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Clinical-pathologic conference
Clinical-pathologic
conference
John R. Dainauskas, M.D. Armando Susmano, M.D. Maurice L. Bogdonoff, M.D. Chicago, Ill.
Clinical
summary
A 56-year-old retired, white fireman had been in good health until developing signs and symptoms of congestive heart failure two years before admission to this hospital. At that time he was hospitalized elsewhere because of severe pedal edema, 30 pound weight gain, and shortness of breath. He was treated with “heart and water pills” and improved, but was again hospitalized a month later with “pneumonia.” Since that time he quit working because of increasing fatigue and shortnass of breath even when climbing one flight of stairs or walking one-half block. There was a history of hypertension with occasional palpitations, but further particulars about duration, severity, or treatment were not available. The patient also had noted dry skin, pruritis, periorbital edema, and increased sensitivity to cold. There was no history of chest pain, paroxysmal nocturnal dyspnea, intermittent claudication, or orthopnea. Apparently, his speech was slow and mentation had deteriorated. He was taking crystodigin (0.2 mg. four times per week), Lasix (80 to 160 mg. per day, depending on the .degree of ankle edema), aminophylline (1% grams three times a day), and Zyloprim (100 mg. three times a day). He stopped smoking, but he had a 90-pack per year history of cigarette smoking. On admission the vital signs were: blood pressure, 110/70 mm. Hg; pulse, 50 to 60 per minute, irregularly irregular; respirations, 16 per minute; and temperature, 97” F. There was bilateral, periorbital edema. Dry, cool, and peeling skin with cracks was described. The skin of the lower extremities was shiny, waxy, and pigFrom the Departments of Pathology, Medicine, and Radiology, RushPresbyterian-St. Luke’s Medical Center, Chicago. Received for publication Oct. 29, 1973. Reprint requesta to: Dr. John R. Dainauskas, Department of Pathology, Rush-Presbyterian-St. Luke’s Medical Center, 1753 W. Congress Parkway, Chicago, Ill. 60612.
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1974, Vol. 88, No. 2, pp. 229-239
mented, but there was no edema. The thyroid was freely movable, slightly enlarged, and the right lobe was larger than the left. The chest was clear to auscultation and percussion. The PMI was in the sixth intercostal space at the anterior axillary line. S, was normal and louder than S,, but both appeared distant. There was no S,, S, OF opening snap. A harsh, low-pitched Grade III/VI pansystolic murmur was heard best at the lateral sternal border. It radiated to the axilla and toward the pulmonic area. Veins in the neck were distended. The peripheral pulses were normal in the upper and dacreased in the lower extremities. The liver had a span of 11 cm. and was palpated with some pulsations 4 cm. below the right costal margin. Fluid wave was not described. The motor and sensory function6 were intact, but his speech was described as slow and slurred, and his voice as husky. Reflexes were generally diminished. There was no peripheral edema. Cardiac catheterization showed the following pressures in millimeters of Hg: RA mean pressure, 17; pulmonary artery, 65 systolic and 32 diastolic with a mean of 40 and a PA wedge of 28; LV, 93 systolic and 28 end-diastolic; and aortic, 93 systolic and 72 diastolic. The cardiac index was 0.83 L. per minute per square meter. The AV oxygen difference was 10.4 vol. per cent. The total systemic, pulmonary, and pulmonary vascular resistance (dynes/sec./cm.? were 3,904, 1,928, and 578, respectively. The metabolic rate was -30 per cent. The respiratory rate was 12 per minute; heart rate, 72 per minute, and the 0, consumption index was 86 ml. per minute per square meter. Selective LV tine showed a very large, dilated chamber with minimal contractility and large end-syrstolic volume. A mild-tomoderate pericardial e&&on was noted. The patient was placed on a cardiac monitor and Cytomel(5 pg per day) therapy was started The next day he developed severe pulmonary
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cent; T, by Murphy-Pat&e, 2.4 pg per cent; TSH, 120 in pml. Immunologic studies showed presence of microsomal antibodies and antibodies to the second colloid antigen. Immunoglobulin electrophoresis showed IgG, 5.48 mg. per cent; IgA, 1.19 mg. per cent; IgM, 0.36 mg. per cent; and IgD, 0.06 mg. per cent. The urinalysis showed specific gravity of 1.006, pH, 6.0, and no protein, sugar, or ketone bodies. The spun sediment contained no cells. Discussion
Fig. 1. Frontal film of four-position series. There is marked, generalized enlargement of cardiac shadow. Pulmonary vasculature shows redistribution. There is moderate basilar pulmonary edema with pleural effusion.
edema and hypotension. Cytomel was discontinued and intravenous digoxin and Lasix increased the blood pressure and decreased the pulmonary edema. Then, the patient developed ventricular irritability with 8 to 9 PVC’s per minute. Questionable ascites but not peripheral edema were described. Serum K at that time was 3.0 mEq. per liter. He died after a cardiorespiratory arrest about two weeks after admission. On admission, the hemogram showed a hemoglobin of 13.1 Gm.; hematocrit, 41.5; RBC, 4.95 million; and WBC, 11,600 with a differential count of 49 polys, 33 bands, 12 lymphocytes, 5 monocytes, and 1 basophil. The platelet count was 62,000. Repeated platelet counts were within normal limits. The RBC indices were normal. The electrolytes showed: Na, 142; K, 3.3; Cl, 97; and CO,, 28.0 mEq. per liter. Calcium was 9.8; phosphorus, 4.4; BUN, 25; creatinine, 1.4 mg. per cent; CPK, 34; ICD, 80; SGCYI’, 28; LDH, 590; SGPT, 5; alkaline phosphatase, 4.1 units; and uric acid, 9.7 mg. per cent. Postprandial glucose was 113 mg. per cent. Total cholesterol was 223 ma;. per cent. Leucine aminopeptidase (LAP) was 194.9 units. The plasma cortisol was 25.4 mg. per cent; urine 17-OH-corticosteroids, 5.8 mg. per 24 hours; T, uptake, 28 per cent; PBI, 2.5 mg. per 230
DR. SUSMANO: In summary, we are confronted with the clinical picture of a 56-year-old man with a two-year history of intermittent and progressive congestive heart failure who has also developed dry skin, increased sensitivity to cold, and slurred speech with a husky voice. We have heard about his physical findings as well as his hemodynamic and biochemical abnormalities. Before proceeding with a detailed analysis of all these data, I would like to see the chest x-rays. DR. BOGDONOFF: Four-position chest films dated Dec. 18,1972, have demonstrated marked generalized cardiomegaly. The aorta is of normal size and the central pulmonary vasculature is normal. There is pulmonary vascular redistribution, venous and lymphatic distention, as well as a small amount of pleural fluid All are findings of cardiac decompensation. I cannot tell how much of this markedly enlarged heart shadow is due to pericardial fluid Portable films dated Dec. 28, 1972, and Dec. 30, 1972, showed a marked worsening of the heart failure and widespread alveolar edema in addition to the previously noted interstitial edema. This marked bilateral pulmonary edema persists on the portable film of Dec. 30,1972. There have been minor changes in the edema, with slight “milking” of edema along the right-heart border and minimal improvement in the edema adjacent to the hilar region. These findings are characteristic of edema due to marked cardiac decompensation. The cardiac findings are nonspecific and are compatible with cardiomyopathy with or without pericardial effusion. on adDR. SUSMANO: The electrocardiogram mission showed atria1 fibrillation with a slow ventricular response, marked intraventricular conduction block with a QRS duration of 0.20 second, and a very low QRS voltage in the standard leads.
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Clinical
Fig. 2. Twelve-lead
Cardiac catheterization revealed mild or, perhaps, a moderate amount of pericardial effusion. The cardiac index was severely decreased and the LV and RV early and end-diastolic pressures were significantly elevated. Selective cineangiocardiogram showed that the left ventricular chamber was markedly dilated, with a significant decrease in left ventricular contractility and very large end-diaetolic and end-systolic volumes. All these findings are consistent with the diagnosis of severe cardiomyopathy associated with a mildto-moderate degree of pericardial effusion. Let me ignore, for the moment, the severe abnormalities of the thyroid function. We are dealing, without any doubt, with a severe case of cardiomyopathy. But which one is responsible for it? On the basis of the history and physical and hemodynamic findings, if we were to follow Drs. Mattingly’s and Abelman’s approach to the cardiomyopathies, ly2 then we could eliminate two important groups: the hypertrophic variety, whether familial or not, and the obstructive type better known as idiopathic hypertrophic subaortic stenosis (also whether familial or not). No intraventricular pressure gradients were found, and the presence of the largely dilated left ventricular chamber with significant decrease in its contractility would easily exclude these two
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admission electrocardiogram.
types. This patient was apparently hypertensive for several years. Although left ventricular hypertrophy with subsequent dilation can be seen in the terminal stages of fixed or malignant hypertension, the clinical and radiologic findings are quite different from the ones encountered in this patient. Besides that, his hypertension was never severe enough as to require strict therapy. Therefore, we would not consider this to be the end-stage of this disease. We should then direct our attention to either the dilated or restricted type of cardiomyopathies. In the restricted, usually called infiltrative type, we should consider’lamyloid heart disease. Amyloidosis can account for up to ten per cent of noncoronary cardiomyopathies. It should be considered in relatively older patients who have progressive and intractable types of congestive heart failure which may be associated with skin and mucous membrane lesions, purpuric changes, nephrosis, peripheral neuropathy, macroglossia, etc. None of the symptoms and physical findings just mentioned was encountered in our patient, and the electrocardiogram was not associated with QRS abnormalities suggesting the possibility of a “dead zone” due to myocardial infarction, as has been so often seen in patients with cardiac amyloidosis. It would also be extremely uncom-
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Fig. 3. A, Frame of selective left ventricular cineangiogram shows a very large ventricular chamber with markedly increased end-diastolic volume. B, Shows the end-systolic volume of the left ventricle. Only the posterobasal and outflow tract areas contract, although the myocardial contractility is diffusely decreased.
mon for the heart to be radiologically enlarged as much as in this case. Usually, it is only slightly enlarged. We do not have any evidence to support the possibility of either neoplastic infiltration of the heart, hemochromatosis, or glycogen disease, the latter exclusively seen in infants and children. There was no history or physical findings of involvement of the peripheral muscles; therefore, myocardial involvement as may occur in heredofamilial neuromyopathic diseases like Friedrich’s ataxia, myotonic dystrophy, etc., can also be excluded. Some patients with the clinical syndrome of constrictive pericarditis have also shown abnormalities in the contractility of the myocardium or what has been called “myocardial misuse” as a secondary change to the severe pericardial involvement. Occasionally, a patient with constrictive pericarditis may have associated pericardial effusion. However, in this case the degree of pericardial effusion was probably greater than that encountered in patients who do have primary pericardial disease. The syndrome of endocardial fibroelastosis, which has been seen in adults, can probably be excluded considering our patient’s advanced age. Certainly, other entities that may also involve the endocardium such as endomyocardial fibrosis, as have been observed in Africa, should be brought into the differential diagnosis of the restrictive types of cardiomyopathies which I am including as part of the differential diagnosis, but not because I strongly believe this to be a diagnostic possibility in our case.
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Our patient did not give any history of heavy alcoholic or beer intake and I can possibly exclude them as an etiologic consideration. We now finally come to the last group or the dilated type of cardiomyopathies which are so common in the adult population. This form of usually called “primary myocardial disease” is also often referred to as the congestive type. Numerous etiologies have been suggested for primary myocardial disease and the number of conditions that could be included is quite large, ranging from injury to the myocardial muscles secondary to malnutrition, myocarditis, unknown toxins, or immunity, trauma, toxic agents, specific infections, or metabolic abnormalities. I like to call primary myocardial disease the type of heart disease where no known etiology can be found Other types which may produce similar myocardial changes but are secondary to a specific etiology, I usually like to refer to as myocarditis which has entered the chronic stage. In’patients in whom a specific etiology is found, the viral, bacterial, mycotic, parasitic, protozoal, and rickettsial infections or toxic agents can be the cause of the myocardial injury. The damage can also be secondary to a metabolic abnormality. As previously mentioned, nutritional and electrolyte imbalance and, most commonly, severe hypokalemia or anemia can be accompanied by severe myocardial disease. Regardless of these different etiologies, they may produce common pathologic changes in the so-called primary myocardial disease, and the findings on physical
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examination are commonly the same. The jugular venous pressure is elevated and very high “V” waves can be seen, suggesting the presence of tricuspid incompetence. The pulse pressure is usually within normal limits or may be low; but, most commonly, there is a very narrow pulse pressure. Pulsus alternans is also frequent, if very clearly sought. There may be no murmurs or just murmurs due to tricuspid or mitral insufficiency which are secondary to ventricular dilation and pulling of the papillary muscles producing valvular incompetence. The presence of filling sounds such as prominent third sound or atria1 gallops can also be heard. All kinds of electrocardiographic abnormalities have been observed ranging from changes in voltage, particularly low voltage in the standard lead, as well as arrhythmias, atria1 fibrillation, or ventricular arrhythmias and conduction abnormalities, whether of the right bundle or the left bundle branch type. First-degree A-V block has commonly been seen, but on many occasions may also be secondary to digitalis therapy. Second-degree or thirddegree A-V block is extremely uncommon. Hemodynamic studies are usually similar with a very low cardiac index and elevated ventricular diastolic pressures. As has been emphasized by Proctor Harvey and colleagues,3 there is a clinical spectrum of primary myocardial disease ranging from mild to severe degree, and the course of the patient’s disease will be related to the degree of involvement of the myocardium, resulting in death, usually in less than two years, when the involvement is severe, or may evolve into a complete recovery when there is only mild involvement of the myocardium. There is a very high incidence of sudden death, particularly in the idiopathic type of primary myocardial disease. Commonly, in patients with primary myocardial disease, when no specific etiology can be found the possibility of viral origin is considered. Coxsackie B virus has been implicated as a common etiologic factor. Virus-like particles have been occasionally noted in cardiac tissues of such patients. It is quite possible that once a patient achieved the chronic stage, circulating antibodies have significantly decreased and then it is almost impossible to establish a cause-and-effect relationship in viral myocardial disease. We do not have any real evidence that our patient has had any severe viral infections in the past; therefore, it would be extremely difficult to relate
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his myocardial disease with a possible viral etiology and I would consider it very unlikely, although I do not have definite proof. We do not have any evidence of specific infections such as brucellosis, tuberculosis, rickettsial diseases, or toxoplasmosis. Therefore, infections would not be considered as a potential etiologic factor in this case. We also have no evidence for any collagen disease such as rheumatoid arthritis or lupus erythematosus with documented vasculitis which might well be a factor in the development of myocardial disease; but again there has been no prior history that may substantiate the possibility of systemic involvement. We do not have any history of severe nutritional deficiency, and the physical findings did not show an emaciated or cachectic individual; nor was he using large amounts of cathartics which may produce extreme hypokalemia and, therefore, a hypokalemic cardiomyopathy, and we can exclude this possibility. I do believe that by now we have narrowed down most of the diagnostic possibilities. I would like to return to what we have concerning real facts in the sense of the history and physical and laboratory findings. Our patient gave a positive history of progressive tiredness, somnolence, slow mentation, increased intolerance to cold, dryness of skin, and also typical changes of a “gravel voice.” His thyroid studies demonstrated the presence of severely depressed function. All of this speaks strongly for myxedema. The question posed to us is whether this entity is responsible for the heart disease or not. Many studies, most of them case reports, have appeared in the literature since Zondek described the condition as a specific entity in 1918. He laid down the criteria of both right- and leftsided dilation associated with abnormalities of conduction with definite reduction in transverse diameter of the heart following thyroid gland therapy. Radiologic enlargement of the heart has been said to be common in myxedema, due either to myocardial damage or to the presence of a pericardial effusion or both.4 However, other factors such as old age, systemic arterial hypertension, and coronary artery disease have been shown in part responsible for the increase in heart size in myxedema. Of 53 patients studied by Aber and Thompson4 55 per cent were found to have cardiac enlargement, most of whom were
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older and had higher systemic hypertension than those patients with normal-sized hearts. Several of them also had some evidence of ischemic heart disease. Conversely, many patients have typical electrocardiographic changes of myxedema heart disease with normal-sized hearts and they conclude that this implies the lack of associated hypertension or coronary artery disease. However, as has been pointed out by Kern and co-workers,s pericardial effusion is a constant, early, and major factor in the myxedematous heart and the one responsible for the roentgenologic changes in the cardiac silhouette and not due to myocardial failure since, in general, it responds to thyroid therapy alone. Our patient has had intermittent episodes of heart failure. The question as to whether or not myxedema heart can evolve into heart failure has been disputed and questioned for many years after Fahr reported the occurrence of heart failure in this disease. Hemodynamic studies have shown that the cardiac output is signiflcantly depressed and parallel, in general, to the decrease in oxygen consumption,. While A-V differences have been observed to be within normal limits or slightly wider, the cardiac output may be depressed out of proportion to the oxygen demands of the body. This represents strong evidence of damage to the heart and of circulatory insufficiency, according to the studies by Ellis and co-workers.6 Studies performed by Graettinger and coworkers’ have shown the cardiac index to be considerably below normal, but an adequate increase occurred during bicycle exercise. Right atria1 pressures were elevated at rest and the right ventricular pressures had a diastolic dip with elevated end-diastolic pressures, findings which were attributed to pericardial effusion rather than to myocardial disease. Their patients had a low-normal heart rate with a significant decrease in stroke volume at rest. This was in sharp contrast with patients who did have primary myocardial disease and who were in congestive failure. Their oxygen consumption at rest and the basal metabolic rates were normal or elevated, and the cardiac output was significantly lower than in patients with myxedema or normal persons. Furthermore, the heart rate was faster, the A-V differences much wider at rest, and the cardiac output did not increase or decrease during exercise.
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Our patient had severe myocardial disease manifested by significantly wide A-V difference, markedly decreased cardiac output, elevated end-diastolic pressures in both ventricles, low stroke volume, and diffuse decreased contractility by selective left ventricular cineangiogram. However, he did have a normal respiratory rate, a slow ventricular rate, a very low oxygen consumption, and a low metabolic rate which is exactly the opposite of what one would expect if this degree of myocardial failure was due to primary myocardial disease. As stated by Ellis and co-workers,6 there appears to be no uniformity in the response of the cardiovascular system to myxedema. It is also true that patients who have been in intractable heart failure were improved in the past by being made myxedematous. Although this appears to be a paradox, total ablation of the thyroid seems to benefit the heart by lessening the circulatory demands through a reduction in the oxygen consumption and, therefore, decreasing the metabolic needs, the cardiac output, and the cardiac work. This also could relieve angina pectoris. In a study of 20 patients with myxedema where 16 had large hearts and only seven were clinically indistinguishable from cardiac failure, pulse pressure response to the Valsalva maneuver showed that apparently only one of the patients was in cardiac failure.8 It was assumed, therefore, by McBrien and Hindlea that myxedema in itself does not cause heart failure and, if it occurs, it is the result of other disease, usually ischemic. This work evidently is at variance with the observation of other authors, where myxedema and heart failure have been observed in the absence of coronary artery disease. Furthermore, a case report was published by Monroe and FearringtorP of a patient with severe myxedema and marked cardiomegaly who continued to have massive cardiomegaly after all pericardial effusion had been removed. The venous angiocardiogram showed the cardiac enlargement to be due primarily to left ventricular dilation, demonstrating then that the persistent cardiomegaly was due to myxedematous cardiomyopathy. Finally and briefly, I would like to make some comments about a possibility of ischemic cardiomyopathy. Although this is a known entity, it usually occurs in patients who have had long-
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4. Hypertrophied stain, X300. Fig.
myocardium
with interstitial
standing evidence of angina pectoris or previous myocardial infarctions, which our patient did not have. He could have, however, small-vessel disease but I doubt it. The unsolved question is whether myxedema leads to or accelerates the development of atherosclerosis. In a study by Willius and HaineslO of 162 patients with severe myxedema, 91 per cent had no subjective symptoms of organic cardiovascular disease and a large proportion of their patients were in the fourth, fifth, and sixth decades of life, the age group where the incidence of ischemic heart disease should be higher. Andrus11 has reported that Bartel and Bell found an incidence of 25 per cent of coronary artery disease in a spontaneous myxedema. The increase in, or the development of, angina pectoris is common, however, during the course of therapy of myxedema. In those patients who have a significant degree of coronary arteriosclerosis the administration of thyroid replacement could be lethal.12 Our patient died rather soon after the initiation of synthetic thyroid therapy. A ventricular arrhythmia and exacerbation of congestive heart failure developed This could suggest the presence of moderately severe and asymptomatic coronary artery disease. However, I do feel that this was not a manifestation of ischemic cardiomyopathy but the lethal result of thyroid replacement in a patient with myxedema heart,
American
Heart Journal
and probable intracellular
pathologic
edema. Hematoxylin
conference
and eosin
manifested by an extremely severe degree of myocardial involvement, who may happen to have associated coronary artery disease. If that were the case with this patient, probably an important conchrsion would be that, in the future, patients with severe myxedema who are to be given thyroid therapy should have coronary arteriographic studies whether symptomatic or not, from that point of view, to determine the extent and degree of disease in the coronary arterial system. This could provide valuable information as to the potential risk of this mode of therapy in this type of disease. Autopsy
results
At autopsy there was generalized edema and the skin had a rather coarse and rough texture with brownish pigmentation over the forearms and lower legs. There were 2,000 C.C. of ascitic, approximately 1,500 C.C. of pleural, and 200 C.C. of pericardial fluid. The heart was hypertrophied, flabby, and somewhat globular. The chambers were dilated It weighed 1,006 grams. The ventricular walls measured in average thickness, 2.2 cm. on the left and 0.5 cm. on the right. The myocardium was of normal color but an illdefined, grayish-white infarct measuring 1.6 cm. in width extended from the base to mid-level in the posterior wall of the left heart. The circumference of the tricuspidvalve was 15 cm. and that 235
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Fig. 6.
Chronic nonsuppurative
thyroiditis.
of the mitral valve, 12 cm. The valves were not deformed. The endocardium of the left atrium was irregular with a crescent-shaped scar opposite the orifices of the right pulmonary veins. However, the veins were not narrowed. The endocardium of the anterior wall of the left atrium was thick and brown. Only a few small foci of endocardial fibrosis were seen in the left ventricle. Although focal coronary atherosclerosis was present, the left circumflex and anterior descending branches were widely patent. The right coronary artery was as large as the left and at its origin was widely patent. However, a 3 mm. segment was almost completely occluded by white fibrous material at the right margin of the heart. From this point onward, the lumen widened to a diameter of 1 to 2 mm. The vessel formed a widely patent posterior descending coronary arbrY* The microscopic examination of the coronary arteries showed an 80 per cent occlusion of the right coronary artery by an atheromatous plaque. The other arteries did have fibrous and atheromatous plaques but their lumina retained at least 70 to 90 per cent of their patency. The small myocardial arteries and arterioles were normal. The myocardial fibers were large and had large, square nuclei. There were scattered intracytoplasmic vacuoles. Sudan IV fat stain, alcian blue-PAS, and trichrome stains were not helpful in defining the nature of the material in
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Hematoxylin
and eosin stain, X100.
the vacuoles. The muscle cells were widely separated from each other, most likely due to interstitial edema. It is possible that the cytoplasmic vacuoles also represented edema. There was no interstitial or perivascular fibrosis, but an old scar was present in the posterior left ventricular wall. Fibroelastosis was noted focally in the left ventricle and some areas resembled old organized mural thrombi, although there was no evidence of organizing or acute thrombi. Fibroelastosis was also noted in sections of the left atrium. The right lung weighed 1,050 grams and the left lung, 760 grams. There was focal pleural fibrosis and the lungs were subcrepitant and wet. In the lower lobes there were ill-defined areas of consolidation. Microscopic examination of the upper lobes showed interstitial fibrosis with aggregates of numerous hemosiderin-containing macrophages, dilation of lymphatic channels, and dilation and some sclerosis of small veins in the intralobular septa. Dilation with some hypertrophy and scarring of the walls of small arteries was also present. Large arteries contained atheromatous plaques but there was no vasculitis. In the lower lobes there were healing infarcts with several areas of necrosis and reactive interstitial fibrosis with lining cell proliferation in the adjacent parenchyma. There were also large, hyalinized scars probably representing healed infarcts. In one such area there was an
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Fig.
6. Upper lung field with interstitial
obliterated artery and there were other arteries with proliferative end-arteritic changes markedly narrowing the lumina. There were also small arteries containing multichanneled lumina suggesting that this entire pathologic process was due to chronic embolization and repair of infarcts. However, there were no healing or acute emboli. Conspicuous capillary telangiectasis in these areas suggested possibility of an A-V shunt, although none was demonstrated. The liver was enlarged (2,280 grams) with changes due to chronic passive congestion. Small scars representing usually obliterated central veins were present. The etiology of the latter change is not clear since there was no history of excessive alcoholic consumption. The spleen was also congested (420 grams) and contained a healed infarct. The pancreas showed interstitial fibrosis with chronic inflammation, fibrosis in adjacent fat, and several hyalinized islets. These changes represent chronic pancreatitis. Although there is no history of alcoholic abuse, in view of these as well as the hepatic changes, one may wonder about the veracity of the patient’s history. The adrenals were rather small (total weight, 6 grams). However, the cells of the zona fasciculata did not appear to be lipid-depleted, as can be seen after episodes of stress. Small nests of mononuclear inflammatory cells were present throughout the zona reticularis. The significance
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fibrosis. Weigert’s stain, X40.
of adrenal size is not clear since the pituitary gland was normal. An adjacent autonomic ganglion had proliferative changes characteristic of neurofibromatosis. Old infarcts were found in the kidneys. The thyroid gland weighed 8 grams. It was grayish brown in color and very firm It was not adherent to surrounding structures. Microscopic examination showed wide bands of collagen surrounding nodules of degenerated acini with very little colloid, scattered, multinucleated giant cells and abundant chronic inflammatory inf&ate. There was no lymphoid follicle formation. There were a few large acini with colloid and the histologic pattern was that of chronic nonsuppurative (giant cell) thyroiditis. Although grossly the skin was described as myxedematous, representative sections did not show a dermal infiltrate or keratotic plugging of hair follicles. Only a few sweat ducts were dilated and filled with keratin-like material. In summary, there was a severe destructive chronic thyroiditis with equivocal histologic evidence of myxedema in the skin to support clinical evidence of hypothyroidism. There was an edematous, markedly hypertrophied, and dilated heart. In myxedema the clinically &spected marked enlargement of the heart is often due to massive pericardial effusion, but not in this case. The massive cardiac enlargement could not be explained on the basis of atherosclerotic coro-
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Fig.
7. Lower lung field with acar and an occluded elastic pulmonary
Fig. 8. Lower lung field with hemangiectasis
nary artery disease. The atherosclerosis was not as severe as one might expect in hypothyroidism13J6 and there was only one small scar in the wall of the left ventricle posteriorly. There also was no histologic evidence of disease in small intramural arteries and arterioles of the myocardium. Although there was histologic evidence of interstitial and intracellular edema of the myocardium, the cardiac enlargement was due principally to muscle hypertrophy. Special stains did
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artery. Weigert’s stain, X40.
in scarred area. Trichrome
stain, X100.
not demonstrate an interstitial accumulation of mucoproteins, as is common in myxedema.13p14 Although cardiac hypertrophy is described in myxedema, there is no convincing evidence that true myocardial hypertrophy in myxedema occurs without some other contributing disease. Idiopathic cardiomyopathy is at times invoked to account for cardiac hypertrophy in some patients. Cardiomyopathy frequently is characterized by paucity of histologic changes in a large
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and dilated heart. This possibility, of course, exists in this patient. As Dr. Susmano mentioned, there was no history of viral infection or alcohol intake. However, presence of chronic pancreatitis and hepatic scars reminiscent of so-called central hyaline sclerosis certainly might suggest the latter etiology. The interstitial pulmonary fibrosis may be due, in part, to prolonged congestive heart failure or some other unknown factor. The lower lobes of the lungs had occluded and partly occluded pulmonary arteries, most likely due to recurring emboli with healing infarcts and scars representing healed infarcts. It is well known that showers of small emboli usually originating from mural intracardiac thrombi tend to recur and can eventually lead to pulmonary hypertension. This is particularly true in patients with cardiac failure characterized by chamber dilation.16 A peculiar vascular capillary ectasia in these areas suggested a possible A-V (bronchopulmonary artery collateral) anastomosis, thus further decreasing the arterial oxygenation. The most severe involvement was in the lower lobes in keeping with the known predilection of pulmonary emboli to localize and produce infarcts in the lower lobes. The pulmonary vascular lesions represented an old process, however, apparently clinically the possibility of pulmonary hypertension induced by chronic embolization was not suspected. Furthermore, the clinically demonstrated hypothyroidism, of course, could have contributed to the cardiac burden. Therefore, there are at least two mechanisms, whether a primary myocardial disease or the so-called myxedema heart, as well as pulmonary vascular impairment secondary to chronic embolization that could account for the progressive and severe congestive heart failure.
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REFERENCES
1. Mattingly, T. W.: Disease6 of the myocardium (cardiomyopathiesl: the viewpoint of a clinical cardiologist, Am. J. Cardiol. 2S:79, 1970. 2. Abelmann. W. H.: The cardiomvouathies. H~I~D. Pratt. 6:101,197i. 3. Harvey, P. W., Segal, J. P. and Gurel, T.: The clinical spectrum of primary myocardial disease, Progr. Cardiovasc. Dia. 7:17, 1964. 4. Aber, C. P., and Thompson, G. S.: Factors associated with cardiac enlargement in myxedema, Br. Heart J. 25:421, 1963. 5. Kern, R. A., Soloff, L. A., Snape, W. J., and Bellow, C. T.: Pericardial effusion-a constant, early, and major factor in the cardiac syndrome of hypothyroidism (myx edema heart), Am. J. Med. Sci. 217:609, 1949. 6. Ellis, L. B., Mebane, G. J., Maresh, G., Hultgren, H. N., and Bloomfreld, R. A.: The effect of myxedema on the cardiovascular system, AM. HEART J. 43:241,1952. 7. Graettinger, J. S., Muenster, J. J., Checchia, C. S., Grissom, R. L., and Campbell, J. A.: A correlation of clinical and hemodynamic studies in patients with hypothyroidism, J. Clin. Invest. 37:502, 1958. 8. McBrien, D. J., and Hindle, W.: Myxedema and heart failure, Lancet 1:1066, 1963. 9. Monroe, E. W., and Fearrington, E. L.: Cardiomegaly in myxedema, AM. HEART J. 72:94,1966. 10. Willius, F. A., and Haines, S. F.: Status of the heart in myxedema, AM.HEART J. 1:67,1925. 11. Andrus, E. C.: The thyroid and the circulation, Circulation 7:437, 1953. 12. Keating, R. F., Jr., Parkin, T. W., Selby, J. B., and Dickinson, L. S.: Treatment of heart disease associated with myxedema, Progr. Cardiovasc. Dia. 3:364,1961. 13. Friedberg, C. K.: Diseases of the heart, Philadelphia, 1966, W. B. Saunders Company. 14. Webster, B., and Cooke, C.: Morphological changes in heart in experimental myxedema. Arch. Intern. Med. S&269,1936. 15. Steinberg, A. D.: Myxedema and coronary artery disease-a comparative autopsy study, Ann. Intern. Med. 68:338, 1968. 16. Gray, F. D., Jr.: Pulmonary embolism, Philadelphia, 1966, Lea and Febiger, Publishers. I
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John R. Dainauskas, M.D. Armando Susmano, M.D. Maurice L. Bogdonoff, M.D. Chicago, Ill.
Clinical
summary
A 56-year-old retired, white fireman had been in good health until developing signs and symptoms of congestive heart failure two years before admission to this hospital. At that time he was hospitalized elsewhere because of severe pedal edema, 30 pound weight gain, and shortness of breath. He was treated with “heart and water pills” and improved, but was again hospitalized a month later with “pneumonia.” Since that time he quit working because of increasing fatigue and shortnass of breath even when climbing one flight of stairs or walking one-half block. There was a history of hypertension with occasional palpitations, but further particulars about duration, severity, or treatment were not available. The patient also had noted dry skin, pruritis, periorbital edema, and increased sensitivity to cold. There was no history of chest pain, paroxysmal nocturnal dyspnea, intermittent claudication, or orthopnea. Apparently, his speech was slow and mentation had deteriorated. He was taking crystodigin (0.2 mg. four times per week), Lasix (80 to 160 mg. per day, depending on the .degree of ankle edema), aminophylline (1% grams three times a day), and Zyloprim (100 mg. three times a day). He stopped smoking, but he had a 90-pack per year history of cigarette smoking. On admission the vital signs were: blood pressure, 110/70 mm. Hg; pulse, 50 to 60 per minute, irregularly irregular; respirations, 16 per minute; and temperature, 97” F. There was bilateral, periorbital edema. Dry, cool, and peeling skin with cracks was described. The skin of the lower extremities was shiny, waxy, and pigFrom the Departments of Pathology, Medicine, and Radiology, RushPresbyterian-St. Luke’s Medical Center, Chicago. Received for publication Oct. 29, 1973. Reprint requesta to: Dr. John R. Dainauskas, Department of Pathology, Rush-Presbyterian-St. Luke’s Medical Center, 1753 W. Congress Parkway, Chicago, Ill. 60612.
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mented, but there was no edema. The thyroid was freely movable, slightly enlarged, and the right lobe was larger than the left. The chest was clear to auscultation and percussion. The PMI was in the sixth intercostal space at the anterior axillary line. S, was normal and louder than S,, but both appeared distant. There was no S,, S, OF opening snap. A harsh, low-pitched Grade III/VI pansystolic murmur was heard best at the lateral sternal border. It radiated to the axilla and toward the pulmonic area. Veins in the neck were distended. The peripheral pulses were normal in the upper and dacreased in the lower extremities. The liver had a span of 11 cm. and was palpated with some pulsations 4 cm. below the right costal margin. Fluid wave was not described. The motor and sensory function6 were intact, but his speech was described as slow and slurred, and his voice as husky. Reflexes were generally diminished. There was no peripheral edema. Cardiac catheterization showed the following pressures in millimeters of Hg: RA mean pressure, 17; pulmonary artery, 65 systolic and 32 diastolic with a mean of 40 and a PA wedge of 28; LV, 93 systolic and 28 end-diastolic; and aortic, 93 systolic and 72 diastolic. The cardiac index was 0.83 L. per minute per square meter. The AV oxygen difference was 10.4 vol. per cent. The total systemic, pulmonary, and pulmonary vascular resistance (dynes/sec./cm.? were 3,904, 1,928, and 578, respectively. The metabolic rate was -30 per cent. The respiratory rate was 12 per minute; heart rate, 72 per minute, and the 0, consumption index was 86 ml. per minute per square meter. Selective LV tine showed a very large, dilated chamber with minimal contractility and large end-syrstolic volume. A mild-tomoderate pericardial e&&on was noted. The patient was placed on a cardiac monitor and Cytomel(5 pg per day) therapy was started The next day he developed severe pulmonary
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cent; T, by Murphy-Pat&e, 2.4 pg per cent; TSH, 120 in pml. Immunologic studies showed presence of microsomal antibodies and antibodies to the second colloid antigen. Immunoglobulin electrophoresis showed IgG, 5.48 mg. per cent; IgA, 1.19 mg. per cent; IgM, 0.36 mg. per cent; and IgD, 0.06 mg. per cent. The urinalysis showed specific gravity of 1.006, pH, 6.0, and no protein, sugar, or ketone bodies. The spun sediment contained no cells. Discussion
Fig. 1. Frontal film of four-position series. There is marked, generalized enlargement of cardiac shadow. Pulmonary vasculature shows redistribution. There is moderate basilar pulmonary edema with pleural effusion.
edema and hypotension. Cytomel was discontinued and intravenous digoxin and Lasix increased the blood pressure and decreased the pulmonary edema. Then, the patient developed ventricular irritability with 8 to 9 PVC’s per minute. Questionable ascites but not peripheral edema were described. Serum K at that time was 3.0 mEq. per liter. He died after a cardiorespiratory arrest about two weeks after admission. On admission, the hemogram showed a hemoglobin of 13.1 Gm.; hematocrit, 41.5; RBC, 4.95 million; and WBC, 11,600 with a differential count of 49 polys, 33 bands, 12 lymphocytes, 5 monocytes, and 1 basophil. The platelet count was 62,000. Repeated platelet counts were within normal limits. The RBC indices were normal. The electrolytes showed: Na, 142; K, 3.3; Cl, 97; and CO,, 28.0 mEq. per liter. Calcium was 9.8; phosphorus, 4.4; BUN, 25; creatinine, 1.4 mg. per cent; CPK, 34; ICD, 80; SGCYI’, 28; LDH, 590; SGPT, 5; alkaline phosphatase, 4.1 units; and uric acid, 9.7 mg. per cent. Postprandial glucose was 113 mg. per cent. Total cholesterol was 223 ma;. per cent. Leucine aminopeptidase (LAP) was 194.9 units. The plasma cortisol was 25.4 mg. per cent; urine 17-OH-corticosteroids, 5.8 mg. per 24 hours; T, uptake, 28 per cent; PBI, 2.5 mg. per 230
DR. SUSMANO: In summary, we are confronted with the clinical picture of a 56-year-old man with a two-year history of intermittent and progressive congestive heart failure who has also developed dry skin, increased sensitivity to cold, and slurred speech with a husky voice. We have heard about his physical findings as well as his hemodynamic and biochemical abnormalities. Before proceeding with a detailed analysis of all these data, I would like to see the chest x-rays. DR. BOGDONOFF: Four-position chest films dated Dec. 18,1972, have demonstrated marked generalized cardiomegaly. The aorta is of normal size and the central pulmonary vasculature is normal. There is pulmonary vascular redistribution, venous and lymphatic distention, as well as a small amount of pleural fluid All are findings of cardiac decompensation. I cannot tell how much of this markedly enlarged heart shadow is due to pericardial fluid Portable films dated Dec. 28, 1972, and Dec. 30, 1972, showed a marked worsening of the heart failure and widespread alveolar edema in addition to the previously noted interstitial edema. This marked bilateral pulmonary edema persists on the portable film of Dec. 30,1972. There have been minor changes in the edema, with slight “milking” of edema along the right-heart border and minimal improvement in the edema adjacent to the hilar region. These findings are characteristic of edema due to marked cardiac decompensation. The cardiac findings are nonspecific and are compatible with cardiomyopathy with or without pericardial effusion. on adDR. SUSMANO: The electrocardiogram mission showed atria1 fibrillation with a slow ventricular response, marked intraventricular conduction block with a QRS duration of 0.20 second, and a very low QRS voltage in the standard leads.
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Fig. 2. Twelve-lead
Cardiac catheterization revealed mild or, perhaps, a moderate amount of pericardial effusion. The cardiac index was severely decreased and the LV and RV early and end-diastolic pressures were significantly elevated. Selective cineangiocardiogram showed that the left ventricular chamber was markedly dilated, with a significant decrease in left ventricular contractility and very large end-diaetolic and end-systolic volumes. All these findings are consistent with the diagnosis of severe cardiomyopathy associated with a mildto-moderate degree of pericardial effusion. Let me ignore, for the moment, the severe abnormalities of the thyroid function. We are dealing, without any doubt, with a severe case of cardiomyopathy. But which one is responsible for it? On the basis of the history and physical and hemodynamic findings, if we were to follow Drs. Mattingly’s and Abelman’s approach to the cardiomyopathies, ly2 then we could eliminate two important groups: the hypertrophic variety, whether familial or not, and the obstructive type better known as idiopathic hypertrophic subaortic stenosis (also whether familial or not). No intraventricular pressure gradients were found, and the presence of the largely dilated left ventricular chamber with significant decrease in its contractility would easily exclude these two
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admission electrocardiogram.
types. This patient was apparently hypertensive for several years. Although left ventricular hypertrophy with subsequent dilation can be seen in the terminal stages of fixed or malignant hypertension, the clinical and radiologic findings are quite different from the ones encountered in this patient. Besides that, his hypertension was never severe enough as to require strict therapy. Therefore, we would not consider this to be the end-stage of this disease. We should then direct our attention to either the dilated or restricted type of cardiomyopathies. In the restricted, usually called infiltrative type, we should consider’lamyloid heart disease. Amyloidosis can account for up to ten per cent of noncoronary cardiomyopathies. It should be considered in relatively older patients who have progressive and intractable types of congestive heart failure which may be associated with skin and mucous membrane lesions, purpuric changes, nephrosis, peripheral neuropathy, macroglossia, etc. None of the symptoms and physical findings just mentioned was encountered in our patient, and the electrocardiogram was not associated with QRS abnormalities suggesting the possibility of a “dead zone” due to myocardial infarction, as has been so often seen in patients with cardiac amyloidosis. It would also be extremely uncom-
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Fig. 3. A, Frame of selective left ventricular cineangiogram shows a very large ventricular chamber with markedly increased end-diastolic volume. B, Shows the end-systolic volume of the left ventricle. Only the posterobasal and outflow tract areas contract, although the myocardial contractility is diffusely decreased.
mon for the heart to be radiologically enlarged as much as in this case. Usually, it is only slightly enlarged. We do not have any evidence to support the possibility of either neoplastic infiltration of the heart, hemochromatosis, or glycogen disease, the latter exclusively seen in infants and children. There was no history or physical findings of involvement of the peripheral muscles; therefore, myocardial involvement as may occur in heredofamilial neuromyopathic diseases like Friedrich’s ataxia, myotonic dystrophy, etc., can also be excluded. Some patients with the clinical syndrome of constrictive pericarditis have also shown abnormalities in the contractility of the myocardium or what has been called “myocardial misuse” as a secondary change to the severe pericardial involvement. Occasionally, a patient with constrictive pericarditis may have associated pericardial effusion. However, in this case the degree of pericardial effusion was probably greater than that encountered in patients who do have primary pericardial disease. The syndrome of endocardial fibroelastosis, which has been seen in adults, can probably be excluded considering our patient’s advanced age. Certainly, other entities that may also involve the endocardium such as endomyocardial fibrosis, as have been observed in Africa, should be brought into the differential diagnosis of the restrictive types of cardiomyopathies which I am including as part of the differential diagnosis, but not because I strongly believe this to be a diagnostic possibility in our case.
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Our patient did not give any history of heavy alcoholic or beer intake and I can possibly exclude them as an etiologic consideration. We now finally come to the last group or the dilated type of cardiomyopathies which are so common in the adult population. This form of usually called “primary myocardial disease” is also often referred to as the congestive type. Numerous etiologies have been suggested for primary myocardial disease and the number of conditions that could be included is quite large, ranging from injury to the myocardial muscles secondary to malnutrition, myocarditis, unknown toxins, or immunity, trauma, toxic agents, specific infections, or metabolic abnormalities. I like to call primary myocardial disease the type of heart disease where no known etiology can be found Other types which may produce similar myocardial changes but are secondary to a specific etiology, I usually like to refer to as myocarditis which has entered the chronic stage. In’patients in whom a specific etiology is found, the viral, bacterial, mycotic, parasitic, protozoal, and rickettsial infections or toxic agents can be the cause of the myocardial injury. The damage can also be secondary to a metabolic abnormality. As previously mentioned, nutritional and electrolyte imbalance and, most commonly, severe hypokalemia or anemia can be accompanied by severe myocardial disease. Regardless of these different etiologies, they may produce common pathologic changes in the so-called primary myocardial disease, and the findings on physical
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examination are commonly the same. The jugular venous pressure is elevated and very high “V” waves can be seen, suggesting the presence of tricuspid incompetence. The pulse pressure is usually within normal limits or may be low; but, most commonly, there is a very narrow pulse pressure. Pulsus alternans is also frequent, if very clearly sought. There may be no murmurs or just murmurs due to tricuspid or mitral insufficiency which are secondary to ventricular dilation and pulling of the papillary muscles producing valvular incompetence. The presence of filling sounds such as prominent third sound or atria1 gallops can also be heard. All kinds of electrocardiographic abnormalities have been observed ranging from changes in voltage, particularly low voltage in the standard lead, as well as arrhythmias, atria1 fibrillation, or ventricular arrhythmias and conduction abnormalities, whether of the right bundle or the left bundle branch type. First-degree A-V block has commonly been seen, but on many occasions may also be secondary to digitalis therapy. Second-degree or thirddegree A-V block is extremely uncommon. Hemodynamic studies are usually similar with a very low cardiac index and elevated ventricular diastolic pressures. As has been emphasized by Proctor Harvey and colleagues,3 there is a clinical spectrum of primary myocardial disease ranging from mild to severe degree, and the course of the patient’s disease will be related to the degree of involvement of the myocardium, resulting in death, usually in less than two years, when the involvement is severe, or may evolve into a complete recovery when there is only mild involvement of the myocardium. There is a very high incidence of sudden death, particularly in the idiopathic type of primary myocardial disease. Commonly, in patients with primary myocardial disease, when no specific etiology can be found the possibility of viral origin is considered. Coxsackie B virus has been implicated as a common etiologic factor. Virus-like particles have been occasionally noted in cardiac tissues of such patients. It is quite possible that once a patient achieved the chronic stage, circulating antibodies have significantly decreased and then it is almost impossible to establish a cause-and-effect relationship in viral myocardial disease. We do not have any real evidence that our patient has had any severe viral infections in the past; therefore, it would be extremely difficult to relate
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his myocardial disease with a possible viral etiology and I would consider it very unlikely, although I do not have definite proof. We do not have any evidence of specific infections such as brucellosis, tuberculosis, rickettsial diseases, or toxoplasmosis. Therefore, infections would not be considered as a potential etiologic factor in this case. We also have no evidence for any collagen disease such as rheumatoid arthritis or lupus erythematosus with documented vasculitis which might well be a factor in the development of myocardial disease; but again there has been no prior history that may substantiate the possibility of systemic involvement. We do not have any history of severe nutritional deficiency, and the physical findings did not show an emaciated or cachectic individual; nor was he using large amounts of cathartics which may produce extreme hypokalemia and, therefore, a hypokalemic cardiomyopathy, and we can exclude this possibility. I do believe that by now we have narrowed down most of the diagnostic possibilities. I would like to return to what we have concerning real facts in the sense of the history and physical and laboratory findings. Our patient gave a positive history of progressive tiredness, somnolence, slow mentation, increased intolerance to cold, dryness of skin, and also typical changes of a “gravel voice.” His thyroid studies demonstrated the presence of severely depressed function. All of this speaks strongly for myxedema. The question posed to us is whether this entity is responsible for the heart disease or not. Many studies, most of them case reports, have appeared in the literature since Zondek described the condition as a specific entity in 1918. He laid down the criteria of both right- and leftsided dilation associated with abnormalities of conduction with definite reduction in transverse diameter of the heart following thyroid gland therapy. Radiologic enlargement of the heart has been said to be common in myxedema, due either to myocardial damage or to the presence of a pericardial effusion or both.4 However, other factors such as old age, systemic arterial hypertension, and coronary artery disease have been shown in part responsible for the increase in heart size in myxedema. Of 53 patients studied by Aber and Thompson4 55 per cent were found to have cardiac enlargement, most of whom were
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older and had higher systemic hypertension than those patients with normal-sized hearts. Several of them also had some evidence of ischemic heart disease. Conversely, many patients have typical electrocardiographic changes of myxedema heart disease with normal-sized hearts and they conclude that this implies the lack of associated hypertension or coronary artery disease. However, as has been pointed out by Kern and co-workers,s pericardial effusion is a constant, early, and major factor in the myxedematous heart and the one responsible for the roentgenologic changes in the cardiac silhouette and not due to myocardial failure since, in general, it responds to thyroid therapy alone. Our patient has had intermittent episodes of heart failure. The question as to whether or not myxedema heart can evolve into heart failure has been disputed and questioned for many years after Fahr reported the occurrence of heart failure in this disease. Hemodynamic studies have shown that the cardiac output is signiflcantly depressed and parallel, in general, to the decrease in oxygen consumption,. While A-V differences have been observed to be within normal limits or slightly wider, the cardiac output may be depressed out of proportion to the oxygen demands of the body. This represents strong evidence of damage to the heart and of circulatory insufficiency, according to the studies by Ellis and co-workers.6 Studies performed by Graettinger and coworkers’ have shown the cardiac index to be considerably below normal, but an adequate increase occurred during bicycle exercise. Right atria1 pressures were elevated at rest and the right ventricular pressures had a diastolic dip with elevated end-diastolic pressures, findings which were attributed to pericardial effusion rather than to myocardial disease. Their patients had a low-normal heart rate with a significant decrease in stroke volume at rest. This was in sharp contrast with patients who did have primary myocardial disease and who were in congestive failure. Their oxygen consumption at rest and the basal metabolic rates were normal or elevated, and the cardiac output was significantly lower than in patients with myxedema or normal persons. Furthermore, the heart rate was faster, the A-V differences much wider at rest, and the cardiac output did not increase or decrease during exercise.
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Our patient had severe myocardial disease manifested by significantly wide A-V difference, markedly decreased cardiac output, elevated end-diastolic pressures in both ventricles, low stroke volume, and diffuse decreased contractility by selective left ventricular cineangiogram. However, he did have a normal respiratory rate, a slow ventricular rate, a very low oxygen consumption, and a low metabolic rate which is exactly the opposite of what one would expect if this degree of myocardial failure was due to primary myocardial disease. As stated by Ellis and co-workers,6 there appears to be no uniformity in the response of the cardiovascular system to myxedema. It is also true that patients who have been in intractable heart failure were improved in the past by being made myxedematous. Although this appears to be a paradox, total ablation of the thyroid seems to benefit the heart by lessening the circulatory demands through a reduction in the oxygen consumption and, therefore, decreasing the metabolic needs, the cardiac output, and the cardiac work. This also could relieve angina pectoris. In a study of 20 patients with myxedema where 16 had large hearts and only seven were clinically indistinguishable from cardiac failure, pulse pressure response to the Valsalva maneuver showed that apparently only one of the patients was in cardiac failure.8 It was assumed, therefore, by McBrien and Hindlea that myxedema in itself does not cause heart failure and, if it occurs, it is the result of other disease, usually ischemic. This work evidently is at variance with the observation of other authors, where myxedema and heart failure have been observed in the absence of coronary artery disease. Furthermore, a case report was published by Monroe and FearringtorP of a patient with severe myxedema and marked cardiomegaly who continued to have massive cardiomegaly after all pericardial effusion had been removed. The venous angiocardiogram showed the cardiac enlargement to be due primarily to left ventricular dilation, demonstrating then that the persistent cardiomegaly was due to myxedematous cardiomyopathy. Finally and briefly, I would like to make some comments about a possibility of ischemic cardiomyopathy. Although this is a known entity, it usually occurs in patients who have had long-
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4. Hypertrophied stain, X300. Fig.
myocardium
with interstitial
standing evidence of angina pectoris or previous myocardial infarctions, which our patient did not have. He could have, however, small-vessel disease but I doubt it. The unsolved question is whether myxedema leads to or accelerates the development of atherosclerosis. In a study by Willius and HaineslO of 162 patients with severe myxedema, 91 per cent had no subjective symptoms of organic cardiovascular disease and a large proportion of their patients were in the fourth, fifth, and sixth decades of life, the age group where the incidence of ischemic heart disease should be higher. Andrus11 has reported that Bartel and Bell found an incidence of 25 per cent of coronary artery disease in a spontaneous myxedema. The increase in, or the development of, angina pectoris is common, however, during the course of therapy of myxedema. In those patients who have a significant degree of coronary arteriosclerosis the administration of thyroid replacement could be lethal.12 Our patient died rather soon after the initiation of synthetic thyroid therapy. A ventricular arrhythmia and exacerbation of congestive heart failure developed This could suggest the presence of moderately severe and asymptomatic coronary artery disease. However, I do feel that this was not a manifestation of ischemic cardiomyopathy but the lethal result of thyroid replacement in a patient with myxedema heart,
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edema. Hematoxylin
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manifested by an extremely severe degree of myocardial involvement, who may happen to have associated coronary artery disease. If that were the case with this patient, probably an important conchrsion would be that, in the future, patients with severe myxedema who are to be given thyroid therapy should have coronary arteriographic studies whether symptomatic or not, from that point of view, to determine the extent and degree of disease in the coronary arterial system. This could provide valuable information as to the potential risk of this mode of therapy in this type of disease. Autopsy
results
At autopsy there was generalized edema and the skin had a rather coarse and rough texture with brownish pigmentation over the forearms and lower legs. There were 2,000 C.C. of ascitic, approximately 1,500 C.C. of pleural, and 200 C.C. of pericardial fluid. The heart was hypertrophied, flabby, and somewhat globular. The chambers were dilated It weighed 1,006 grams. The ventricular walls measured in average thickness, 2.2 cm. on the left and 0.5 cm. on the right. The myocardium was of normal color but an illdefined, grayish-white infarct measuring 1.6 cm. in width extended from the base to mid-level in the posterior wall of the left heart. The circumference of the tricuspidvalve was 15 cm. and that 235
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Fig. 6.
Chronic nonsuppurative
thyroiditis.
of the mitral valve, 12 cm. The valves were not deformed. The endocardium of the left atrium was irregular with a crescent-shaped scar opposite the orifices of the right pulmonary veins. However, the veins were not narrowed. The endocardium of the anterior wall of the left atrium was thick and brown. Only a few small foci of endocardial fibrosis were seen in the left ventricle. Although focal coronary atherosclerosis was present, the left circumflex and anterior descending branches were widely patent. The right coronary artery was as large as the left and at its origin was widely patent. However, a 3 mm. segment was almost completely occluded by white fibrous material at the right margin of the heart. From this point onward, the lumen widened to a diameter of 1 to 2 mm. The vessel formed a widely patent posterior descending coronary arbrY* The microscopic examination of the coronary arteries showed an 80 per cent occlusion of the right coronary artery by an atheromatous plaque. The other arteries did have fibrous and atheromatous plaques but their lumina retained at least 70 to 90 per cent of their patency. The small myocardial arteries and arterioles were normal. The myocardial fibers were large and had large, square nuclei. There were scattered intracytoplasmic vacuoles. Sudan IV fat stain, alcian blue-PAS, and trichrome stains were not helpful in defining the nature of the material in
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Hematoxylin
and eosin stain, X100.
the vacuoles. The muscle cells were widely separated from each other, most likely due to interstitial edema. It is possible that the cytoplasmic vacuoles also represented edema. There was no interstitial or perivascular fibrosis, but an old scar was present in the posterior left ventricular wall. Fibroelastosis was noted focally in the left ventricle and some areas resembled old organized mural thrombi, although there was no evidence of organizing or acute thrombi. Fibroelastosis was also noted in sections of the left atrium. The right lung weighed 1,050 grams and the left lung, 760 grams. There was focal pleural fibrosis and the lungs were subcrepitant and wet. In the lower lobes there were ill-defined areas of consolidation. Microscopic examination of the upper lobes showed interstitial fibrosis with aggregates of numerous hemosiderin-containing macrophages, dilation of lymphatic channels, and dilation and some sclerosis of small veins in the intralobular septa. Dilation with some hypertrophy and scarring of the walls of small arteries was also present. Large arteries contained atheromatous plaques but there was no vasculitis. In the lower lobes there were healing infarcts with several areas of necrosis and reactive interstitial fibrosis with lining cell proliferation in the adjacent parenchyma. There were also large, hyalinized scars probably representing healed infarcts. In one such area there was an
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6. Upper lung field with interstitial
obliterated artery and there were other arteries with proliferative end-arteritic changes markedly narrowing the lumina. There were also small arteries containing multichanneled lumina suggesting that this entire pathologic process was due to chronic embolization and repair of infarcts. However, there were no healing or acute emboli. Conspicuous capillary telangiectasis in these areas suggested possibility of an A-V shunt, although none was demonstrated. The liver was enlarged (2,280 grams) with changes due to chronic passive congestion. Small scars representing usually obliterated central veins were present. The etiology of the latter change is not clear since there was no history of excessive alcoholic consumption. The spleen was also congested (420 grams) and contained a healed infarct. The pancreas showed interstitial fibrosis with chronic inflammation, fibrosis in adjacent fat, and several hyalinized islets. These changes represent chronic pancreatitis. Although there is no history of alcoholic abuse, in view of these as well as the hepatic changes, one may wonder about the veracity of the patient’s history. The adrenals were rather small (total weight, 6 grams). However, the cells of the zona fasciculata did not appear to be lipid-depleted, as can be seen after episodes of stress. Small nests of mononuclear inflammatory cells were present throughout the zona reticularis. The significance
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fibrosis. Weigert’s stain, X40.
of adrenal size is not clear since the pituitary gland was normal. An adjacent autonomic ganglion had proliferative changes characteristic of neurofibromatosis. Old infarcts were found in the kidneys. The thyroid gland weighed 8 grams. It was grayish brown in color and very firm It was not adherent to surrounding structures. Microscopic examination showed wide bands of collagen surrounding nodules of degenerated acini with very little colloid, scattered, multinucleated giant cells and abundant chronic inflammatory inf&ate. There was no lymphoid follicle formation. There were a few large acini with colloid and the histologic pattern was that of chronic nonsuppurative (giant cell) thyroiditis. Although grossly the skin was described as myxedematous, representative sections did not show a dermal infiltrate or keratotic plugging of hair follicles. Only a few sweat ducts were dilated and filled with keratin-like material. In summary, there was a severe destructive chronic thyroiditis with equivocal histologic evidence of myxedema in the skin to support clinical evidence of hypothyroidism. There was an edematous, markedly hypertrophied, and dilated heart. In myxedema the clinically &spected marked enlargement of the heart is often due to massive pericardial effusion, but not in this case. The massive cardiac enlargement could not be explained on the basis of atherosclerotic coro-
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Fig.
7. Lower lung field with acar and an occluded elastic pulmonary
Fig. 8. Lower lung field with hemangiectasis
nary artery disease. The atherosclerosis was not as severe as one might expect in hypothyroidism13J6 and there was only one small scar in the wall of the left ventricle posteriorly. There also was no histologic evidence of disease in small intramural arteries and arterioles of the myocardium. Although there was histologic evidence of interstitial and intracellular edema of the myocardium, the cardiac enlargement was due principally to muscle hypertrophy. Special stains did
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artery. Weigert’s stain, X40.
in scarred area. Trichrome
stain, X100.
not demonstrate an interstitial accumulation of mucoproteins, as is common in myxedema.13p14 Although cardiac hypertrophy is described in myxedema, there is no convincing evidence that true myocardial hypertrophy in myxedema occurs without some other contributing disease. Idiopathic cardiomyopathy is at times invoked to account for cardiac hypertrophy in some patients. Cardiomyopathy frequently is characterized by paucity of histologic changes in a large
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1974, Vol. 88, No. 2
Clinical
and dilated heart. This possibility, of course, exists in this patient. As Dr. Susmano mentioned, there was no history of viral infection or alcohol intake. However, presence of chronic pancreatitis and hepatic scars reminiscent of so-called central hyaline sclerosis certainly might suggest the latter etiology. The interstitial pulmonary fibrosis may be due, in part, to prolonged congestive heart failure or some other unknown factor. The lower lobes of the lungs had occluded and partly occluded pulmonary arteries, most likely due to recurring emboli with healing infarcts and scars representing healed infarcts. It is well known that showers of small emboli usually originating from mural intracardiac thrombi tend to recur and can eventually lead to pulmonary hypertension. This is particularly true in patients with cardiac failure characterized by chamber dilation.16 A peculiar vascular capillary ectasia in these areas suggested a possible A-V (bronchopulmonary artery collateral) anastomosis, thus further decreasing the arterial oxygenation. The most severe involvement was in the lower lobes in keeping with the known predilection of pulmonary emboli to localize and produce infarcts in the lower lobes. The pulmonary vascular lesions represented an old process, however, apparently clinically the possibility of pulmonary hypertension induced by chronic embolization was not suspected. Furthermore, the clinically demonstrated hypothyroidism, of course, could have contributed to the cardiac burden. Therefore, there are at least two mechanisms, whether a primary myocardial disease or the so-called myxedema heart, as well as pulmonary vascular impairment secondary to chronic embolization that could account for the progressive and severe congestive heart failure.
America
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REFERENCES
1. Mattingly, T. W.: Disease6 of the myocardium (cardiomyopathiesl: the viewpoint of a clinical cardiologist, Am. J. Cardiol. 2S:79, 1970. 2. Abelmann. W. H.: The cardiomvouathies. H~I~D. Pratt. 6:101,197i. 3. Harvey, P. W., Segal, J. P. and Gurel, T.: The clinical spectrum of primary myocardial disease, Progr. Cardiovasc. Dia. 7:17, 1964. 4. Aber, C. P., and Thompson, G. S.: Factors associated with cardiac enlargement in myxedema, Br. Heart J. 25:421, 1963. 5. Kern, R. A., Soloff, L. A., Snape, W. J., and Bellow, C. T.: Pericardial effusion-a constant, early, and major factor in the cardiac syndrome of hypothyroidism (myx edema heart), Am. J. Med. Sci. 217:609, 1949. 6. Ellis, L. B., Mebane, G. J., Maresh, G., Hultgren, H. N., and Bloomfreld, R. A.: The effect of myxedema on the cardiovascular system, AM. HEART J. 43:241,1952. 7. Graettinger, J. S., Muenster, J. J., Checchia, C. S., Grissom, R. L., and Campbell, J. A.: A correlation of clinical and hemodynamic studies in patients with hypothyroidism, J. Clin. Invest. 37:502, 1958. 8. McBrien, D. J., and Hindle, W.: Myxedema and heart failure, Lancet 1:1066, 1963. 9. Monroe, E. W., and Fearrington, E. L.: Cardiomegaly in myxedema, AM. HEART J. 72:94,1966. 10. Willius, F. A., and Haines, S. F.: Status of the heart in myxedema, AM.HEART J. 1:67,1925. 11. Andrus, E. C.: The thyroid and the circulation, Circulation 7:437, 1953. 12. Keating, R. F., Jr., Parkin, T. W., Selby, J. B., and Dickinson, L. S.: Treatment of heart disease associated with myxedema, Progr. Cardiovasc. Dia. 3:364,1961. 13. Friedberg, C. K.: Diseases of the heart, Philadelphia, 1966, W. B. Saunders Company. 14. Webster, B., and Cooke, C.: Morphological changes in heart in experimental myxedema. Arch. Intern. Med. S&269,1936. 15. Steinberg, A. D.: Myxedema and coronary artery disease-a comparative autopsy study, Ann. Intern. Med. 68:338, 1968. 16. Gray, F. D., Jr.: Pulmonary embolism, Philadelphia, 1966, Lea and Febiger, Publishers. I
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