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Clinical pathologic conference
Clinical pathologic
conference
Robert C. Speckhals, M.D. Paul Winchell, M.D. Kurt Amplatz, M.D. Jesse E. Edwards, M.D.* Arthur H. L. From, M.D. St. Paul and Minneapolis,
Clinical
Minn.
abstract
DR. SPECKHALS: A 22-year-old white woman in the eighth month of her first pregnancy was admitted to the hospital for the first time with the chief complaints of cough, dyspnea, and orthopnea. The patient had noticed the onset of a nonproductive cough approximately 6 weeks prior to admission. This was not associated with fever, chills, or hemoptysis. For 10 days prior to admission, increasing dyspnea on exertion had been noticed. Early on the morning of admission, an episode of sudden onset of orthopnea and an increase in the degree of dyspnea and cough was experienced. The patient denied having thoracic pain, chills, fever, abdominal pain, or swelling of the ankles. There was no history of any recent febrile illness, hypertension, or albuminuria. There had been no significant gain in body weight. The past history revealed that an episode of acute glomerulonephritis had occurred when she was 5 years old. No significant neuromuscular symptoms were reported and there was no history of swelling or pain in joints. Two cousins had had rheumatic fever. Physical examination revealed a well-developed, well-nourished, white, pregnant, acyanotic woman, dyspneic and orthopneic, who appeared to be acutely ill. Except for signs of pregnancy consistent with the history, the positive physical findings were related to the cardiovascular system. The pulse was regular and the rate was 100 per minute. There was no fever. The blood pressure was 94 mm. Hg systolic, and 60 mm. Hg diastolic. No cervical venous distention was apparent, and there was no edema of the extremities. Palpation of the precordium revealed a left ventricular thrust. The pulmonic component of the second sound was accentuated. From
A third heart sound, not typical of an opening snap, was heard early in diastole. A Grade 2/6 systolic ejection type of murmur was present over the cardiac apex. No diastolic murmur was noted. A few &es were present at the pulmonary bases. The thyroid gland was diffusely enlarged to a minor degree. An electrocardiogram revealed a sinus tachycardia and left axis deviation. Laboratory studies showed the hemoglobin concentration to be 11.2 Gm. per 100 ml. of blood. The total leukocyte count was 9,650 per cubic millimeter of blood. The pH of the urine was 5, and the specific gravity was 1.004. Glycosuria and proteinuria were absent. Microscopic examination of the urine revealed no formed elements. The patient was placed on a regimen of bed rest and a lowsodium diet and was given 2 ml. of Thiomerin intramuscularly. Digitalization was accomplished by the administration of Acylanid. The patient’s condition gradually improved on this program and she was discharged after 15 days of hospitalization. The patient was readmitted 5 days later because of aching pain across the shoulders. The results of the physical examination and the electrocardiographic features were essentially like those of the first admission. The erythrocyte sedimentation rate (Westergren) was 106 mm. in 1 hour. The antistreptolysin titer of the serum was at a normal level, being 12 Todd units. The report on a specimen of stool sent to the Minnesota State Board of Public Health was “no virus isolated.” The level of urea nitrogen in the blood was 17 mg. per 100 ml. of blood. Three blood cultures, both aerobic and anaerobic, remained sterile. The test for the lupus erythematosus cell and Kline flocculation test gave
the Departments of Medicine and Pathology, The Charles T. Miller Hosp:tal, St. Paul, Minn.. and the Departments of Medicine, Radiology, and Pathology, University of Minnesota, Minneapolis. Minn. This study was supported by Public Health Service Training Grant No. 5 Tl HE 5570 and Reasearch Grant No. HE 5694 from the National Heart Institute. United States Public Health Service. Received for publication Jan. 6. 1965. *Address: Department of Pathology, The CharlesT. Miller Hospital, 125 West College Ave., St. Paul 2, Minn.
551
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The patient’s colu-se uvas then stable for the nest 10 day, after which increasing cl>-spnea nrld orthopne:t and pain in the right upper quadrant of the abdomen developed. Txhycardia persisted. ‘I‘hc systolic blood pressure measured 80 mm. Hg, :md the diastolic, 60 mm. Hg. The heart was enl;trgvtl to the left anterior axillary line, and a Grade 1 to 3 systolic ,,~~,~,,~~~r was heard ;A)ng the left sternal border. :I gallop rhythm dercloped, while the pulmo~rary fields remained clear and the liver cnlnrged to about 5 cm. below the right costal margin. ‘I’hc patient’s c.ondition showed increasing deterioration a rid she died 16 days after delivq-.
Discussion
DR. WNC‘HELL: To summarize, this was a La-year-oId woman who developed severe congestive cardiac failure toward the end of the third trimester of her first. pregnancq~ and ultimately died in the postpartum period in spite of vigorous medical treatment. The differential diagnostic possibilities are numerous. One of the first things to be considered is toxemia of pregnancy with hypertension, sodium retention, and, ultimately, severe cardiac failure. The patient was never hypertensive and gave no evidence of renal inlpairment, in spite of the history of gloilierLllonephritis at the age of 5 years. t4Ythout supporting evidence, we may rapidly discard toxemia as the cause of the cardiac problem. The most likely cause of failure in 3 young pregnant patient would be rheuInatic disease of the mitral valve. Here, physical findings give us scme help. There was, on palpation, evidence of left ventricular hyperactivity. The pulmonic component of the second sound was considerably increased in intensity, indicating pulmonary hypertension. At the apex there was a systolic ~l~~rlllur which was described as ejection in type, but which possibl?; could have been pansystolic-. These findings, coupled with the histot-!*
v2
Y3
v4
v5
V6
of cardiac failure beginning in the third trimester and becoming more severe in the immediate postpartal period, make a fair case for rheumatic mitral reflux. In addition to valvular disease, one would also have to consider strongly the possibilit, of recurrent rheumatic myocarditis. We get little help from the laboratory, however, since the antistreptolysin and the more specific antideoxyribonuclease titers were not raised. In spite of this, we cannot exclude rheumatic carditis. Another area which we should explore is congenital cardiac disease. Our co~illlents should be restricted to the acyanotic types, since the patient was not cyanotic. There was no clinical evidence of pulmonary stenosis, atria1 septal defect, or left-sided congenital valvular disease. Moreover, most types of acyanotic cardiac disease commonly seen in adults are compatible with a normal pregnancy. I think that, on the basis of the information already available, we can rule out congenital lesions of the ordinary types. The possibility of myocarditis should also be considered in this case. Instances of viral or nonspecific myocarditis occur, developing fortuitously during the latter half of pregnancy and terminating fata&. Although the results of viral studies performed in this patient were negative, the possibility of a viral myocarditis cannot be excluded. The possibility of idiopathic myocardiopathy, either of a familial or nonfamilial sort, should also be raised. With no positive family history, the former would seenl
Clinical pathologic conference
unlikely, but a nonfamilial type could not be excluded. Another diagnosis to be considered is that of the “myocardiopathy or myocardiosis of pregnancy.” In this condition, the patient usually develops congestive cardiac failure, tachycardia, and anginoid thoracic pain in the last trimester, or more commonly in the immediate or late postpartal peri0d.l Often in such patients, necropsy reveals subendocardial fibrosis and necrosis, as well as endocardial thickening with mural thrombi frequently adherent to the thickened endocardium. Embolization is quite frequent in this disorder. This entity, if it is an entity,2 is thought by some to be caused by pregnancy itself in some yet unknown fashion.’ Lastly, we must always consider atherosclerotic cardiac disease with myocardial infarction or fibrosis, and failure secondary to this. I place this problem last on our list of differential diagnoses because I think that it is by far the least likely. Myocardial infarction in pregnant young women occurs sporadically, but the incidence of coronary arterial disease in young women with functioning ovaries is very low. I mention this possibility for the sake of completeness, and I anticipate that it will get no support from the electrocardiogram. We might now review the electrocardiogram (Fig. 1).
Fig. 2. Thoracic for discussion.
roentgenograms
made
during
first
553
The electrocardiogram shows definite left axis deviation of the QRS complex in the frontal plane. There is no intraventricular conduction defect, and there are ST-T changes in the precordial leads compatible with the results of administration of digitalis. The P waves in Leads II, V1, and V:! are strongly suggestive of P mitrale. This electrocardiogram is rather interesting. The P mitrale would suggest left atria1 enlargement and may be seen not only in cases of rheumatic mitral valvular disease, but in any disorder that leads to increased resistance to filling of the left ventricle, such as systemic hypertension with left ventricular hypertrophy. However, we do not see a pattern of left ventricular hypertrophy. Left axis deviation in a young woman is also an uncommon and, I think, on the basis of the recent literature, an ominous finding. Strong correlation has been shown between true left axis deviation and significant myocardial disease.3 Even in cases of pure and rather severe mitral reflux, left axis deviation is not very common. In most patients the mean QRS axis in the frontal plane is either normal or tends toward the right. The electrocardiogram, then, would be compatible with either mitral valvular disease or primary disease of the left ventricle. Dr. Amplatz, may we see the roentgenograms next (Fig. 2).
admission
(a) and
during
second
ndmission
(6).
See text
DR. AMPIATZ: ,4 thoracic roe~ltgenogra~~~ taken during the first admission on April 9, 1964, shows marked cardiomegaly. There is enlargement of the left atria1 appendage, and a left atriall’double density” is present. No valvular calcification is apparent. There is marked pulmonary congestion; Kcrley’s I3 lines are also present. There is a right pleural effusion. A second study done on May 11, 1964, shows an increased degree of cardiac enlargement. Fluid has now appeared at both bases. The other findings are unchanged. The findings would be compatible with congestive cardiac failure on the basis of mitral reflux or myocardiopathy. DR. WINCI~ELL: Dr. Amplatz, do you see any suggestion of pericardial fluid? DR. AMPLATZ: The left atria1 enlargement, pulmonary congestion, and pleural effusion would suggest a failing cardiac muscle rather than pericardial fluid, but the latter possibility cannot definitely be excluded by these films. DR. WINCHELL: I think that we can eliminate toxemia of pregnancy and coronary arterial disease as reasonable possibilities. This leaves us with three possible choices: (1) rheumatic cardiac disease with predominant mitral reflux and, possibly, rheumatic active carditis; (2) a nonspecific l~yocarditis occurring fortLIitously during and (3) the so-called myopregnancy; cardiopathy of pregnancy. The left atria1 enlargement in the roentgenograms, as well as the P mitrale in the electrocardiogram and the physical findings of a probable pansystolic murmur, would certainly be strongly suggestive of significant mitral reflux. However, whether the mitral reflux is secondary or primary cannot be decided with any certainty from the information available. I would feel more certain of primary mitral valvular disease if an opening snap and a mitral rumble were present. On the other hand, the findings would be perfectly compatible with a nonspecific myocarditis occurring during late pregnancy. Certainly, one does not have to stretch one’s il~a~ination to postulate myocarditis with subsequent dilatation of the left ventricle and of the mitral orifice as a cause of mitral reflux. In view of the lack of a history of previous rheumatic fever, and because of the clew-tro-
cardiographic findings, 1 would have to choose a form of primar?- myocardial disease as the most likely cause of the patient’s problem. 1 cannot exclude the ” myocardiopathy of pregnancy.” The patient, however, was not Negro, and the rarity of the entity itself, combined with its racial predilection, would make it an extremely unlikely possibility.’ My final diagnosis will, therefore, be myocarditis of unknown cause occurring late in pregnancy, with rheumatic mitral reflux and/or myocarditis as a close second choice. DR. SPECKHALS: Thank you, Dr. Winchell. Dr. Edwards, would you now present the pathologic findings. DR. EDWARDS: The main pathologic findings were confined to the heart, lungs, and liver. The heart was slightly enlarged, weighing 345 grams. The right ventricle was considerably dilated, but not thickened; the wall measured 5 mm. in thickness. The left ventricle was also somewhat dilated, although not nearly so much as the right, and its wall showed slight hypertrophy, illeasuring 1.6 cm. in thickness. The left atrium \n-as also moderately enlarged and the wall was somewhat thickened, The most striking finding in the heart was diffuse thickening of the endocardium of all chambers, particularly of the left ventricle, giving the mural endoc~~rdiun~ a pearly white appearance (Fig. 3). The anterior and posterior leaflets of the mitral valve were thickened, and the edges of the anterior leaflet were rolled inward. There were two small clefts in the anterior leaflet but chordae tendineae supported the edges of the clefts. The other valves were not remarkable and there were no other defects in the heart. The coronary arteries were normal. The liver was enlarged and showed the typical nutmeg appearance of chronic passive congestion. The lungs had obvious areas of infarction in the right upper and middle lobes. A moderate amount of pulmonary edema was also present. Histologic examination of sections taken from several areas in the left ventricle showed the endocardium to be thickened to the degree that this layer measured up to 1.5 mm. The thickening was caused by deposits of collagenous and elastic- fibers, as well as by bundles of h~~pertrophied
Clinical $athologic conference
muscle (Fig. 4). The process of endocardial thickening extended into the intratrabecular sinusoids (Fig. 4). The myocardium was normal in each of the many sections examined. Histologic examination of the lungs showed atelectasis, edema, and hemosiderosis. Medial thickening of the walls of the pulmonary veins (Fig. 5,a), as well as medial thickening of the walls of the muscular pulmonary arteries (Fig. .S,b), were present in moderate degrees. Intimal proliferation was seen in arterioles and in venules (Fig. 5,~). The pathologic findings would suggest mitral insufficiency. The anterior leaflet of the mitral valve was thickened and more rigid than usual and, as a result, may not have been able to close properly. In addition, the papillary muscles probably exerted undue tension on the valve during ventricular systole because of their being pulled away from the valve by the dilatation of the left ventricle. Also, minor degrees of regurgitation might have occurred through the clefts in the anterior leaflet. The pulmonary vascular changes are also of some interest, in that, beside the changes of acute congestion, they show evidence of a long-standing increase in
5.55
pulmonary venous pressure. One would have to conclude that the patient had had pulmonary venous hypertension for some time prior to the apparent clinical onset of the disease. The lack of histologic abnormalities in the myocardium and the obvious cardiac failure in this patient is not an unusual phenomenon. In many instances of myocardiopathy, no histologic abnormalities can be discovered with light microscopy, even with the aid of special stains. It should be pointed out, however, that the histologic findings do not support a diagnosis of an acute myocarditis. The question arises whether the fibroelastosis, which was striking, was a primary or secondary problem or, more pointedly, whether this was a case of congenital endocardial fibroelastosis surviving to adulthood. From the appearance of the heart, this seems unlikely. There was relatively minimal hypertrophy of the left ventricle, in contrast to the marked hypertrophy seen in cases in which the endocardial fibroelastosis seems clearly to be of congenital origin. I would favor the view that, in this case, the endocardial fibroelastosis was secondary to the effects
Fig. 3. Gross specimen of heart. Q, Left atrium and left ventricle. Mild left ventricular hypertrophy. The endocardium of the atrium and the ventricle is grossly thickened, giving an opaque pale appearance. In the anterior leaflet of the mitral valve there are two clefts (arrows). The edges of the clefts are supported by chordae. b, Left ventricle and opened aortic valve. The aortic valve is normal. The endocardium of the left ventricle is thickened. The endocardial thickening in the myocardial sinusoids is also evident.
of myocardial failure. Dr. l;rom, you have reviewed a considerable amount of the literature on adult endocardial fibroelastosis and on the myocarditis of pregnancy. Would you please comment on these entities in the light of existing literature. DR. FROM: Endocardial fibroelastosis (EFE) is not uncoil111lon in adults. The distribution, however, is usuallg patch) and related to common clinical entities. One of the most common causes of EFE is myocardial infarction. In this situation, the endocardium is thickened where it overlies areas of healed m\.ocardial infarction.” ilnother common cause of EFE in adults is rheumatic cardiac disease with secondary valvular reflus. The so-called jet lesions may be considered to be esamples of localized EFE.j Another interesting entity is the endomyocardial fibrosis seen in Africa, in which there is diffuse and patchy fibrosis of the endocardiunl and of the m)~ocardiunl.” The etiology- of this entity is unknown. Another disease in which there may be marked thickening of the endocardium is the myocarditis of pregnant)-. In this situnt ion, in addition to endocardial thickening and illural
thrombi, there is usualfy a marked fibrotic and inflammatory reaction in the subendocardial myocardium.’ Another group of patients who inconsta~tiy d~nlonstr~~~~ diffusely thickened endocardium, especially of the left ventricle, are those with chronic cardiac failure and marked ventricular dilatation. EFE is also associated with numerous types of congenital cardiac nialfornlations.7 In such cases, the endocardial thickening ma>’ be related to the abnormal stresses placed upon the affected chamber by the nialforntation.5 Lastly, there are patients with endocardial thickening in whom the myocardium is histologically normal, as in the case presented here. i‘here is no evidence of coronary arterial disease, and it is in this group that the pathology is most similar to the congenital form of EFE. Many theories have been advanced to explain the genesis of EFE, but none has been colnpletely satisfactory. Myocardial an d endocardial hypoxia has been suggested as a possible etiology by Johnson.8 The frequent presence of viable smooth muscle cells in the thickened cndocardiurn itself, however, refutes this suggestion.”
Clinical pathologic conference
Others have discussed the occurrence of primary inflammatory processes involving the endocardium alone or both the endocardium and the myocardium and causing secondary EFE.‘” The suggestion of Still and Boult” on the basis of electron microscopy is that deposits of fibrin on the endocardial surface become incorporated into the endocardium, with resultant thickening. Recently, Miller and associateP have shown EFE to develop in dogs after the lymphatic drainage of the heart was obstructed. The endocardial thickening occurred in the absence of clinical cardiac failure or ventricular dilatation. These authors suggested that there may be a
557
relationship between the experimental disease and the human disease.13 As yet, it is to be seen whether their observations will receive confirmation by others. At the present time, Black-Schaffer’s suggestions have received the most experimental support.g He considers that all EFE is a secondary rather than a primary process, and that the primary fault in almost all of the various forms of EFE is underlying myocardial weakness, either generalized or localized. A weakened or failing heart has a tendency to dilate, and the tension of the ventricular wall increases for any given intraluminal pressure as the radius increases, according to the law
Fig. 5. Photomicrographs of pulmonary vessels. a. media1 hypertrophy considered to be indicative of tension. Elastic tissue stain; X55. 6, A muscular Each segment shows media1 hypertrophy. Elastic arteriole or venule. The intima is grossly thickened lumen to be markedly narrowed. Elastic tissue stain;
An intrapuhnonary vein. There is chronic pulmonary venous hyperartery and an arteriolar branch. tissue stain; X85. c, A pulmonary with fibrous tissue, causing the X5.50.
of Laplace. Blacl~-Scllaffer would envision endocardial thickening as a response to the increasing diastolic endocardial tension as the heart dilates. Support for his suggestion comes from evidence that physical forces may stimulate the development of the elastic tissue.‘* The vast differences in the amount of endocardial thickening in patients with the various types of cardiac failure might be ascribed to individual variation in the ability to bring forth a specific connective-tissue response comparable to the individual variation in the ability to form keloid. The adult patient with myocardiopathy and EFE may be an “endocardial keloid” former. Because there are so many postulated causes of EFE, it is obvious that much more work will have to be done before one can present a secure etiological classilication of the progress. Moreover, since the heart has a relatively limited pattern of response to a large and diverse number of possible agents or processes, the identification of definite cause-and-effect relationships will require the de~~eloplllent of methods of analyses which go beyond light and electron microscopy. The question whether there is a specific myocardiopathy associated with and caused by pregnancy is a difficult one. As has already been mentioned, there are some who favor the view that such an entity exists,’ and others who think that it does not exist.” As Benchimol and his associates15 have pointed out, however, most patients with cardiac failure in pregnancy, if carefully analyzed, can be placed in a standard diagnostic category, without resort to the creation of a specific entity peculiar to pregnant?. alone. In summary then, I think that our patient represents a case of myocardiopathy of undeterlllined cause, with secondary EFE and secondary mitral reflux. Because the pathologic findings indicate longstanding left ventricular dysfunction, I think that the problem was not related to pregnancy in any way other than that the cardiovascular stresses of pregnant?
forced an already weakened heart in to complete decompensation. Diagn0.G: Idiopathic myocardiopath) with endocardial fibroelastosis occurring during pregnancy. REFERENCES 1.
Meadows, W. R. : Idiopathic myocardial failure in the last trimester of pregnancy and the puerperium, Circulation 15:903, 1957. F., and Winchell, P.: “Postpartal” 2. Bashour, heart disease-A syndrome? Ann. Int. Med. 40:803, 1954. t.3 Eliot, R. S., Millhon, W. A., and ~~illhol~, J.: The clinical significance of uncomplicated marked left axis deviation in men without known disease, Am. J. Cardiol. 12:767, 1963. A. Dyson, B. C., and Decker, J. P.: Endocardial !i;ogclastosis in the adult, Arch. Path. 66:190, Edwards, J. E., and Burchell, H. B.: Endocardial and intimai lesions (jet impact) as possible sites of origin of murmurs, Circulation 18:946, 1958. J. N. I’.: Some considerations regard6. Davies, ing obscure diseases affecting the mural endocardium, AM. HEART J. 59:600, 1960. D. I-I., and Kelly, J.: Endocardial 7. Andersen, fibroelastosis. 1. Endocardial fibroefastosis associated with congenital ~lalforlnations of the heart, Pediatrics 18:513,1956. F. R. : Anoxia as a cause of endocardial 8. Johnson, fibroelastosis of infancy, Arch. Path. 54:237, 1952. B.: Infantile endocardial fibro9. Black-Schaffer, elastosis. *4 suRgested etiology,-. Arch. Path. 63:281,1957. -W. A.. Randall. R. V.. Bland. E. F.. 10. Thomas. and Castleman, B. : Endocardial fibroelastosis : A factor in heart disease of obscure etiology, New England J. Med. 251:327, 19.54. 11. Still, W. J. S., and Boult, E. H.: Pathogenesis of endocardial fibroelastosis, Lancet 2:117, 1956. 12. Milier, A. J., Pick, R., and Katz, L. N.: t-entricular endomyocardial changes after impairment of cardiac lymph flow in dogs, Brit. Heart J. 25:182, 1963. I. K., Miller, A. J., Pick, R., and Katz, 13. Kline, I.. N.: The relationship between human endocardial fibroelastosis and obstruction of the cardiac lymphatics, Circulation 30:528, 1964. 14. Bunting, C. I-I.: New formation of elastic tissue in adhesions between serons membranes and in myocardial scars, Arch. Path. 28:306, 1939. A. B., Carneiro, R. D., and Schle15. Benchimol, singer, P.: Postpartum heart disease, Brit. Heart J. 21&Q, 1959. 5.
conference
Robert C. Speckhals, M.D. Paul Winchell, M.D. Kurt Amplatz, M.D. Jesse E. Edwards, M.D.* Arthur H. L. From, M.D. St. Paul and Minneapolis,
Clinical
Minn.
abstract
DR. SPECKHALS: A 22-year-old white woman in the eighth month of her first pregnancy was admitted to the hospital for the first time with the chief complaints of cough, dyspnea, and orthopnea. The patient had noticed the onset of a nonproductive cough approximately 6 weeks prior to admission. This was not associated with fever, chills, or hemoptysis. For 10 days prior to admission, increasing dyspnea on exertion had been noticed. Early on the morning of admission, an episode of sudden onset of orthopnea and an increase in the degree of dyspnea and cough was experienced. The patient denied having thoracic pain, chills, fever, abdominal pain, or swelling of the ankles. There was no history of any recent febrile illness, hypertension, or albuminuria. There had been no significant gain in body weight. The past history revealed that an episode of acute glomerulonephritis had occurred when she was 5 years old. No significant neuromuscular symptoms were reported and there was no history of swelling or pain in joints. Two cousins had had rheumatic fever. Physical examination revealed a well-developed, well-nourished, white, pregnant, acyanotic woman, dyspneic and orthopneic, who appeared to be acutely ill. Except for signs of pregnancy consistent with the history, the positive physical findings were related to the cardiovascular system. The pulse was regular and the rate was 100 per minute. There was no fever. The blood pressure was 94 mm. Hg systolic, and 60 mm. Hg diastolic. No cervical venous distention was apparent, and there was no edema of the extremities. Palpation of the precordium revealed a left ventricular thrust. The pulmonic component of the second sound was accentuated. From
A third heart sound, not typical of an opening snap, was heard early in diastole. A Grade 2/6 systolic ejection type of murmur was present over the cardiac apex. No diastolic murmur was noted. A few &es were present at the pulmonary bases. The thyroid gland was diffusely enlarged to a minor degree. An electrocardiogram revealed a sinus tachycardia and left axis deviation. Laboratory studies showed the hemoglobin concentration to be 11.2 Gm. per 100 ml. of blood. The total leukocyte count was 9,650 per cubic millimeter of blood. The pH of the urine was 5, and the specific gravity was 1.004. Glycosuria and proteinuria were absent. Microscopic examination of the urine revealed no formed elements. The patient was placed on a regimen of bed rest and a lowsodium diet and was given 2 ml. of Thiomerin intramuscularly. Digitalization was accomplished by the administration of Acylanid. The patient’s condition gradually improved on this program and she was discharged after 15 days of hospitalization. The patient was readmitted 5 days later because of aching pain across the shoulders. The results of the physical examination and the electrocardiographic features were essentially like those of the first admission. The erythrocyte sedimentation rate (Westergren) was 106 mm. in 1 hour. The antistreptolysin titer of the serum was at a normal level, being 12 Todd units. The report on a specimen of stool sent to the Minnesota State Board of Public Health was “no virus isolated.” The level of urea nitrogen in the blood was 17 mg. per 100 ml. of blood. Three blood cultures, both aerobic and anaerobic, remained sterile. The test for the lupus erythematosus cell and Kline flocculation test gave
the Departments of Medicine and Pathology, The Charles T. Miller Hosp:tal, St. Paul, Minn.. and the Departments of Medicine, Radiology, and Pathology, University of Minnesota, Minneapolis. Minn. This study was supported by Public Health Service Training Grant No. 5 Tl HE 5570 and Reasearch Grant No. HE 5694 from the National Heart Institute. United States Public Health Service. Received for publication Jan. 6. 1965. *Address: Department of Pathology, The CharlesT. Miller Hospital, 125 West College Ave., St. Paul 2, Minn.
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The patient’s colu-se uvas then stable for the nest 10 day, after which increasing cl>-spnea nrld orthopne:t and pain in the right upper quadrant of the abdomen developed. Txhycardia persisted. ‘I‘hc systolic blood pressure measured 80 mm. Hg, :md the diastolic, 60 mm. Hg. The heart was enl;trgvtl to the left anterior axillary line, and a Grade 1 to 3 systolic ,,~~,~,,~~~r was heard ;A)ng the left sternal border. :I gallop rhythm dercloped, while the pulmo~rary fields remained clear and the liver cnlnrged to about 5 cm. below the right costal margin. ‘I’hc patient’s c.ondition showed increasing deterioration a rid she died 16 days after delivq-.
Discussion
DR. WNC‘HELL: To summarize, this was a La-year-oId woman who developed severe congestive cardiac failure toward the end of the third trimester of her first. pregnancq~ and ultimately died in the postpartum period in spite of vigorous medical treatment. The differential diagnostic possibilities are numerous. One of the first things to be considered is toxemia of pregnancy with hypertension, sodium retention, and, ultimately, severe cardiac failure. The patient was never hypertensive and gave no evidence of renal inlpairment, in spite of the history of gloilierLllonephritis at the age of 5 years. t4Ythout supporting evidence, we may rapidly discard toxemia as the cause of the cardiac problem. The most likely cause of failure in 3 young pregnant patient would be rheuInatic disease of the mitral valve. Here, physical findings give us scme help. There was, on palpation, evidence of left ventricular hyperactivity. The pulmonic component of the second sound was considerably increased in intensity, indicating pulmonary hypertension. At the apex there was a systolic ~l~~rlllur which was described as ejection in type, but which possibl?; could have been pansystolic-. These findings, coupled with the histot-!*
v2
Y3
v4
v5
V6
of cardiac failure beginning in the third trimester and becoming more severe in the immediate postpartal period, make a fair case for rheumatic mitral reflux. In addition to valvular disease, one would also have to consider strongly the possibilit, of recurrent rheumatic myocarditis. We get little help from the laboratory, however, since the antistreptolysin and the more specific antideoxyribonuclease titers were not raised. In spite of this, we cannot exclude rheumatic carditis. Another area which we should explore is congenital cardiac disease. Our co~illlents should be restricted to the acyanotic types, since the patient was not cyanotic. There was no clinical evidence of pulmonary stenosis, atria1 septal defect, or left-sided congenital valvular disease. Moreover, most types of acyanotic cardiac disease commonly seen in adults are compatible with a normal pregnancy. I think that, on the basis of the information already available, we can rule out congenital lesions of the ordinary types. The possibility of myocarditis should also be considered in this case. Instances of viral or nonspecific myocarditis occur, developing fortuitously during the latter half of pregnancy and terminating fata&. Although the results of viral studies performed in this patient were negative, the possibility of a viral myocarditis cannot be excluded. The possibility of idiopathic myocardiopathy, either of a familial or nonfamilial sort, should also be raised. With no positive family history, the former would seenl
Clinical pathologic conference
unlikely, but a nonfamilial type could not be excluded. Another diagnosis to be considered is that of the “myocardiopathy or myocardiosis of pregnancy.” In this condition, the patient usually develops congestive cardiac failure, tachycardia, and anginoid thoracic pain in the last trimester, or more commonly in the immediate or late postpartal peri0d.l Often in such patients, necropsy reveals subendocardial fibrosis and necrosis, as well as endocardial thickening with mural thrombi frequently adherent to the thickened endocardium. Embolization is quite frequent in this disorder. This entity, if it is an entity,2 is thought by some to be caused by pregnancy itself in some yet unknown fashion.’ Lastly, we must always consider atherosclerotic cardiac disease with myocardial infarction or fibrosis, and failure secondary to this. I place this problem last on our list of differential diagnoses because I think that it is by far the least likely. Myocardial infarction in pregnant young women occurs sporadically, but the incidence of coronary arterial disease in young women with functioning ovaries is very low. I mention this possibility for the sake of completeness, and I anticipate that it will get no support from the electrocardiogram. We might now review the electrocardiogram (Fig. 1).
Fig. 2. Thoracic for discussion.
roentgenograms
made
during
first
553
The electrocardiogram shows definite left axis deviation of the QRS complex in the frontal plane. There is no intraventricular conduction defect, and there are ST-T changes in the precordial leads compatible with the results of administration of digitalis. The P waves in Leads II, V1, and V:! are strongly suggestive of P mitrale. This electrocardiogram is rather interesting. The P mitrale would suggest left atria1 enlargement and may be seen not only in cases of rheumatic mitral valvular disease, but in any disorder that leads to increased resistance to filling of the left ventricle, such as systemic hypertension with left ventricular hypertrophy. However, we do not see a pattern of left ventricular hypertrophy. Left axis deviation in a young woman is also an uncommon and, I think, on the basis of the recent literature, an ominous finding. Strong correlation has been shown between true left axis deviation and significant myocardial disease.3 Even in cases of pure and rather severe mitral reflux, left axis deviation is not very common. In most patients the mean QRS axis in the frontal plane is either normal or tends toward the right. The electrocardiogram, then, would be compatible with either mitral valvular disease or primary disease of the left ventricle. Dr. Amplatz, may we see the roentgenograms next (Fig. 2).
admission
(a) and
during
second
ndmission
(6).
See text
DR. AMPIATZ: ,4 thoracic roe~ltgenogra~~~ taken during the first admission on April 9, 1964, shows marked cardiomegaly. There is enlargement of the left atria1 appendage, and a left atriall’double density” is present. No valvular calcification is apparent. There is marked pulmonary congestion; Kcrley’s I3 lines are also present. There is a right pleural effusion. A second study done on May 11, 1964, shows an increased degree of cardiac enlargement. Fluid has now appeared at both bases. The other findings are unchanged. The findings would be compatible with congestive cardiac failure on the basis of mitral reflux or myocardiopathy. DR. WINCI~ELL: Dr. Amplatz, do you see any suggestion of pericardial fluid? DR. AMPLATZ: The left atria1 enlargement, pulmonary congestion, and pleural effusion would suggest a failing cardiac muscle rather than pericardial fluid, but the latter possibility cannot definitely be excluded by these films. DR. WINCHELL: I think that we can eliminate toxemia of pregnancy and coronary arterial disease as reasonable possibilities. This leaves us with three possible choices: (1) rheumatic cardiac disease with predominant mitral reflux and, possibly, rheumatic active carditis; (2) a nonspecific l~yocarditis occurring fortLIitously during and (3) the so-called myopregnancy; cardiopathy of pregnancy. The left atria1 enlargement in the roentgenograms, as well as the P mitrale in the electrocardiogram and the physical findings of a probable pansystolic murmur, would certainly be strongly suggestive of significant mitral reflux. However, whether the mitral reflux is secondary or primary cannot be decided with any certainty from the information available. I would feel more certain of primary mitral valvular disease if an opening snap and a mitral rumble were present. On the other hand, the findings would be perfectly compatible with a nonspecific myocarditis occurring during late pregnancy. Certainly, one does not have to stretch one’s il~a~ination to postulate myocarditis with subsequent dilatation of the left ventricle and of the mitral orifice as a cause of mitral reflux. In view of the lack of a history of previous rheumatic fever, and because of the clew-tro-
cardiographic findings, 1 would have to choose a form of primar?- myocardial disease as the most likely cause of the patient’s problem. 1 cannot exclude the ” myocardiopathy of pregnancy.” The patient, however, was not Negro, and the rarity of the entity itself, combined with its racial predilection, would make it an extremely unlikely possibility.’ My final diagnosis will, therefore, be myocarditis of unknown cause occurring late in pregnancy, with rheumatic mitral reflux and/or myocarditis as a close second choice. DR. SPECKHALS: Thank you, Dr. Winchell. Dr. Edwards, would you now present the pathologic findings. DR. EDWARDS: The main pathologic findings were confined to the heart, lungs, and liver. The heart was slightly enlarged, weighing 345 grams. The right ventricle was considerably dilated, but not thickened; the wall measured 5 mm. in thickness. The left ventricle was also somewhat dilated, although not nearly so much as the right, and its wall showed slight hypertrophy, illeasuring 1.6 cm. in thickness. The left atrium \n-as also moderately enlarged and the wall was somewhat thickened, The most striking finding in the heart was diffuse thickening of the endocardium of all chambers, particularly of the left ventricle, giving the mural endoc~~rdiun~ a pearly white appearance (Fig. 3). The anterior and posterior leaflets of the mitral valve were thickened, and the edges of the anterior leaflet were rolled inward. There were two small clefts in the anterior leaflet but chordae tendineae supported the edges of the clefts. The other valves were not remarkable and there were no other defects in the heart. The coronary arteries were normal. The liver was enlarged and showed the typical nutmeg appearance of chronic passive congestion. The lungs had obvious areas of infarction in the right upper and middle lobes. A moderate amount of pulmonary edema was also present. Histologic examination of sections taken from several areas in the left ventricle showed the endocardium to be thickened to the degree that this layer measured up to 1.5 mm. The thickening was caused by deposits of collagenous and elastic- fibers, as well as by bundles of h~~pertrophied
Clinical $athologic conference
muscle (Fig. 4). The process of endocardial thickening extended into the intratrabecular sinusoids (Fig. 4). The myocardium was normal in each of the many sections examined. Histologic examination of the lungs showed atelectasis, edema, and hemosiderosis. Medial thickening of the walls of the pulmonary veins (Fig. 5,a), as well as medial thickening of the walls of the muscular pulmonary arteries (Fig. .S,b), were present in moderate degrees. Intimal proliferation was seen in arterioles and in venules (Fig. 5,~). The pathologic findings would suggest mitral insufficiency. The anterior leaflet of the mitral valve was thickened and more rigid than usual and, as a result, may not have been able to close properly. In addition, the papillary muscles probably exerted undue tension on the valve during ventricular systole because of their being pulled away from the valve by the dilatation of the left ventricle. Also, minor degrees of regurgitation might have occurred through the clefts in the anterior leaflet. The pulmonary vascular changes are also of some interest, in that, beside the changes of acute congestion, they show evidence of a long-standing increase in
5.55
pulmonary venous pressure. One would have to conclude that the patient had had pulmonary venous hypertension for some time prior to the apparent clinical onset of the disease. The lack of histologic abnormalities in the myocardium and the obvious cardiac failure in this patient is not an unusual phenomenon. In many instances of myocardiopathy, no histologic abnormalities can be discovered with light microscopy, even with the aid of special stains. It should be pointed out, however, that the histologic findings do not support a diagnosis of an acute myocarditis. The question arises whether the fibroelastosis, which was striking, was a primary or secondary problem or, more pointedly, whether this was a case of congenital endocardial fibroelastosis surviving to adulthood. From the appearance of the heart, this seems unlikely. There was relatively minimal hypertrophy of the left ventricle, in contrast to the marked hypertrophy seen in cases in which the endocardial fibroelastosis seems clearly to be of congenital origin. I would favor the view that, in this case, the endocardial fibroelastosis was secondary to the effects
Fig. 3. Gross specimen of heart. Q, Left atrium and left ventricle. Mild left ventricular hypertrophy. The endocardium of the atrium and the ventricle is grossly thickened, giving an opaque pale appearance. In the anterior leaflet of the mitral valve there are two clefts (arrows). The edges of the clefts are supported by chordae. b, Left ventricle and opened aortic valve. The aortic valve is normal. The endocardium of the left ventricle is thickened. The endocardial thickening in the myocardial sinusoids is also evident.
of myocardial failure. Dr. l;rom, you have reviewed a considerable amount of the literature on adult endocardial fibroelastosis and on the myocarditis of pregnancy. Would you please comment on these entities in the light of existing literature. DR. FROM: Endocardial fibroelastosis (EFE) is not uncoil111lon in adults. The distribution, however, is usuallg patch) and related to common clinical entities. One of the most common causes of EFE is myocardial infarction. In this situation, the endocardium is thickened where it overlies areas of healed m\.ocardial infarction.” ilnother common cause of EFE in adults is rheumatic cardiac disease with secondary valvular reflus. The so-called jet lesions may be considered to be esamples of localized EFE.j Another interesting entity is the endomyocardial fibrosis seen in Africa, in which there is diffuse and patchy fibrosis of the endocardiunl and of the m)~ocardiunl.” The etiology- of this entity is unknown. Another disease in which there may be marked thickening of the endocardium is the myocarditis of pregnant)-. In this situnt ion, in addition to endocardial thickening and illural
thrombi, there is usualfy a marked fibrotic and inflammatory reaction in the subendocardial myocardium.’ Another group of patients who inconsta~tiy d~nlonstr~~~~ diffusely thickened endocardium, especially of the left ventricle, are those with chronic cardiac failure and marked ventricular dilatation. EFE is also associated with numerous types of congenital cardiac nialfornlations.7 In such cases, the endocardial thickening ma>’ be related to the abnormal stresses placed upon the affected chamber by the nialforntation.5 Lastly, there are patients with endocardial thickening in whom the myocardium is histologically normal, as in the case presented here. i‘here is no evidence of coronary arterial disease, and it is in this group that the pathology is most similar to the congenital form of EFE. Many theories have been advanced to explain the genesis of EFE, but none has been colnpletely satisfactory. Myocardial an d endocardial hypoxia has been suggested as a possible etiology by Johnson.8 The frequent presence of viable smooth muscle cells in the thickened cndocardiurn itself, however, refutes this suggestion.”
Clinical pathologic conference
Others have discussed the occurrence of primary inflammatory processes involving the endocardium alone or both the endocardium and the myocardium and causing secondary EFE.‘” The suggestion of Still and Boult” on the basis of electron microscopy is that deposits of fibrin on the endocardial surface become incorporated into the endocardium, with resultant thickening. Recently, Miller and associateP have shown EFE to develop in dogs after the lymphatic drainage of the heart was obstructed. The endocardial thickening occurred in the absence of clinical cardiac failure or ventricular dilatation. These authors suggested that there may be a
557
relationship between the experimental disease and the human disease.13 As yet, it is to be seen whether their observations will receive confirmation by others. At the present time, Black-Schaffer’s suggestions have received the most experimental support.g He considers that all EFE is a secondary rather than a primary process, and that the primary fault in almost all of the various forms of EFE is underlying myocardial weakness, either generalized or localized. A weakened or failing heart has a tendency to dilate, and the tension of the ventricular wall increases for any given intraluminal pressure as the radius increases, according to the law
Fig. 5. Photomicrographs of pulmonary vessels. a. media1 hypertrophy considered to be indicative of tension. Elastic tissue stain; X55. 6, A muscular Each segment shows media1 hypertrophy. Elastic arteriole or venule. The intima is grossly thickened lumen to be markedly narrowed. Elastic tissue stain;
An intrapuhnonary vein. There is chronic pulmonary venous hyperartery and an arteriolar branch. tissue stain; X85. c, A pulmonary with fibrous tissue, causing the X5.50.
of Laplace. Blacl~-Scllaffer would envision endocardial thickening as a response to the increasing diastolic endocardial tension as the heart dilates. Support for his suggestion comes from evidence that physical forces may stimulate the development of the elastic tissue.‘* The vast differences in the amount of endocardial thickening in patients with the various types of cardiac failure might be ascribed to individual variation in the ability to bring forth a specific connective-tissue response comparable to the individual variation in the ability to form keloid. The adult patient with myocardiopathy and EFE may be an “endocardial keloid” former. Because there are so many postulated causes of EFE, it is obvious that much more work will have to be done before one can present a secure etiological classilication of the progress. Moreover, since the heart has a relatively limited pattern of response to a large and diverse number of possible agents or processes, the identification of definite cause-and-effect relationships will require the de~~eloplllent of methods of analyses which go beyond light and electron microscopy. The question whether there is a specific myocardiopathy associated with and caused by pregnancy is a difficult one. As has already been mentioned, there are some who favor the view that such an entity exists,’ and others who think that it does not exist.” As Benchimol and his associates15 have pointed out, however, most patients with cardiac failure in pregnancy, if carefully analyzed, can be placed in a standard diagnostic category, without resort to the creation of a specific entity peculiar to pregnant?. alone. In summary then, I think that our patient represents a case of myocardiopathy of undeterlllined cause, with secondary EFE and secondary mitral reflux. Because the pathologic findings indicate longstanding left ventricular dysfunction, I think that the problem was not related to pregnancy in any way other than that the cardiovascular stresses of pregnant?
forced an already weakened heart in to complete decompensation. Diagn0.G: Idiopathic myocardiopath) with endocardial fibroelastosis occurring during pregnancy. REFERENCES 1.
Meadows, W. R. : Idiopathic myocardial failure in the last trimester of pregnancy and the puerperium, Circulation 15:903, 1957. F., and Winchell, P.: “Postpartal” 2. Bashour, heart disease-A syndrome? Ann. Int. Med. 40:803, 1954. t.3 Eliot, R. S., Millhon, W. A., and ~~illhol~, J.: The clinical significance of uncomplicated marked left axis deviation in men without known disease, Am. J. Cardiol. 12:767, 1963. A. Dyson, B. C., and Decker, J. P.: Endocardial !i;ogclastosis in the adult, Arch. Path. 66:190, Edwards, J. E., and Burchell, H. B.: Endocardial and intimai lesions (jet impact) as possible sites of origin of murmurs, Circulation 18:946, 1958. J. N. I’.: Some considerations regard6. Davies, ing obscure diseases affecting the mural endocardium, AM. HEART J. 59:600, 1960. D. I-I., and Kelly, J.: Endocardial 7. Andersen, fibroelastosis. 1. Endocardial fibroefastosis associated with congenital ~lalforlnations of the heart, Pediatrics 18:513,1956. F. R. : Anoxia as a cause of endocardial 8. Johnson, fibroelastosis of infancy, Arch. Path. 54:237, 1952. B.: Infantile endocardial fibro9. Black-Schaffer, elastosis. *4 suRgested etiology,-. Arch. Path. 63:281,1957. -W. A.. Randall. R. V.. Bland. E. F.. 10. Thomas. and Castleman, B. : Endocardial fibroelastosis : A factor in heart disease of obscure etiology, New England J. Med. 251:327, 19.54. 11. Still, W. J. S., and Boult, E. H.: Pathogenesis of endocardial fibroelastosis, Lancet 2:117, 1956. 12. Milier, A. J., Pick, R., and Katz, L. N.: t-entricular endomyocardial changes after impairment of cardiac lymph flow in dogs, Brit. Heart J. 25:182, 1963. I. K., Miller, A. J., Pick, R., and Katz, 13. Kline, I.. N.: The relationship between human endocardial fibroelastosis and obstruction of the cardiac lymphatics, Circulation 30:528, 1964. 14. Bunting, C. I-I.: New formation of elastic tissue in adhesions between serons membranes and in myocardial scars, Arch. Path. 28:306, 1939. A. B., Carneiro, R. D., and Schle15. Benchimol, singer, P.: Postpartum heart disease, Brit. Heart J. 21&Q, 1959. 5.