Sen Koyama

FK506 therapy of experimental autoimmune myocarditis after onset of the disease

Preventive effects of FK506 on autoimmune myocarditis have been demonstrated, but the therapeutic efficacy of the agent in established myocarditis yet remains to be assessed. In this study, effects of FK506 on experimental autoimmune myocarditis were investigated by the use of the agent after the onset of the disease. Lewis rats were immunized with either cardiac myosin or bovine serum albumin (BSA) in complete Freunds adjuvant. The onset of the disease was ascertained by examining randomly chosen cardiac myosin-immunized rats. Animals were divided into four groups: the BSA-immunized saline-treated group (group A, n = 6); the BSA-immunized FK506-treated group (group B, n = 6); the myosin-immunized saline-treated group (group C, n = 6); and the myosin-immunized FK506-treated group (group D, n = 11). Saline or 1.0 mg/kg/day of FK506 were intramuscularly injected from day 16 to day 27. All the rats were put to death on day 28. Rats of group C became severely ill by the third week, while in contrast, rats of group D remained active, as did rats of groups A and B. The heart weight/body weight ratio was significantly lower in group D than in group C rats. Group mean values were 3.48 +/- 0.10 gm/kg for group A, 3.48 +/- 0.16 gm/kg for group B, 4.94 +/- 0.66 gm/kg for group C, and 3.88 +/- 0.43 gm/kg for group D. Rats of group C showed severe myocarditis with mononuclear cell infiltration, myocardial necrosis, and interstitial edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of 15-Deoxyspergualin on Experimental Autoimmune Giant Cell Myocarditis of the Rat

BACKGROUND The benefits of immunosuppressive therapy for human myocarditis are controversial. The effects of a new immunosuppressant agent, 15-deoxyspergualin (DSG), on rats with experimental autoimmune myocarditis (EAM), an animal model of human giant cell myocarditis, were examined. METHODS AND RESULTS Lewis rats were immunized with cardiac myosin in Freunds complete adjuvant on day 0. In the first experiment, the effective doses of DSG required to prevent EAM were investigated. Rats were placed into one of five groups: the control group (A) was administered saline from days 1 to 10; group B, 0.3 mg/kg per day of DSG; group C, 1.0 mg/kg per day of DSG; group D, 3.0 mg/kg per day of DSG, and group E, 10.0 mg/kg per day of DSG. Rats were killed on day 28. The heart weight/body weight ratios of the rats of groups D and E were significantly lower than that of the control group. Macroscopic and microscopic scores for myocarditis decreased in groups D and E. In the next experiment, the effects of delayed administration of DSG in preventing autoimmune myocarditis were studied. Two groups of rats received 3.0 and 10.0 mg/kg per day of DSG from days 6 to 15, respectively. Two other groups of rats received the same doses of DSG from days 11 to 20. No preventive effect of delayed DSG treatment was observed. The effects of long-term, delayed initiation therapy then were evaluated. Rats were administered 10.0 mg/kg per day of DSG from days 6 to 25. The heart weight/body weight ratio and macroscopic and microscopic scores of the rats so treated significantly decreased compared with the controls. CONCLUSIONS It was demonstrated that DSG can prevent the development of cardiac myosin-induced autoimmune myocarditis.

Immediate effects of percutaneous transvenous mitral commissurotomy on pulmonary hemodynamics at rest and during exercise in mitral stenosis

Hemodynamics were evaluated during exercise in 33 patients with mitral stenosis who underwent percutaneous transvenous mitral commissurotomy (PTMC). PTMC was performed using an Inoue balloon. Each patient underwent a supine ergometer exercise test before and on the day after PTMC. Ergometer work load was started at 20 W and increased in increments of 20 W at 3-minute intervals until terminated by the patients fatigue or shortness of breath. Mitral valve area increased by 0.8 +/- 0.4 cm2 (1.1 +/- 0.3 to 1.9 +/- 0.4 cm2, p less than 0.001). Mean mitral pressure gradient decreased (12 +/- 5 to 6 +/- 2 mm Hg, p less than 0.001). Pulmonary arterial pressure significantly decreased and the cardiac index significantly increased both at rest and during exercise after PTMC. Before PTMC, the increases in pulmonary arterial pressure, total pulmonary resistance and pulmonary arteriolar resistance during exercise were greater in patients with a mitral valve area less than 1.0 cm2 than in patients with an area greater than or equal to 1.0 cm2. After PTMC, total pulmonary resistance still increased during exercise. However, pulmonary arteriolar resistance did not change during exercise in patients with a mitral valve area greater than or equal to 1.5 cm2, whereas it increased in patients with an area less than 1.5 cm2. An enlarged mitral valve area greater than or equal to 1.5 cm2, which may prevent pulmonary vasoconstriction and permits a greater increase in pulmonary blood flow during exercise, is considered a good result immediately after PTMC.

Experimental rat model representing both acute and chronic heart failure related to autoimmune myocarditis

SummaryThe most important clinical manifestation of myocarditis is congestive heart failure. The precise mechanisms of heart failure during myocarditis have not been elucidated because no animal model that would permit in vivo study of hemodynamics in severe active myocarditis has been available. We monitored hemodynamics and left ventricular function in a rat model of experimental autoimmune myocarditis to determine if this model could be useful for the study of in vivo hemodynamics in severe active myocarditis. Lewis rats were immunized with human cardiac myosin suspended in complete Freunds adjuvant. Baseline hemodynamics were measured using an ultraminiature catheter pressure transducer via the right internal carotid artery, 4 weeks after immunization in one group of rats (acute phase) and 3 months after immunization in another group (chronic phase). Untreated rats served as the control group. Hemodynamic measurements were also obtained after infusion of dobutamine in the acute-phase and chronic-phase groups. The heart weight-to-body weight ratios were significantly higher in both the acute-phase group and the chronic-phase group compared with normal control rats. The baseline left ventricular systolic pressure was significantly lower in the chronic phase group than in the control group. Peak dP/dt and peak -dP/dt were significantly lower in both the acute-phase group and the chronic-phase group compared with the control group. Dobutamine significantly increased left ventricular systolic pressure, peak dP/dt, and peak -dP/dt in the chronic-phase group but caused only minor changes in hemodynamic variables in the acute-phase group. In vivo measurements of hemodynamic variables indicated the presence of left ventricular dysfunction in rats with experimental autoimmune myocarditis. This animal model may be useful for the study of both acute heart failure related to acute myocarditis and chronic heart failure due to diffuse myocardial fibrosis.

Efficacy of amlodipine besilate therapy for variant angina: evaluation by 24-hour Holter monitoring.

SummaryThe efficacy of amlodipine, a calcium antagonist, was investigated in 12 patients with variant angina. Amlodipine was administered at a dose of 5 mg once daily, and efficacy was assessed from the frequency of anginal attacks, the frequency of ST elevation or depression, and the extent of ST segment changes [ST segment elevation or depression (mm) × duration (seconds)] on the Holter ECG before and after treatment. The frequency of ST elevation during the observation period was 1.67 ± 0.33 times/day (symptomatic attacks: 1.17±0.21/day; asymptomatic attacks: 0.50±0.19/day), and this significantly decreased to zero per day (both symptomatic and asymptomatic attacks) after treatment (p<0.05). The extent of ST segment elevation during the observation period was 507.5±156.6 mm·sec/day (symptomatic: 382.5±102.9 mm·sec/day; asymptomatic: 125.0±62.0 mm·sec/day), and such changes were completely suppressed (both symptomatic and asymptomatic) by treatment (p<0.05). The frequency of ST depression was 2.08±0.42 times/day (symptomatic: 0.25±0.13/day; asymptomatic: 1.83±0.37/day) during the observation period, while it was 1.50±0.36 times/day (symptomatic: 0.25±0.13/day; asymptomatic: 1.25±0.30/day) after treatment. Although anginal attacks remained unchanged, asymptomatic attacks tended to decrease (p=0.07). The extent of ST depression during the observation period was 632.5±239.4 mm·sec/day (symptomatic: 105.0±64.4 mm·sec/day; asymptomatic: 527.5±189.5 mm·sec/day), and this significantly decreased to 333.8±111.4 mm·sec/day (symptomatic: 50.0±31.2 mm·sec/day; asymptomatic: 283.8±102.6 mm·sec/day) after treatment (p<0.05). The frequency of anginal attacks during the observation period was 1.27±0.18 times/day, and this significantly decreased to 0.40±0.12/day after 1 week of treatment and to 0.22±0.07/day after 2 weeks of treatment (p<0.05). These results suggest that amlodipine is effective for treating variant angina at a daily dose of 5 mg.