To determine abnormal immune regulation in biopsy-proven active and healed myocarditis cases, lymphatic subpopulations in myocardial tissue and peripheral blood were studied. Among 53 cases examined, 19 were active myocarditis (M) and 34 were healing or healed (HM). Five cases of myocarditis were studied sequentially. The percentages of pan T-cells, B-cells, helper/inducer T-cells (Th/i), suppressor/cytotoxic T-cells (Ts/c), etc per total marker positive cells were calculated by use of monoclonal antibodies. In myocardial tissue, the percentage of Th/i was significantly lower in HM than M (p<0.01). The helper/suppressor ratio (OKT4/8) in peripheral blood was 2.43 ± 0.43 (mean ± SE) in M, 1.61 ± 0.19 in HM and 1.34 ± 0.12 in age-matched controls. In 5 progressive studied cases of M, there was a decrease of the helper/suppressor ratio at 1 to 6 months after the myocarditis. It was concluded that subsidence of the immune reaction in myocardium is related to the healing process of myocarditis and may suggest improved prognosis.

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The blood pressures (BP) and anthropometric values of 1, 014 Japanese rural school children aged 12-17 years old were measured at one-year interval. The strongest correlation for systolic BP(SBP) was weight and for diastolic BP(DBP) it was age. smaller increment of height showed significant discriminative powers in differentiating the subjects who had been above the age-sex specific 80th percentile value (H-H group) from those who had been below the 20th percentile value (L-L group) for both SBP than those without a FHH, and were more prevalent in H-H group for SBP. These results indicate that larger body size and more mature stature are determinants of higher levels of BP during adolescence, and FHH affects SBP only in this period.

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The aim of this study was to examine the impact of a family history of hypertension (FHH) on blood pressure levels in Japanese rural adolescents. The study population consisted of 458 and 553 subjects, aged 13 and 16 years, respectively. Particular attention was focussed on subjects with a FHH (13 years old, n=83 ; 16 years old, n=97 ;). Significant associations were found between FHH and systolic blood pressure for buys and girls at 16 years old and diastolic blood pressure for girls at 16 years old. The impact of a FHH on blood pressure mainly affected systolic blood pressure in late adolescence (16 years of age). In early adolescence (13 years of age), different physical maturation status may have masked the real impact of a FHH on blood pressure.

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To evaluate the clinical role of afterload in progression of dilated cardiomyopathy (DCM), a loading examination (study 1) and a follow-up study (study 2) were carried out, using echocardiography, and analysed with Force-Velocity relation (FVR). FVR) was defined as the relation between endsystolic wall stress (WSes) and mean circumferential fiber shortening velocity (mVcf). In study 1, the cardiac responses to angiotensin II loading in 30 cases with DCM (17 cases with presumed causes, and 13 without) were observed. These cardiac responses could be described by a hyperbola (Y=197/(X+9)+0.04, r=0.63) on the graph of FVR, and each response also seemed to fit the hyperbola (Y=0.86+29.9, r=-0.64, p<0.02). In study 2 during a mean clinical course of 3.7 years, the cardiac function (mVcf) in 19 out of 25 cases with DCM changed inversely with the changes of WSes on FVR. The "a" value calculated by the same method as study 1 did not differ before and after the follow-up. It did, however, vary according to the clinical outcome. These results suggest that afterload plays an important role in progression of DCM, and that an evaluation of cardiac function employing FVR may be helpful for assessing the myocardial damage, causative factors, and the prognosis of DCM.

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Seventy-eight dogs with graded constriction of the left main coronary artery were studied to determine the coronary blood flow at which the heart is vulnerable to catecholamine induced ischemia. The left main coronary artery was cannulated with a Griggs' type selfperfusing cannula. The coronary blood flow (CBF) was reduced by graded constriction of the extra-corporeal circuit connected with this cannula. Blood flow rates between 12 and 117 ml/min/100g were studied. Cardiac activation was achieved by either intracoronary administration of a physiological dose of catecholamine (noradrenaline ; 0.4 μg/kg/min or adrenaline ; 0.2μ/kg/min), or by electrical stimulation of the left stellate ganglion (4 Hz, 2 msec, 10 V for 5 min). When CBF was below 30 ml/min/100g, accentuated myocardial ischemia was always indicated by lactate production, myocardial creatine phosphate depletion, ischemic ST segment changes, and elevated left ventricular end diastolic pressure (LVEDP) during these simulations. When CBF was above 50 ml/min/100g, catecholamine clearly accelerated the cardiac function and myocardial metabolism with no sign of ischemia. When CBF was between 30 and 50 ml/min/100g signs of accelerated myocardial ischemia appeared during catecholamine activation in only 1/2 of the dogs. This study indicated that the critical level for CBF at which endogenenous or exogenous catecholamine can produce ischemia is between 30 and 50 ml/min/100g.

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Among a total of 634, 440 autopsy cases in "The Annulas of Pathological Autopsy Cases in Japan" from 1958 to 1984, 929 cases with nonspecific myocarditis were registered. The average incidence was 0.15%, fluctuating myocarditis were registered. The average incidence was 0.15%, fluctuating around 3- to 5-year intervals with a remarkable rise observed after 1974. The major complications in cases of myocarditis were pneumonitis, hepatitis or hepatic cirrhosis, pancreatitis, malignancies, lymphatic or thymic involvements. A clinicopathological study of 36 cases of myocarditis and 27 cases of postmyocarditic cardiomegaly indicated a classification of acute, subacute, healing and chronic or recurrent stages as well as dilatation-hypertrophy-and right ventricle-dominant types. Acute myocarditis was characterized by diffuse inflammatory cell infiltration and showed various types of arrhythmias and shock. Subacute myocarditis showed ventricular dilatation, edematous interstitium and severe congestive heart failure. Chronic myocarditis with dilatation and/or hypertrophy and irregular fibrosis included right ventricular involvement, endomyocardial disease, sick sinus syndrome in selected cases, congestive heart failure in most cases, and showed a male predominancy. Postmyocarditic cardiomegaly was similar to chronic myocarditis but showed more hypertrophy, preexcitation waves and prominent negative T waves in electrocardiography and sudden death.

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We studied the conduction system of 65 cases of proven active or healed myocarditis and related diseases among 7120 autopsy samples. For this purpose, we prepared serial sections by Lev's method. The pathological diagnoses were idiopathic acute myocarditis (5), giant cell myocarditis (3), chronic myocarditis (13), healed myocarditis (22), sarcoidosis (4), collagen or autoimmune disease (13) and complication of cardiomyopathy, and 15 out of 25 cases of sick sinus syndrome. Conduction system lesions were divided into two groups. In order cases manifesting mainly arrhythmia, the SA node, atrial muscle and AV node were involved concomitantly with perimyocarditis. In younger cases mainly showing heart failure, the RBB, LBB and Purkinje fibers were damaged by endomyocarditis. Histologically, interstitial myocarditis was observed in the former group and parenchymatous myocarditis in the latter.

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Serial changes in lymphocyte subset were investigated in an animal model of encephalomyocarditis (EMC) virus myocarditis in mice. The lymphocyte subset in the peripheral blood was measured by flow cytometry and, T cell subset in the myocardium was stained by labeled avidin-biotin technique. Helper-inducer T cells (Lyt 1 cells) decreased significantly on day 7, but there was no change in cytotoxic-suppressor T cells in the peripheral blood. During the acute stage a significant number of T cells (Thy 1.2 cells) were seen in the heart with helper-inducer T cells precominating. The effect of prednisolone and cyclosporine on viral myocarditis was studied in our experimental model. Prednisolone or cyclosporine given in the early stage aggravated the course, and they did not have beneficial effects during the early recovery period.

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The cellular immune mechanism of cardiocyte injury in viral myocarditis was investigated by observing and analyzing the interactions among cardiocytes, T cells, B cells, natural killer (NK) cells and macrophages in situ in the myocardium of our murine model (C3H/He mice) and of human patients. In murine coxsackie B3 virus myocarditis, lymphocyte subsets were identified by light and electron microscopic immunohistochemical techniques with antibodies against specific antigens of pan T (Thy 1.2), helper/inducer T (Th/i)(Lyt 1⁺), cytotoxic/supressor T (Tc/s) Lty 2⁺), B (Ig⁺) and asialo GM₁⁺ cells in the myocardium. In the acute phase of myocarditis, asialo GM₁⁺ (mostly NK) cells predominated over pan T cells and peaked on day 9. Pan T cells than reached a peak on day 14. The T4/T8 (Lty 1⁺/Lty 2⁺) ratio was 1.3 ± 0.5 on day 5 and reached a peak of 9.1 ± 3.6 with an increase of Lty 1⁺ cells on day 14. Thereafter, NK cells and T cells gradually decreased and could still be seen in fibrotic foci even 3 and 12 months later. B cells were so scarce that no quantitative evaluation could be made. Electron microscopy revealed that macrophages were in close contact with Th/i cells, target cardiocytes and less commonly, B cells: Tc/s and NK cells also occasionally conjugated with apparently viable or degenerated cardiocytes. Some lymphocytes were located in widened intercellular spaces of dissociated intercalated discs, and in intracytoplasmic widened confines of some cardiocytes (emperipolesis). These results suggest that in the acute phase of myocarditis, NK cells initiate the reaction, and then sensitized cytotoxic T cells and activated macrophages aggravate cell-mediated injury by their close contacts with target cardiocytes; close contacts among macrophages, Th/i cells and a few B cells, and the increased T4/T8 ratio may facilitate regulation of the complex immune network; in the chronic phase, residual but active NK and cytotoxic T cells may sustain cytotoxicity. In the endomyocardial biopsies obtained from 8 patients with viral or idiopathic myocarditis from 3 to 48 days a after the clinical onset, conventional electron microscopy revealed actual contacts among cardiocytes, macrophages and lymphocytes. As in our murine model, some lymphocytes had emperipolesed in cardiocytes or were located in widened spaces of dissociated intercalated discs. In 4 of these 8 patients infiltration of Leu 2a⁺ Tc/s, Leu 3⁺ Th/i and Leu 7⁺ cells was indentified immunohistochemically, and T4/T8 ratios varied widely from 0.1 to 3.8 in the endomyocardial biopsides. These morphologic features and immunohistochemical evidence of interaction among effector lymphocytes, macrophages and target cardiocytes appeared to be essentially similar to those seen in the animal model of coxsackie B3 virus myocarditis.

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To investigate the role of immunoregulatory function in determining the clinical course of acute myopericarditis, lymphocyte subsets were analysed by laser flow cytometry in 20 patients with acute myopericarditis, 30 with various arrhythmias or atrio-ventricular block and 31 with dilated cardiomyopathy. During the healing stage of acute myopericarditis, patients with residual electrocardiographic or left ventricular wall motion abnormalities presented altered frequencies of lymphocyte subsets, increased B 1 and reduced OKT 8 positive cells with an elevated OKT 4/8 ratio. The abnormal pattern was not evident in patients with acute pericarditis nor in those with acute myocarditis who recovered completely without residual abnormalities. This observation suggests that an imbalance of helper/suppressor T cells could modulate the clinical course of acute myopericarditis, wither by producing extensive and irreversible myocardial damage during acute illness or by inducing chronic smoulding myocardial inflammation. Patients with ventricular arrhthmias and left ventricular wall motion abnormalities also presented reduced suppressor/cytotoxic T cells, implying that they had bee suffering from chronic smoulding myocarditis mediated by immunoregulatory dysfunction. However, we could not mediate the progression from myocarditis to dilated cardiomyopathy, since no association was demonstrated between the abnormal lymphocyte subsets and mononuclear cell infiltration in endomyocardial biopsy sample from patients with dilated cardiomyopathy.

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This review delineates the impact of molecular biology on the diagnosis and pathogenesis of coxsackie B viral myocarditis. The etiological role of the coxsackie B viruses in acute myocarditis is well established. A hallmark of most coxsackie B virus infections is extension cytopathology of the host cell. Recent evidence from studies of a nonlytic infection show that a coxsackie B virus can alter an infected cell which results from persistent infection. There are two other mechanisms for cardiac injury during coxsackie B virus infection. The first phase usually occurs during the first week after infection, and is probably a direct result of lytic infection to the myocytes and of the accompanying inflammatory response. The second phase of coxsackie B virus-induced myocarditis is accompanied by an autoimmune response to heart tissue, which occurs 3 weeks after infection. Genetic factors probably play a role, but their contribution has not yet been evaluated.

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