Plasminogen activator therapy for acute myocardial infarction has become standard medical practice. Bleeding complications, however, limit the utility of the currently available agents. This article reviews how the tools of immunology, molecular biology and protein engineering are being used to develop safer and more effective plasminogen activators.

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A 17-year-old female patient with hypertrophic cardiomyopathy whose serum cardiac enzymes (creatine phosphokinase = CPK, lactic dehydrogenase = LDH) showed persistent elevation was presented. Percent of CPK-MB and LDHl in 6-year-follow-up period ranged from 3.2% to 8.5%, and 58.0% to 63.2%, respectively. This finding strongly suggests the existence of a small amount of continuous myocardial necrosis for a long time. The influence of cardiac enzyme release on the heart was assessed by serial checks of electrocardiogram, echocardiogram and 201-thallium myocardial scintigram. In serial checks of electrocardiograms, markedly decreased R wave amplitude ranging between 31% and 47% was observed in II, III, aVF and V3-6. On echocardiograms, asymmetric septal hypertrophy and a narrow left ventricular cavity were observed in all echocardiograms through the follow-up period. But, in most recent apical two-dimensional echocardiograms, hourglass appearance of the left ventricle due to a distinct cavity-formation at the apex was observed. In 201-thallium single photon emission computed tomogram, hypoperfusion area markedly extended in anterior and lateral parts. These changes in electrocardiograms, echocardiograms and 201-thallium myocardial scintigrams seemed to reflect myocardial necrosis. Our case points to a mechanism for hypertrophic cardiomyopathy to change, over time, to dilated cardiomyopathy-like features.

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Contributions of rapid filling, slow filling and atrial systole to the left ventricular (LV) filling volume were analyzed with the use of radionuclide ventriculography at rest, both globally and regionally, in 34 patients with isolated disease of the left anterior descending coronary artery. The patients included 17 with a normal ejection fraction (EF&ges;50%; group 1 ) and 17 with a depressed EF (<50%; group 2), and the data were compared with those. obtained from 13 normal subjects. A computer program subdivided the LV image into 4 regions, and time-activity curves were constructed globally and regionally by reverse-gating from the R wave. In both groups the contribution of rapid filling to the LV filling volume was decreased significantly in the affected septal and apical regions, and in the global left ventricle compared with that in normal subjects. In group l, the contribution of atrial systole showed an increase in these affected regions and in the global left ventricle. In contrast, in group 2, the atrial contribution was not increased globally or regionally as much as was expected. However, the contribution of slow filling was either increased significantly or tended to increase in the affected regions an, d in the global left ventricle. There were negative correlations between the contribution of rapid filling and that of slow filling in the global left ventricle (r = -0.73, p<0.001) and in each of the septal, apical and lateral regions (r &ges;-0.60, p<0.001), which suggested that the contribution of slow filling as well as of atrial systole undergoes an increase as rapid filling is impaired . Thus, in patients with coronary artery disease, the left ventricle relies on slow filling as well as atrial systole to affect diastolic LV filling in the affected regions and in the global left ventricle In the presence of LV systolic dysfunction.

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To determine the effect of aging and concentric hypertrophy on the reseve of the left ventricle (LV), 36 patients with hypertension (HT), 22 with hypertrophic cardiomyopathy (HCM) and 25 age-matched normal subjects (N)were studied by isoproterenol (ISP) infusion echocardiography. The end-diastolic LV relative wall thickness (RWT), fractional shortening (FS), peak mitral flow velocity during the rapid filling phase (R) and atrial systole (A), and the A/R ratio were measured. At rest, the RWT and A/R were larger in groups HT and HCM than in group N. There were no significant differences in age, heart rate (HR), and FS among the groups. The A/R of all groups showed a good positive correlation with increasing age. The A/R of the HT group was also positively correlated with RWT. During ISP infusion, the HR, R, A, A/R and FS increased in all groups. The changes in R and FS were smaller in groups HT and HCM than in group N. The change in HR in groups N and HT, and the change in FS in all groups during ISP infusion were all inversely correlated with increasing age. The change in FS during ISP infusion was inversely correlated with RWT in the HT group, but not in HCM. Thus, it was suggested that the impairment of LV reserve in patients with HCM is not only caused by concentric hypertrophy and the aging process, but also by other myocardial factor.

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To determine whether or not platelet noradrenaline (NA) content reflects a long-term variation of plasma NA concentration, the following experiments were carried out. During a 2-hour intravenous infusion of NA in rabbits, plasma NA concentration increased rapidly to an almost consistent level 1 h later, but platelet NA content increased linearly. One hour after the infusion, the plasma NA concentration returned to normal level, while platelet NA content decreased little and only returned to the original level about 80h later. By the 24-hour cold exposure stimulation (4 ± 0.5°C, platelet NA content and urinary NA excretion increased significantly in rats. There was a significant correlation between the urinary NA excretion and platelet NA content. In a patient with pheochromocytoma, the high plasma NA concentration returned to nearly normal levels a few hours after removal of the tumor, platelet NA content returned to normal levels 4 days after surgery. These results indicate that the measurement of platelet NA content serves as a better index for obtaining an average variation of NA concentration and sympathetic nerve activity. The measurement of platelet NA content also provides a reliable means of diagnosing pheochromocytoma.

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This work is a detailed study of the relevance of three sets of criteria to define myocarditis: Dallas meeting criterion, Edwards criterion and Dallas meeting criterion modified by the authors. Two groups were evaluated: normal autopsied hearts and endomyocardial biopsy from chronic chagasic patients at high risk of having myocarditis. Furthermore, endomyocardial biopsies from patients with dilated cardiomyopathy (DCM) were also evaluated . Applying the Edwards criterion, incidences of myocarditis in normal and chagasic hearts were 0% and 67% while with Dallas meeting criterion they were 0% and 42% and using our criterion the incidences were 0% and 92% respectively. In endomyocardial biopsies from DCM patients, the incidence of myocarditis was 7% with Edwards criterion, 22% with Dallas meeting and 33% with the authors own criterion. The authors concluded that their criterion, which defines myocarditis as the presence of inflammatory mononuclear cells enclosing more than 2 lymphocytes/400X aggregated to the cardiac fiber sarcolemma, is the most appropriate criterion of the three. Myocarditis was found in 33% of the 27 endomyocardial biopsy specimens from patients with DCM.

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For 2 years, from January 1985 to December 1986, we carried out a thorough investigation of sudden death or apparent sudden death in a population between 5 and 19 years of age in Osaka Prefecture. Sudden death (unexpected death caused by intrinsic factors within 24h after the onset of symptoms) occurred in 62 boys and 30 girls, with an annual sudden death rate of 3.0 per 100, 000 for boys and 1.5 per 100, 000 for girls. Of these 92 deaths, 64 occurred among school children (elementary or high school students), and it was these that were subjected to further analyses. Of the school children deaths, 29.7% seemed to be apparent sudden cardiac death (based on circumstances immediately before death, although these was no definite evidence for sudden cardiac death), and 29.7% were sudden death clearly attributable to underlying heart diseases (hence, sudden cardiac death in the usual meaning of this term accounted for about 60% of the 64 sudden deaths). In addition, 17.2% of the 64 cases were sudden death from bronchial asthma. Analysis of seasonal variation in the incidence of sudden death showed that apparent sudden cardiac death frequently occurred in summer, while sudden death clearly attributable to underlying cardiac diseases often took place in winter, sudden death from bronchial asthma occurred chiefly in summer and fall. Of the total number of sudden deaths, death occurred during exercise in 29.7%, and during sleep in 18.8% of individuals. The percentage of sudden deaths occurring during school hours was as low as 23.4% ( 15/64). Analysis of the physical condition of the 64 sudden death cases immediately before death disclosed the presence of respiratory infection in 10.9%, fatigue in 21.9%, lack of sleep in 4.7% and other conditions in 4.7%. Thus, the percentage of sudden deaths which occurred under ordinary physical conditions was 57.8% (37/64), of which 14 deaths (21.9% of the total) were associated with exercise.

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The incidence of coronary heart disease (CHD) was determind from a 26-year follow-up study of a fixed population of 19.961 subjects. The study also examined secular trends and relationship to risk factors. The age-adjusted incidence of myocardial infarction was found to have remained almost constant during this 26-year follow-up period, averaging 2.1/1, 000 person-years in men and 0.79/1, 000 person-years in women. An accurate trend of angina pectoris was difficult to evaluate in this study. Both age and elevated systolic blood pressure were confirmed to be important and independent risk factors. The risk of developing CHD was found to increase linearly with respect to systolic blood pressure. An increased risk was also observed in subjects with diastolic blood pressure of 110 mmHg or higher. Serum cholesterol and cigarette smoking were additional independent risk factors, indicating that the so-called three major risk factors for CHD were all confirmed in this Japanese population of both men and women.

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Samples of out patient sudden cardiac deaths in Kanagawa Urban prefecture from 1972-1987 and coronary risk factors were studied to determine the increase and/or decrease of myocardial infaction deaths. On the whole death from myocardial infarction increased chronologically, and the rate for females tended to be increased further. The age adjusted myocardial infarction deaths doubled over 10 years, while non-ischemic acute cardiac failure decreased with each generation. Other cardiac diseases tended to be reduced. Cigarette smoking was the highest in advanced countries in male. These findings suggest that deaths from myocard infarction approximately doubled in 10 years in all out-of hospital sudden cardiac deaths. Cigarette smoking from a young age was as great risk as future ischemic heart disease.

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Epidemiologic and pathologic studies were conducted between 1965 and 1986 to investigate trends for the incidence of coronary heart disease (CHD) and its risk factors in urban and rural populations and to relate the risk factor changes to trends for CHD incidence and pathologic findings. The epidemiologic study included men aged 4059 years who urban residents of Osaka. clerical and manual workers in Osaka, and rural residents of Akita prefecture. The pathologic study subjects were autopsied men aged 30 and over, admitted to a local hospital in Akita, whose autopsy rate was 88%. From a cohort of 8, 835 urban employees between 1975 and 1987, risk factors for myocardial infarction were identified: blood pressure, total serum cholesterol, blood glucose and cigarette smoking all which were compatible with findings in the US and European countries. For rural residents, serum cholesterol was less likely to be associated with the CHD incidence. Little contribution of serum cholesterol to development of coronary heart disease in rural men was supported by the pathologic study showing no significant association between serum cholesterol and the coronary atherosclerosis. Myocardial infarction from urban patients was characterized as massive necrosis in the myocardium with coronary artery stenosis and minimum atherosclerosis of basal cerebral arteries while that from rural men was small scattered necrosis in myocardium with atherosclerosis in both coronary and basal cerebral arteries. There was an increasing trend in the incidence of myocardial infarction in urban men but no change in rural men. The difference in the incidence trend can be attributed in part to differences in pathologic etiology and in blood pressure and serum cholesterol levels. Systematic surveillance is underway in both urban and rural population to clarify future trends for coronary heart disease and its risk factors.

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We reviewed the histories and laboratory data of 67 young patients with ischemic heart disease under the age of 40 years. Twenty-three cases were associated with hypercholesterolemia. Of these. 10 were of the familial type. Twenty patients had hypertension, while 14 were diabetics and 13 were heavy smokers. It is noteworthy that 13 of 17 patients with multi-vessel disease had hypercholesterolemia. Significant atherosclerotic coronary stenosis was demonstrated in 51 cases. The incidences of hypercholesterolemia, hypertension and diabetes mellitus in these 51 patients were not only significantly higher than those in age-matched normal healthy subjects and young patients with non-ischemic heart disease, but also higher than those in patients with ischemic heart disease over the age of 40 years. The results indicated that hypercholesterolemia is the most important risk factor for ischemic heart disease in young patients. although the three previously accepted risk factors (hypertension, diabetes mellitus and cigarette smoking) were all associated with the development of the disease. We could not find any obvious risk factor in 18 young patients with ischemic heart disease, including 12 cases of myocardial infarction. Myocardial infarction in the absence of any obvious risk factor occurred during strenuous physical exercise in 5 patients and following excessive alcohol consumption in 4.

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Coronary arteriography was performed in 1, 029 consecutive patients with ischemic heart disease and the relationship between the arteriographic features of coronary atherosclerosis and coronary risk factors was analyzed by case control studies. Patients were divided into four groups according to coronary arteriographic findings. Patients with normal or near normal coronary arteriograms (Group I) showed a high prevalence of smoking habit and a higher value of serum uric acid compared with the control group, so smoking and hyperuricemia were considered to be the risk factors for coronary atherosclerosis in patients of group . Four selected variables: smoking, hyperuricemia. hypertension and hyperlipidemia. were identified to be risk factors for the patients with minor plaques in the coronary arteries (Group II). As in Group I. smoking and hyperuricemia had a close relationship to solitary tight plaque in a branch of the coronary artery (Group III). Multiple tight stenoses in the coronary arteries (Group IV) correlated closely with smoking. hyperuricemia, hypertension, hyperlipidemia and diabetes mellitus. Thus, there were many strong risk factors for patients with diffuse, extended coronary atherosclerosis (Group II and Group IV), while only two factors. smoking and hyperuricemia, were considered to be risk factors for the patients with near normal coronary arteries ies or a solitary plaque in a branch of the coronary artery. These findings suggest that the role of the coronary risk factors on the pathogenesis of coronary atherosclerosis is not uniform but variable depending on the morphologic variability of the coronary atherosclerosis and on the pathophysiology of the ischemic heart disease.

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We analyzed serum lipoproteins and apolipoprotein E (apo E) from 199 patients in CCU, having ischemic heart disease. and from 211 healthy subjects. It was suggested that serum lipoprotein abnormalities, especially elevated low density lipoprotein (LDL) levels, are closely related to atherogenesis in relatively young patients and subjects with severe coronary lesions. The frequency of apo E-4 was higher and that of E-2 was lower in the CCU group than in the control group. Apo E mutants. E-7 (Glu₂₄₄→Lys, Glu₂₄₅Lys) and E-5 (Glu₃→<245>Lys), were also frequent in the CCU group. Apo E isoproteins have higher pI in the order E-2, E-3. E-4, and we observed that LDL-cholesterol levels in-creased in the same order. The apo E mutants. E-5 and E-7, are also more basic than E-4. These findings suggest that basic apo Es were associated with the development of atherosclerosis. The prevalence of familial hypercholesterolemia (FH) in the CCU group was more than 10 times higher than the reported frequency of FH heterozygotes in normal population. The persistence of marked hypercholesterolemia from infancy probably makes FH patients susceptible to atherosclerosis. Based on the analysis of LDL-receptor protein synthesis, various types of mutations were observed even in phenotypically homozygous FH patients. FH homozygotes were divided into 2 groups, a receptor-negative group and a receptor-defective group. We found a great difference in the frequency of coronary heart disease depending on whether even a small number of receptors were present or not.

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This is a study of type A behavior pattern in patients with coronary heart diseases (CHD). Type A behavior pattern (coronary-prone behavior pattern) has been recognized as a risk factor for CHD in western countries. Three hundred patietns with new onset of CHD (243 cases of acute myocardial infarction and 57 cases of unstable angina pectoris) between 1981 and 1987 were analysed from the standpoint of behavior pattern. Type A behavior pattern assessed by Jenkins Activity Survey (JAS) was found in 64.6% of subjects and in 43.0% of healthy controls (p<0.05). Concerning occupational position, the majority of patients' in the administrative class showed type A behavior pattern. Type A behavior pattern was not related with other traditional risk factors (hypertension, hypercholesterolemia and smoking) and was related with aniographically documented severity of coronary atherosclerosis. Emotional stress load by mirror drawing test (MDT) evoked more elevation of blood pressure and plasma catecholamine level in type A patients than in type B patients. A follow-up of post CHD patietns. whose occupational position belonged to the administrative class and/or whose work load did not decrease after CHD. modification of type A behavior pattern seemed to be difficult. In conclusion. we consider that type A behavior pattern exists also in Japanese CHD patients. and plays an important role in the development of CHD.

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We investigated, by case-control study. the relevance of psychosocial factors on the prevalence of acute ischemic heart disease (IHD) in middle aged Japanese men. We questioned 109 acute IHD patients and 80 individuals in an age-adjusted sampled control group. Multiple logistic regression analysis showed the following statistically significant factors: hypertension (odds ratio 4.01, p<0.001). Type A behavior pattern (2.25, p<0.05) and high job demand (2.23, p<0.02). No direct influence of family function or social support to the prevalence of acute IHD was apparent. These results suggest that, among men in Japan. Type A behavior pattern and high job demand represent psychosocial risk factors of IHD. Due to the case-control protocol. causal relationships cannot be decided. The limitation of the study design is discussed within that context.

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