Small Cardiac Lesions

Fibrosis of Papillary Muscles and Focal Cardiac Myocytolysis

Arthur STEER, M.D.,1 Teruyuki NAKASHIMA, M.D.,2 Taketsugu KAWASHIMA, M.D.,1 Kelvin K. LEE, M.A.,3 Michael D. DANZIG, M.D.,4* Thomas L. ROBERTSON M.D.,4** and Donald S. DOCK, M.D.4

SUMMARY Three types of small cardiac lesions were described and illustrated: (1) focal type of papillary muscle fibrosis, evidently a healed infarct of the papillary muscle present in 13% of the , is a histologically characteristic lesion associated with coronary artery and healed myocardial , (2) diffuse type of papillary muscle fibrosis, prob- ably an aging change present in almost half of the autopsies, is associated with sclerosis of the arteries in the papillary muscle, is identifiable his- tologically, and apparently is not associated with any cardiac abnormal- ity, and (3) focal cardiac myocytolysis, a unique histologic lesion, usually multifocal without predilection for any area of the heart, is associated with ischemic heart disease, death due to cancer complicated by non- bacterial thrombotic endocarditis and microthrombi in small cardiac arteries as well as with other . Differentiation of the 2 types of papillary muscle fibrosis is important in the study of papillary muscle and mitral valve dysfunction. Focal cardiac myocytolysis may contribute to the fatal extension of myocardial infarcts.

From the Radiation Effects Research Foundation Hiroshima and Nagasaki. A Cooperative Research Institute supported by funds from the U.S.A. National Academy of Sciences-National Research Council, Atomic Energy Commission and Environmental Protection Agency and from the Japanese National Institute of Health of the Ministry of Health and Welfare. 1 Department of , Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiro- shima City 730. 2 Department of Pathology , Kurume University School of Medicine, 67 Asahi-machi, Kurume City 830. 3 Department of Epidemiology and Statistics , Radiation Effects Research Foundation, 5-2 Hiji- yama Park, Hiroshima City 730. 4 Department of Medicine , Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiro- shima City 730. + Hiroshima Branch Laboratory , Japanese National Institute of Health, Ministry of Health and Welfare. * Surgeon and ** Senior Surgeon , U.S. Public Health Service. Address for reprint request to: Teruyuki Nakashima, M.D., Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume City 830, Japan. Received for publication May 27, 1977. 812 Vol.18 No.6 SMALL CADIAC LESIONS 813

Additional Indexing Words: Focal and diffuse papillary muscle fibrosis Healed papillary muscle infarct

HERE is considerable discrepancy in the reported incidence of fibrosis of papillary muscles and even less agreement on . In an extensive review of changes after , Schechter1) stated, under the heading of papillary muscle infarction, that fibrous scars were re- ported present in cardiac papillary muscles in 25% to 80% of random au- topsies. In 1969, Brand et a12) distinguished the papillary muscle scar of infarction, which he called focal papillary muscle fibrosis, from the more fre- quent diffuse type of papillary muscle scar. There has been little subsequent attention paid to this distinction.3)-7) We undertook an study of papillary muscle scars in which we attempted to associate their presence with available clinical observations in the same subjects. During this study another small myocardial lesion, focal cardiac my- ocytolysis, was observed. This lesion had been described previously by Schle- singer and Reiners8)in 1955 and repeatedly since then under a variety of titles by others9)-12)culminating in the report by Baroldi13) of 3 distinguishable morphologic types of myocardial including this type which he called colliquative myocytolysis. Focal cardiac myocytolysis has attracted little organized attention and although often found associated with myocardial infarction, it may be the only myocardial lesion in some conditions and can be a cause of death (low output failure, beer drinker's heart, etc). Pathologists and clinicians are generally unfamiliar with this lesion. Focal cardiac my- ocytolysis was observed in 21 of the 375 autopsies.

METHODS

This study included all autopsies performed at the Radiation Effects Research Foundation (RERF, formerly the Atomic Bomb Casualty Commission, ABCC) on members of the Adult Health Study sample14> during 1965-70 in Hiroshima and 1968-70 in Nagasaki. Most of the subjects had been examined at least once in the RERF clinics at which time information was obtained on blood pressure levels, evi- dence of heart disease including electrocardiograms, and the presence of diabetes mellitus. In most instances, the only information available concerning the terminal illness was contained in the death certificate. At least 7 blocks of tissue were taken from every heart, including 2 from the interventricular septum, 4 from the left ventricle, and 1 from the right ventricle. One section of the anterior left ventricle and one of the posterior left ventricle were cut parallel to the base of the heart and each included a transection of the attached pa- pillary muscle at a level near its origin and away from the insertion of the chordae tendineae. In 2 cases there was insufficient papillary muscle for evaluation. Hema- 814 STEER ET AL. Novemberap. Heart, 1977 J. toxylin and eosin were routinely used in all cases. It was supplemented by trichrome, elastic and amyloid stains for the study of blood vessels and with , iron, PAS, acid fast, alcian blue and reticulum stains for study of pigment and the lesions of myocytolysis. The severity of coronary atherosclerosis was determined by the American Heart Association method15) in which the proximal 5cm of the arteries (left anterior de- scending, left circumflex, and right circumflex) were opened longitudinally and compared with a standard illustration showing 7 degrees of coronary atherosclerosis, Thickening and sclerosis of the arteries in the papillary muscles was determined by examination of histological sections. Hypertension was defined as blood pressure readings of 160mmHg or higher systolic and 95mmHg or higher diastolic on 2 or more occasions. Hypertensive heart disease was diagnosed when hypertension as defined above was accompanied by any of the following: cardiomegaly (X-ray), atrial fibrillation, left bundle branch block, left axis deviation, S-T depression, or T wave inversion of 1.0mm or more. Diabetes mellitus was diagnosed when serum glucose values exceeded any of the following on 2 or more occasions: fasting 125mg%, 1 hour 215mg%, 2 hour 145mg%, or 3 hour 130mg%. The focal type of papillary muscle fibrosis was defined as a sharply demarcated, hyalinized scar separated from the endocardial surface of the papillary muscle by a rim or palisade of viable muscle fibers (Fig.1). If patent vessels are present in the scar, they were usually thin-walled and surrounded by viable muscle fibers. Often most of the central portion of the papillary muscle was involved. In some cases of acute myocardial infarction, acute was also present in the pa- pillary muscle and then it had the same distribution as the focal type of papillary muscle fibrosis. The diffuse type of papillary muscle fibrosis was poorly demarcated. It ex- tended between and replaced muscle fibers (Fig.2). It was dense, hyalinized, and

Fig.1. Focal type of papillary muscle fibrosis with palisade of viable

muscle fibers beneath the moderately thickened endocardium and about small

vessels. 72-year-old male, carcinoma of the stomach with healed myocardial

infarct, heart weight 380 Gm. Elastica trichrome•~38 Vol.18 No.6 SMALL CARDIAC LESIONS 815

Fig.2. Diffuse type of papillary muscle fibrosis is poorly demarcated,

extends to the endocardial surface and contains prominent sclerosed arteries.

66-year-old female, hypertensive heart disease, heart weight 250 Gm. Elastica

trichrome•~28

Fig.3. Arterial sclerosis and diffuse type of papillary muscle fibrosis.

Same patient as in Fig.2. Elastica trichrome•~68

acellular. The scars were often situated in the periphery of the papillary muscle and extended to the endocardial surface without an intervening layer of viable mus- cle fibers. Prominent, thickened, and sclerotic arteries were almost always evident and appeared to be related to the areas of fibrosis (Fig.3). An acute, necrotic or healing stage was never observed. In some cases, both the focal and diffuse types of papillary muscle fibrosis were present. The 2 types could be distinguished even when they occurred in the same papillary muscle (Fig.4). Focal cardiac myocytolysis was defined as areas of apparently simple muscle fiber lysis marked by an empty but intact scaffold of stroma and sarcolemma sheaths containing varying numbers of mononuclear cells many of which were filled with 816 STEER ET AL. Jap.November Heart J. , 1977

Fig.4. Both focal (right) and diffuse (left) types of papillary muscle

fibrosis in the same papillary muscle. 71-year-old male, death due to chronic

pyelonephritis, heart weight 380 Gm, healed myocardial infarct. Elastica trichrome•~6

Fig.5. Focal cardiac myocytolysis. Empty sarcolemma sheaths, round-

ed pigment-containing mononuclear cells. Note absence of necrosis, inflam-

matory infiltrate or evidence of repair. 75-year-old female died of carcinoma

of the gall bladder. Heart weight 240 Gm. Lytic lesions were present in an-

terior and posterior interventricular septum and postero-lateral portion of the

left ventricle. No infarction present. H&E •~375 lipofuscin-like pigment (Fig.5). Coagulative necrosis, hemorrhage, polymorphonu- clear cell infiltration or other evidence of acute was never present in foci of cardiac myocytolysis, and there was no reaction in the cells and tissues adjacent to these foci. They were found in sections from all 7 sampled areas of the heart. Most were small and involved only a group of muscle fibers within a muscle bundle but, in a few cases, they extended in irregular foci from epicardium to endocardium. Foci of myocytolysis could be distinguished from myocardial infarcts even when Vol.18 No.6 SMALL CARDIAC LESIONS 817 both were present in the same histologic section because of the absence in the foci of myocytolysis of the coagulation necrosis and cellular reaction present in adjacent acute myocardial infarcts or of the fibroblast and vascular proliferation present in healing infarcts.

RESULTS Papillary muscle fibrosis: In 373 of the 375 autopsies there was sufficient papillary muscle for evalua- tion. The focal type of papillary muscle fibrosis was present in 16 (4.3%) cases, the diffuse type in 169 (42.6%), and both focal and diffuse types in 34 (9.1%). The 2 types were approximately equally frequent in men and women. Both types were more frequent in older persons when all cases with each type were considered (Table I). Clinical correlations (Table II) showed that

Table I. Percentage of Autopsies with Various Kinds of Fibosis of Papillary Muscle by Age at Death

Test of significance (chi square): NS: not significant; * 0.01

there was only moderate, if any, relation between the presence of either type of papillary muscle fibrosis and simple hypertension, hypertensive heart disease, and diabetes mellitus. Only 14 patients had had definite electrocardiographic evidence of myocardial infarction (63 other patients had electrocardiographic changes suggestive but not diagnostic of myocardial infarction). The focal type of papillary muscle fibrosis (all focal in Table II) was significantly in- creased in the 14 subjects with definite electrocardiographic changes and the diffuse type only was decreased. Autopsy correlations (Table III) showed that the focal type of papillary muscle fibrosis (both focal only and all focal) was significantly more frequent in persons who died of cardiovascular disease, in those with severe coronary atherosclerosis, in those with heart weight above 818 STEER ET AL. Jap.November Heart, 1977 J.

Table II. Percentage of Autopsies with Fibrosis of Papillary Muscles by Clinical Diagnosis of Hypertension, of Hypertensive Heart Disease, of Myocardial Infarction by Electrocardiogram and of Diabetes Mellitus

Test of significance (chi square): NS: not significant; * 0.01

350 Gm and in those with healed myocardial infarcts. The diffuse type of papillary muscle fibrosis showed none of these correlations and in fact was significantly less frequent when healed myocardial infarction was present. In histologic sections, thick walled sclerotic arteries were observed in most papillary muscles. They were very prominent at the periphery of areas of diffuse type of papillary muscle fibrosis (Fig.5) but were not associated with the focal type. The presence of the diffuse type of papillary muscle fi- brosis, in either the anterior lateral or the posterior medial papillary muscle or both, was associated with the presence of artery sclerosis in the corresponding papillary muscle (Table IV).

Focal cardiac myocytolysis: Focal cardiac myocytolysis was identified in 21 of the 375 autopsies: in 4 of 18 (22.2%) who died of ischemic heart disease, in 12 of 112 (10.7%) who died of cancer, and in 5 of the 245 (2.0%) remaining autopsies. Six of 16 patients (37.5%) who had recent or both old and recent myocardial infarcts Vol.18 No.6 SMALL CARDIAC LESIONS 819

Table III. Percentage of Autopsies with Fibrosis of Papillary Muscles by Autopsy Cause of Death, Highest Coronary Atherosclerosis Score, Heart Weight and Myocardial Infarction

Test of significance (chi square): NS: not significant; * 0.01

Table IV. Percentage of Autopsies with Papillary Muscle Artery Sclerosis in the Presence of Diffuse Type Fibrosis

* Cases with focal papillary muscle fibrosis excluded . 820 STEER ET AL. Jap.November Heart, 1977 J.

Table V. Number and Percentage of Autopsies with Focal Cardiac Myocytolysis by Presence and Absence of Non-bacterial Thrombotic Endocarditis and Microthrombi of Cardiac Intramural Arteries

Significance test (chi square): absent vs present; ** P<0.01 Focal cardiac myocytolysis, non-bacterial thrombotic endocarditis (NBTE), and microthrombi were all present in 3 cases.

Fig.6. Thrombosed vessel near area of focal cardiac myocytolysis. 82-

year-old male died of adenocarcinoma of the stomach. No other cardiac le- sions present. Heart weight 300 Gm. H&E•~80

at autopsy had focal cardiac myocytolysis. There was no association between focal cardiac myocytolysis and any particular type of cancer but there was an association between focal cardiac myocytolysis and non-bacterial throm- botic endocarditis (NBTE) and microthrombi in myocardial arteries (Table V). In histologic sections, foci of cardiac myocytolysis appeared to be in the area of distribution of thrombosed arteries when these were present (Fig. 6). Focal cardiac myocytolysis was usually found in more than one site in the heart. It was present in 47 of the 147 blocks of tissue obtained from the 21 cases with focal cardiac myocytolysis. The subjects in this autopsy series included atomic bomb survivors. Com- parison of the frequency of these lesions, focal and diffuse papillary muscle Vol.18 No.6 SMALL CARDIAC LESIONS 821 fibrosis and focal cardiac myocytolysis, showed that they were not more frequent in radiation exposed subjects than in non-irradiated controls.

DISCUSSION The focal type of papillary muscle fibrosis which is actually a healed infarct of the papillary muscle, has a characteristic histologic appearance that permits identification and separation from other papillary muscle scars. The essential morphologic features have been described and illustrated, and their association with the presence of coronary heart disease and myocardial in- farction has been demonstrated. These scars may be large and may occupy a major portion of the papillary muscle which as a result becomes distorted as the original area of necrosis undergoes scar contraction. However, in this series, there were no cases in which there was evidence that the focal type of papillary muscle fibrosis was sufficiently extensive to interfere with papillary muscle or mitral valve function. The diffuse type of papillary muscle fibrosis occurs much more frequently than the focal type. It appears to be a manifestation of aging and may pos- sibly be due to sclerosis of the arteries of the papillary muscles. Apparently these scars develop very slowly without a preceding necrotic or inflammatory stage since none was observed. Sections stained with congo red are negative, and the areas of fibrosis and the vessel changes do not resemble amyloid de- posits. We found no evidence that the diffuse type of papillary muscle fibrosis affects the function of the papillary muscles or is related to any cardiac abnor- mality. The pathogenesis of focal cardiac myocytolysis is not at all clear although appears to be an important factor. The lesions differ from the coag- ulation necrosis of myocardial infarction, yet the two may be found together. NBTE or arterial microthrombi or both were present in 6 of the 12 patients who died of cancer and who had focal cardiac myocytolysis.16) Theoretically, disseminated intravascular coagulation could be a mechanism for the produc- tion of microthrombi.17) Experimental lesions resembling focal cardiac my- ocytolysis have been produced by isoproterenol. It is thought that focal myocytolysis can result from the release effect of catecholamines on ionic and metabolic processes.18) It is possible that focal cardiac myocytolysis may be an important lesion because it has been suggested that it may be involved in post-infarction extension of myocardial infarcts as well as being a significant factor in post-infarction cardiac rupture.13) The significance of the pigment in the mononuclear cells is undetermined. Of all of the special stains it reacted like lipofuscin in neighboring intact myocardial cells raising the possibility 822 STEER ET AL. Jap.November Heart, 1977 J. that the mononuclear cells may include almost naked myocyte nuclei with re- tained pigment as well as small phagocytes.

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