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Background: Proto-oncogenes have been implicated in the pathogenesis of gene-mediated myocardial remodeling. In the human heart, however, it has not been clarified whether these proto-oncogenes are related to contractile impairment and structural alteration of the myocardium. The present study is designed to investigate the relationship between the c-Myc protein expression in the myocardium and the myocardial contractile dysfunction in patients with chronic aortic regurgitation who underwent indicated for aortic valve replacement., Methods and Results: Twelve patients (11 males and one female) with an average age of 55 years who underwent aortic valve replacement for isolated chronic aortic regurgitation were studied. The preoperative New York Heart Association class was II in four patients and III in eight. Ejection fraction, end-systolic volume index, end-systolic stress (Mirsky's form), and mass index of the left ventricle before surgery were 47+/-13%, 93+/-37 mL/m2, 223.2+/-44.4 Kdyn/cm2, and 210+/-38 g/m2, respectively. A left ventricular endomyocardial biopsy was performed to assess the myocardial cell diameter, fibrous content, and c-Myc protein expression in the myocardium. Cell diameter and fibrous content were significantly higher than those in five normal controls. C-Myc was detected in 9 of 12 present patients but in none of the normal controls. The degree of c-Myc expression had significant positive correlations with ejection fraction (r=0.93; P<.01) and end-systolic stress/end-systolic volume index (r=0.96; P<.01) and significant negative correlations with end-systolic volume index (r=-0.90; P<.01), cell diameter (r=-0.97; P<.01), and fibrous content (r=-0.92; P<.01), which suggested that the degree of c-Myc expression may have a significant negative correlation with myocardial contractility and myocardial hypertrophy., Conclusions: C-Myc expression may be related to the pathogenesis of myocardial remodeling in patients with chronic aortic regurgitation.

An immunocytochemical study was performed to examine the expression of cellular c-myc protein in the heart of 30-, 120- and 180-day-old cardiomyopathic Syrian UM-X7.1 hamsters. The heart of age- and sex-matched BIO-RB hamster was used as normal control. In paraffin sections, an immunostaining for c-myc was markedly increased in cytoplasm of cells from the UM-X7.1 heart as compared with that of the BIO-RB heart which showed a weak staining. However, c-myc was localized in nuclei of cells in frozen sections of the heart. Specific cell types of the heart were differentiated with anti-vimentin, and we found that the increased expression of c-myc was present in nuclei of muscle cells of the UM-X7.1 myocardium. A quantitative study of c-myc-positive nuclei of muscle and nonmuscle cells was carried out by a video micrometer. The mean number of c-myc-positive nuclei of muscle cells was significantly higher in the cardiomyopathic heart than in the control heart from hamsters of all ages studied. These results suggest that the increase of c-myc protein may relate to the pathological state or pathogenesis of the hereditary cardiomyopathy.

As the myocardium in patients with dilated cardiomyopathy (DCM) is deteriorating progressively, resulting in a decrease in left ventricular function, patients with end-stage DCM may require implantation of a left ventricular assist device (LVAD) unless they undergo heart transplantation. Although LVAD has been reported to provide excellent hemodynamic support, no data are currently available about the effects of long-term LVAD support on the myocardium in patients with DCM. We describe two patients with end-stage DCM who underwent LVAD implantation and were supported with LVAD for 524 and 245 days, respectively. Serial myocardial biopsies showed increases in myocardial cell diameter and intercellular fibrosis, despite excellent hemodynamic support by LVAD. These data suggest that the myocardium in patients with end-stage DCM deteriorates progressively, even if the pre-load of the left ventricle is reduced by LVAD.

Cardiovascular complications associated with methamphetamine abuse have increasingly been reported. However, chronic cardiotoxicity of methamphetamine is not experimentally well documented. In this study, methamphetamine (1 mg/kg/day) was subcutaneously injected into 5-week-old male Wistar Kyoto rats (n = 30). Age- and sex-matched Wistar Kyoto rats served as controls (n = 30). After 14 and 56 days, hearts were examined by light and electron microscopy. Foci of myocytic degeneration and necrosis appeared in the sub-endocardial areas on day 14 of methamphetamine exposure. Myocytic degeneration and necrosis became more extensive on day 56. At this stage, myocytolysis, contraction bands, atrophied myocytes, and spotty fibrosis were patchily distributed throughout the myocardium in most of rats treated with methamphetamine. The accompanying ultrastructural features included marked degeneration of cardiac mitochondria with fractured and disrupted cristae, hypercontraction of myofibrils, and loss of myofilament. In contrast, cardiac myocyte lesions were not observed in control rats. These myocardial lesions in rats treated with methamphetamine for 56 days resemble the cardiomyopathy associated with methamphetamine abuse in humans.

Immunocytochemical investigation was performed on the cytoskeletal proteins in cardiac tissue of the cardiomyopathic hamster. Male cardiomyopathic UM-X7.1 hamsters at 180 days of age (n = 8) and age- and sex-matched normal BIO-RB hamsters (n = 8) were used in this study. Immunofluorescence microscopy using monoclonal antibodies against desmin, alpha-actinin, titin, and vincullin was employed. The heart weight to body weight ratio was significantly increased in the heart of cardiomyopathic hamster compared with that of normal hamster. In cardiomyopathic hamster, the left ventricular cavity was markedly dilated. Light microscopically, hypertrophy and atrophy of myocytes and myocardial fibrosis were prominently observed in cardiomyopathic myocardium. Immunocytochemically, desmin, alpha-actinin and titin showed the cross striations along the myofibers in normal myocardium. In contrast, in cardiomyopathic myocardium, desmin was irregularly distributed in myocytes and the amount of desmin was increased. Loss of cross striations of alpha-actinin and titin were frequently observed. Immunofluorescence against vinculin was not significantly altered. We conclude that the alterations of cytoskeletal proteins in myocardial cells may relate to decreased myocardial function in cardiomyopathic hamster failing heart.

In ten brain death patients circulatory stability was attained with both vasopressin and a minimum dose of epinephrine for more than a week. Clinical and pathological changes of the heart after brain death were examined in this model. ST-T wave changes of ECG were initially observed in 57%. The required dose of epinephrine to maintain the systemic blood pressure was rather high in the first two days after brain death and could be reduced below 0.1 kg/min in a steady state. Normal level of CPK-MB in this study indicated that the damage of the heart was reversible. The cardiac biopsy specimens from the right ventricular septum were obtained serially and they showed normal or slightly swollen mitochondria. The mitochondrial scores were below 1.0 in seven patients, and they were elevated to more than 1.0 in three patients with prolonged shock. The heart of brain death was suppressed by the shock at brain death, but it could be preserved in good condition for several days with our circulatory support which uses both arginine vasopressin and epinephrine.

Cardiac ventricular actomyosin was prepared from autopsy samples from humans ranging in age from one to 83 years, and its Ca2(+)-ATPase and K(+)-EDTA-ATPase activities were determined in the presence or absence of a sulfhydryl reagent, N-ethylmaleimide (NEM). The Ca2(+)-ATPase activity increased in the presence of appropriate concentrations of NEM. The extent of the stimulation of Ca2(+)-ATPase activity by NEM decreased significantly with age. The ratio of K(+)-EDTA-ATPase activity to Ca2(+)-ATPase activity also decreased with age. This suggests that there is an age-related modification of sulfhydryl groups in the myosin molecule.

The existence in an inbred strain of Syrian hamster (BIO 14.6) of a genetically transmitted cardiomyopathy (CM) that results in congestive heart failure offers unique opportunities to study causes of myocardial damage and the sequence of events leading to cardiac insufficiency. It is well known that the clinical course and pathologic aspects of the cardiac condition of the CM hamster resemble a type of idiopathic CM in man. This paper presents the findings obtained from light- and electron-microscopic observations of the CM heart muscle of the BIO 14.6 hamster. The investigation included qualitative X-ray micro-analysis of intra- and extracellular calcific deposits in the damaged myocardium, biochemical data of calcium-activated neutral protease in cardiomyolysis, and morphometric analysis for cardiac hypertrophy. It is concluded that the myocardial damage is due to disturbed biosynthesis of contractile components and the cellular membrane system. This defect, being accompanied by persistent hypoxia together with a large amount of Ca2+ and Ca-activated protease, leads progressively to necroses and scar formation with calcification in the cardiomyopathic heart muscle of the left (and later also the right) ventricle. It also leads to hypertrophy as a compensatory mechanism of unaffected cardiomyocytes and ultimately to fatal heart failure.

The turnover of cholesterol of red blood cells in healthy hamsters was faster than that in cardiomyopathic hamsters. The uptake of 2-deoxy-D-glucose by heart cells was more rapid in the diseased hamsters compared with that of the healthy ones. Freeze-etch study of heart cells disclosed a difference of membrane structure between the two groups. Results of lactate content in hearts with nonexercised and exercised hamsters of both the diseased and healthy groups revealed the retention of lactate in the diseased hearts, even in a nonexercised state. Electron microscopic findings confirmed that an increased hypoxic condition caused by exercise aggravates the diseaes in the cardiomyopathic hamsters. These two conditions, membrane abnormality and hypoxia, probably play a role fundamental to the genesis of the disease, because hypoxia in the cellular level may well be caused by membrane abnormality.

Eight fatalities due to cardiac rupture, of 40 consecutively autopsied myocardial infarctions, were clinicopathologically examined. Total duration of infarctions in 8 cases ranged from 9 hours to 14 days. The longer the period, the more the infarction extended, and aneurysmal dilatation of infarcted wall and tissue weakness were striking. The weakness was caused by the lack of replacement of necrotic muscle fibers by granulation, and was related to aneurysmal structure per se and also to its paradoxical pulsations. Postinfarction cardiac rupture occurring in relatively later phase was considered to be mainly due to weakness of infarcted wall, with less influence factors of mechanical stress such as physical exertion, hypertension, or intracardiac pressure. In the case where cardiac rupture took place in a relatively early stage of the episodes, infarction covered only a small range and aneurysmal change of the ventricle was slight, for which dynamic factors, represented by the degree of a localized strain elicited by myocardial contraction of non-infarcted site, seemed to play a significant role.

A histologic mapping of myocardium was deviced for the evaluation of myocardial infarction in autopsy cases. By this method, it is possible to understand the three dimensional extension, density and spreading or repairing mode of an infarct in the heart, and should be also possible to estimate the damaged myocardial mass. Furthermore, references of both clinical information and the findings from simultaneously examined coronary arteries gave this technic an efficient means for the clinicopathologic evaluation of myocardial infarction.

The expression of various proto-oncogenes was evaluated in the Syrian hamster with hereditary idiopathic cardiomyopathy. mRNA from the heart and aorta of controls (BIO-RB) and cardiomyopathic hamsters (UM-X7.1 strain, BIO 14.6 line) was tested using RNA hybridization techniques. Of the 19 different v-oncogene probes used in the study, only the v-myc probe revealed a substantially greater expression of oncogene in the 30th day of cardiomyopathic hamster heart than in control hamster heart. The amplified expression of c-myc was also observed in the heart of 1-year-old, but not of 7-day-old cardiomyopathic hamster. Overexpression of c-myc, otherwise associated with the regulation of cell differentiation or rapid growth, may relate to the pathological state or pathogenesis of the hereditary cardiomyopathy.

Fifty right ventricular endomyocardial biopsy specimens taken from patients with Kawasaki disease were studied. These were taken from 33 male and 17 female patients. Biopsies were examined for inflammatory cell infiltration, fibrosis, myocardial fibre disarrangement, and the cellular and nuclear changes of hypertrophy. A score of severity was prepared. The degree of abnormality was found to correlate with the duration of the disease, as did fibrosis found in 18 cases (36%), but inflammatory cell infiltration did not (13 cases, 26%). Coronary involvement was restricted to the male patients but the myocardial changes occurred in both sexes.