstrated pathologically, these murmurs were probably related to dilatation of the mitral ring. Tricuspid systolic murmurs were heard in 20 per cent of the cases. Forty-five per cent of the patients developed shock, which was probably cardiogenie, since in most instances it improved with rapid digitalization. Hemoptysis, pleuritic pain, and x-ray changes compatible with pulmonary embolism were very common and even a prominent clinical aspect. Peripheral embolism, usually to the brain and lower extremities, was present in about one third of the patients. The embolic phenomena correlate well with the high frequency of mural thrombi found in the right and left cavities of the heart at autopsy. One third of the patients developed digitalis intoxication at usual doses. However, since most of them also required very vigorous diuretic regimes, electrolyte im-

ParainetPrs

III (4)”

c;* -___-~

I-------No. I Age Sex

(yr.)

% ~

I

51 (16-8O)t

Male Female

18 1.5

54 45

1G 15

52 48

4

4

4 3 16 12 (l-60)t

17 :i

2 1

1 1

11 22

33 77

1 3

0 4

20 12 18

62 2

1 3 3

4 0 1

14 6 1.5 22 11 9

42 13 45 67 33 27

3 1 2 1 0 2

2 1 1 2 0 2

Race Mestizo Negro Nutrition Good Fair Poor Duration of illness (months) Clinical course Recurrent Progressive Cardiomegaly Severe Moderate Protodiastolic gallop NIurmurs Apical systolic Tricuspid systolic Shock Pulmonary embolism Systemic embolism Digitalis intoxication

"Sumber iMean

14 (l-36)1

2 (l&f

of cases. and range values

are

given.

balance could have contributed to the digitalis intoxication. Thirty-three per cent of the patients had a course characterized by several bouts of congestive heart failure. Despite vigorous treatment, some hepatomegaly almost always persisted and there was very little variation of heart size. In the rest of the patients the course was progressively downhill despite therapy. When the cardiopathy was associated with other illnesses, the course was progressive and tended to be more accelerated. Sudden unexpected death occurred in 30 per cent. GROUPS II AND III. The patients with myocarditis and three of the four with endomyocardial fibrosis presented with a

clinical picture similar to that already described. One of the cases of endomyocardial fibrosis resembled rheumatic valvular disease in that systolic and diastolic murmurs were heard at the apex. Radiologic ,&dings. Cardiomegaly was prominent in most patients. All cavities were dilated, but enlargement of the left ventricle was more noticeable. Pulmonary congestion was the rule during heart failure. The cardiac configuration was similar among the three different pathologic groups including a patient with endomyocardial fibrosis in which there was severe endocardial thickening of the left ventricle involving also the mitral valve (Fig. 1). Pleural effusion and images suggestive of

B

Fig. 1. Posteroanterior chest roentgenograms of different groups of cardiomyopathies. 6, Group II. D, Myocarditis. There is global cardial enlargement in all of them. pulmonary infarction were frequent. On Buoroscopic examination motion of the reduced. heart chambers was markedly

Electrocardiographic findings. Table II shows that the electrocardiographic characteristics of all groups were very similar with the exception of two patients with myocarditis who presented with complete

right was

bundle probably

A and B, Group f.

branch block. One .a case of Chagas’

of these disease,

$Iost patients were in normal sinus rhythm, Premature ventricular contractions were frequent in ali groups. Some electrocardiograms showed a Q-S pattern from Vr to Va or Va. Extreme mean QRS left axis deviation in the frontal plane was a fre-

Parameters

1

!

III (4)

Sinus rhythm Atria1 fibrillation

23 5

19 17

4

Nodal rhythm Premature ventricular beats Low R waves VI to VS. 1st Degree LBBB Complete LBBB Complete RBBB Generalized low voltage ST and T-wave changes Left ventricular hypertrophy Biauricular enlargement Left atria1 enlargement

1 1.5 13 12 5

5; 4.5 41 17

2 3 3

1 3 1 1

7 17 3 5 6 3

24 59 10 17 20 10

1 3

2 I. 2

1st Degree A-V block

LBBB = Left bundle branch block; RBBB = right bundle *Number of patients for which ECG’s were available.

branch

quent finding in all groups (46 per cent) (Fig. 2). Left bundle branch block (incomplete and complete) was the most common conduction defect (62 per cent). Atrioventricular block was infrequent. Nonspecific ST-T changes were present in 65 per cent of all cases. Generalized low voltage and left ventricular hypertrophy were not common. The latter does not correlate with the frequent finding of left ventricular hypertrophy at autopsy. There was not a single instance of right ventricular hypertrophy. Almost half of the cases showed atria1 changes, with left atria1 abnormalities predominant. Laboratory data. Most patients had serum albumin levels below 3.5 Gm. per 100 ml. while one third had serum cholesterol levels below 150 Gm. per 100 ml. Half of all cases presented with an elevation of total serum bilirubin ranging from 1.5 to 30 mg. per cent, with a mean of 6 mg. This finding is probably related to the high of embolic phenomena and frequency severe hepatic congestion. Prothrombin time was infrequently prolonged. Five

2 1

1 3

block.

cases presented with moderate eievation of the blood urea nitrogen. Fasting blood sugar and alkaline phosphatase were within normal limits. There was one positive test from the Venereal Disease Research Laboratories out of 15 determinations. In this cases there was no evidence of cardiovascular syphilis at autopsy. One third of Group I subjects presented with moderate leukocytosis at the time of admission. A!1 of these patients had pulmonary embolism at autopsy. Mild eosinophilia was infrequent but whenever present it was associated with intestinal parasitic infection. Hemoglobin levels were below 10 Gm. per 100 ml. in one sixth of the patients. Urinalysis was normal with the exception of those cases with associated renal diseases. Multiple intestinal parasitism was present in most patients with a predominance of Ascaris, hookworm, Strongyloides, and Trichuris. High thyroidal 1311 uptakes were present in two clinically hyperthyroid patients. The complement fixation test for Chagas’

Fig. 2. A, Typical electrocardiogram of a Group I patient (81. G.) showing marked QRS left axis deviation in the frontal plane. There are also Q-S complexes from Vr to V4. B, Electrocardiogram from a Group I patient (E. B.) (post partum) showing ST-T changes compatible with acute anterior myocardial infarction. At autopsy, the coronary arteries were normal.

disease

was

positive

in one

patient

in Group

I and in one with myocarditis. A total of 11 determinations were done. Sickle cell preparations, performed in seven patients, were positive in three from Group I ; sickle cells and multiple thrombosis were demonstrated at post mortem. These were the only cases that showed sickle cells at autopsy. Serum protein electrophoresis was performed in eight patients; in seven the albumin was low and in five there was elevation of alpha-l, alpha-2, and gamma globulins. Cardiac catheterization. Right heart cardiac catheterization was performed in five Group I patients and in one with endomyocardial fibrosis during maximal cardiac compensation (Table III). The mean “capillary pressure” (wedge pressure) was moderately elevated in all except one

(Patient 37) in whom the elevation was marked. The mean pulmonary artery pressure in all cases was also moderately elevated. In five there was elevation of the right ventricular end-diastolic pressure, but only in one (patient 37) was this elevation marked. Two cases presented with a postsystolic dip in the right ventricular tracing followed by an early elevation of the diastolic pressure. There was transmission of the atria1 A wave to the right ventricular tracing in two cases. The arteriovenous oxygen difference was wide in three patients. Discussion Heart diseases of undetermined etiology are present in many parts of the world; in tropical and subtropical countries they constitute one of the major clinical and

Pressures cmnz. Hg)

8

I

14

19

I

20

20

1

19

32 (alcoholism) 13

PCW = Pulmonary

II

20

capillary

“wedge”

46/24 M (34) 45/20 M (30) 45/25 M (37) 35/18 M (28) 60/35 14 (45) S/20 M (31)

p~ssure;

36/7

10

5.7

40/7

7

4.5

42/10

6

8

34/7

5

4.3

65/33

22

55/3

2

PA = puimona~~y artery;

health problems.17 Efforts are currently being made by several investigators to define their etiology and pathogenesis. Trypanosoma crzlzi has been suspected as the dominant element in the etiology of the rural cardiomyopathies of Latin America.l* Despite the fact that Chagas’ heart disease has been reported in only two instances in Colombia,12,r3 this etiologic possibility must be considered in relation to our cases in view of the fact that the vector of Chagas disease has been found in several areas of the Colombian territory. Chronic Chagas heart disease has many aspects similar to our cases, such as thinning of the apex, generalized cardiac dilatation, mural thrombosis, myocytolysis, and scattered areas of mural fibrosis. However, myocarditis is a feature of Chagas’ heart disease and it is to be noted that signs of inflammation such as cellular infiltration were constantly absent in our patients except in four instances. One of these latter patients probably had chagasic cardiomyopathy since Trypanosomn crzizi was found in the xenodiagnosis test and there was a positive complement fixation test for Chagas disease. This latter test was performed in 10 additional patients and was positive in one more. This patient is of special interest since myocarditis was

3.7

i -

1.45

+

-I__t

7.4 9.3 (exercise) 6.6

M = mean pressure;

KV = right ventricle;

RA = rbht

atriuni.

not found ac autopsy. The Chagas’ infection was probably unrelated to the cardiomyopathy. Another point to support the rarity of Chagas’ disease in our area is that the complement fixation test for Chagas’ disease was performed in a group of 41 patients with cardiomyopathies (not included in the present report) and was found positive in only one instance. This case as well as the probable chagasic Inyo’carditis we have already referred to, came from areas where Triatoma (the vectors of Chagas’ disease) are known to exist. Triatoma have not been found in the Cali area. From the clinical, patho!ogic, laboratory, and epidemiologic studies, therefore, the chagasic etiology of our cardiomyopathies appears highly improbable. All our patients belonged to low socioeconomic classes. Although this study was not conducted in a representative sample of our population, we have the distinct impression, based both on clinical and pathologic grounds, that heart diseases of the type described in this paper are of low incidence among our high socioeconomic classes. On the other hand, heart diseases of undetermined etiology are frequent in underdeveloped areas of the world and Qf rare occurrence in highly industrialized

Cardiomyopathies

and developed countries. These observations suggest that socioeconomic factors are primordial in the genesis of these disorders. Among those factors dietary conditions are to be considered. Preliminary observations in our laboratory on rats placed on different diets have shown pathologic changes in the heart that are comparable to those observed in our patients. lg These findings are in agreement with the experimental studies conducted by Reid and associates in South Africa.” Other factors associated with poverty, present in most of our patients, such as living under precarious hygienic conditions in overcrowded quarters, increased susceptibility to contagious diseases, and multiple intestinal parasitism may have important etiologic implications although these are difficult to define at the present time. The sickle cell abnormality does not seem to be an important etiologic factor. It was present in only three cases and in the rest of the patients it was ruled out by hemoglobin electrophoresis, sickle cell preparation, or at autopsy. Anemia was present in 18 cases, but only in seven was the hemoglobin less than 10 Gm. per 100 ml. of blood. Anemia does not seem to have played an important etiologic role in our cases. With the exception of a mild eosinophilia in five cases (all of which had intestinal parasites), there was no evidence of any kind of allergic mechanism. Recently, Connor and associates14 using special staining techniques have found abnormalities suggesting hypersensitivity as the underlying mechanism in the endomyocardial fibrosis observed in Uganda. The connection between intestinal parasites (which were present in about 70 per cent of our cases) and cardiomyopathies is not apparent to us. However, we are aware that this point should be investigated. The finding of pathologic abnormalities characteristic of Group I in the heart of patients with varied conditions such as hyperthyroidism, sickle cell trait, postpartum state, alcoholism, and nephroesclerosis poses the following question. Are we dealing with a specific cardiomyopathy to which other conditions are associated

,in Colombia

169

by chance or is it that the pathologic findings of Group I are nonspecific so that they can be produced by several conditions? Myocytolysis (one of the characteristics of our Group I cases) has been found in several different entities3 and in Chagas’ heart disease.4 Pathologic findings by light microscopy with some resemblances to our Group I have also been found in postpartum heart disease,5-7 alcoholic cardioand llyperthyroidism.8 It is myopathy,7 evident that other techniques will have to be applied to this problem such as electron as done microscopy, and histochemistry by Ferrans and associatesg,10 to differentiate alcoholic from nonalcoholic cardiomyopathies. In 44 per cent of the cases the clinical diagnosis was correct. The most common confusion was with coronary artery disease, and this was related to the age factor since most of our patients were middle-aged. With one exception the differential diagnosis with pericardial constriction or effusion has not been difficult since in our cases of cardiomyopathy the enlarged heart could usually be palpated well beyond normal limits to the left. Our case of endomyocardial fibrosis with involvement of the mitral valve was diagnosed as rheumatic heart disease because of systolic and diastolic murmurs at the apex. Since many patients had apical systolic murmurs the possibility of rheumatic mitral insufficiency was frequently entertained. The observation of the motion of the left ventricle on Auoroscopy was very helpful since there is hypoactivity in cardiomyopathies and usually normal motion or even hyperactivity in rheumatic mitral insufficiency. The common finding of complete and incomplete left bundle branch block is another point against the chagasic etiology of our noninflammatory cardiomyopathies. It is well known that right bundle branch block is a common conduction defect in Chagas’ heart disease.i5 The absence of the R wave from Vl to Va led to the diagnosis of myocardial infarction in three patients. Since the latter was not confirmed at autopsy, we believe that fibrous changes in the interventricular septum were responsible for the abnormality of the QRS complex. These changes may also explain the

frequent finding of extreme left axis deviation in our cardiomyopathies which constitute the so-called left superior intraventricular block (SIVB) or parietal block of the superior division of the left bundle. This type of conduction defect has also been reported by Davies and Evans16 in 64 per cent of their patients with obscure cardiomyopathies. Although the electrocardiographic abnormalities present in our cases are not specific, the association of incomplete left bundle branch block and extreme mean QRS left axis deviation may constitute an important diagnostic clue. Our experience with right cardiac catheterization in cardiomyopathies inchrdes also a substantial number of patients not considered in this report because of lack of postmortem material. The procedure has not been helpful for the diagnosis of cardiomyopathies. It has shown either normal dynamics at rest or signs compatible with failure of both ventricles and low cardiac output. Summary

Forty-one patients with heart diseases of unknown etiology seen in Cali, Colombia, were studied clinically, pathologically, and with laboratory procedures, which included electrocardiograms, chest x-ray films, and, in some instances, cardiac catheterization. Pathologically, three groups were defined. Group I (33 patients) was characterized by degenerative lesions of the cardiac muscle; 12 cases were associated with other conditions such as the sickle cell trait, the postpartum state, hyperthyroidism, and alcoholism. Group II (4 patients) showed predominant endomyocardial fibrosis, Group III consisted of 4 patients with myocarditis. With the exception of one case of endomyocardial fibrosis that suggested rheumatic valvular disease, the clinical features among the three groups were similar. Etiologic possibilities such as Chagas’ sickle cell abnordisease, malnutrition, mality, anemia, and intestinal parasites are discussed. The authors are grateful to Dr. Antonio D’Alessandro for the laboratorv studies for Chagas’ disease and to Drs. Jacob0 Ghitis and Eduardo Gaitan for their editorial advice.

1. Correa, P., Restrepo, C., Garcia, C., and QuiroL, X. C.: Pathologyof heart diseases of undetermined etiology which occur in Cali, Colombia, .hER. HURT J. 66:584, 1963. 2. Davies, J. N. P., and Ball, J. D.: The pathology of endomyocardial fibrosis in L’ganda, Brit. Heart J. 17:337, 195.5. 3. Schlesinger,M. J., and Reiner, I~.: Focal myocytolysis of the heart, Amer. J. Path. 31:443, 1955. -1. Torres, II. C.: Miocitolise e fibrose do miocardio na dolenca de chagas, Mem. Inst. Cruz 58:161, 1960. 3. Meadows, VI’. R.: Postpartum heart disease, Amer. J. Cardiol. 6:788, 1960. 6. Meadows, W. I~.: Idiopathic myocardial failure in the last trimester bf pregnancy and pueruerium. Circulation 15:903. 1957. 7. iValsh,‘f. J., Burch, G. E., ‘Black, W. C., Ferrans, V. I., and Hibbs, R. G.: Idiopathic myocardiopathy of the puerperium (postpartal heart disease), Circulation 32:19, 196.5. 8. Schlesineer. P.. and Benchimol. A. B.: The nure form of ~hyrotbxic heart disease, A clinical&and pathological study, Amer. J. Cardiol. 2:430, 1958. 9. Ferrans, V. J., Hibbs, R. G., Weilbaecher, D. G., Black, W. C., ivalsh, J. J., and Burch, G. E.: Alcoholic cardiomyopathy, AMER. HEART J. 69:748, 1965. 10. Hibbs, R. G., Ferrans, V. J., Black, W. C., Weilbaecher. D. G.. Walsh. 1. T.. and Burch. G. E.: Alcoholic cardiomyopithy: A~zB. HEAR; j. 69:766, 1965. 11. Reid, J. V. O., and Berjak, P.: Dietary production of myocardial fibrosis in the rat, A?*IER. HEART J. 71240, 1966. 11. Martinez, H. V., Diaz, C., and Leiderman, E.: Miocarditis chagasica aguda, Antioquia Med. 16:415, 1966. 13. ITribe, G. B.: Miocarditis chag6sica. Presentaci6n de un case comprobado, Antioquia Med. 15:573, 1965. 14. Connor, D. H., Somers, K., Hutt, M. S. R., Manion, W. C., and D’Arbela, I’. G.: Endotnvocardial fibrosis in lJeanda (Davies’ disease). il&. HEART J. Part 1: 74:6$7, 1967; Part Iii 75:107, 1968. F. S., Diaz, E., Nobrega, G., and 15. Laranja, Miranda, A.: Chagas disease. ‘4 clinical, epidemiologic and pathologic study, Circulation f4:1035, 19.56. 16. Davies, H., and Evans, I%‘.: The significance of deep S waves in Leads II and III, Brit. Heart J. 22551, 1969. 17. Cardiomyopathies. Bull. WHO 33:X7, 196.5. 18. Pifano, F.: Algunos aspectos de la enfermedad de chagas en Venezuela, Gac. Med. Caracas 3:73, 1960. 19. Sanchez. G.. Linares. F.. Bolafios. 0.. Garcia. C., Araijo, J., and Tripathy, K.: Experimental production of myocardial necrosis and subendocardial ilbroais in the rat. In press.