福井 重文

Diastolic heart failure (DHF) is a major cardiovascular disorder with poor prognosis; however, its molecular mechanism still remains to be fully elucidated. We have previously demonstrated the important roles of Rho-kinase pathway in the molecular mechanisms of cardiovascular fibrosis/hypertrophy and oxidative stress, but not examined in the development of heart failure. Therefore, we examined in this study whether Rho-kinase pathway is also involved in the pathogenesis of DHF in Dahl salt-sensitive rats, an established animal model of DHF. They were maintained with or without fasudil, a Rho-kinase inhibitor (30 or 100 mg/kg/day, PO) for 10 weeks. Untreated DHF group exhibited overt heart failure associated with diastolic dysfunction but with preserved systolic function, characterized by increased myocardial stiffness, cardiomyocyte hypertrophy, and enhanced cardiac fibrosis and superoxide production. Fasudil treatment significantly ameliorated those DHF-related myocardial changes. Western blot analysis showed that cardiac Rho-kinase activity was significantly increased in the untreated DHF group and was dose-dependently inhibited by fasudil. Importantly, there was a significant correlation between the extent of myocardial stiffness and that of cardiac Rho-kinase activity. These results indicate that Rho-kinase pathway plays an important role in the pathogenesis of DHF and thus could be an important therapeutic target for the disorder.

Heart failure is the most common cardiovascular disease with high mortality and morbidity. Both enhanced microtubule polymerization and cardiomyocyte apoptosis are involved in the pathogenesis of heart failure. However, the link between the two mechanisms remains to be elucidated. In this study, we thus address this important issue in cultured cardiomyocytes from Wistar rats in vitro and in angiotensin II (ATII)-infused rats in vivo. Confocal microscopy examination showed that in cultured rat cardiomyocytes, micrographic density of microtubules was increased by paclitaxel, a microtubule-polymerizing agent, and decreased by colchicine, a microtubule-depolymerizing agent, but not affected by ATII, isoproterenol, or tumor necrosis factor-alpha alone. Immunoblotting analysis showed that Bax/Bcl-2 ratio, which is associated with the activation of caspase-3, was significantly increased in ATII-stimulated cultured cardiomyocytes in vitro and in ATII-infused rats in vivo, both of which were inhibited by co-treatment with colchicine. Caspase-3 and TUNEL assay to detect apoptosis in vitro demonstrated that paclitaxel or ATII alone significantly enhanced and their combination further accelerated cardiomyocyte apoptosis, which was again significantly inhibited by colchicine. Caspase-3 and TUNEL assay in vivo also demonstrated that ATII infusion significantly increased myocardial apoptosis and that co-treatment with colchicine significantly suppressed the apoptosis. In conclusion, these results indicate that a microtubule-depolymerizing agent could be a potential therapeutic strategy for treatment of heart failure.

BACKGROUND: The specific incidence of thrombotic pulmonary embolism (PE), tumor PE and tumor invasion into large veins according to tumor type and tumor site remains unclear. METHODS AND RESULTS: A total of 65,181 cancer patients were identified from 98,736 postmortem examinations. Thrombotic PE occurred in 2.32% of all cancer patients and comprised 88.6% of the total number of all PE events. The incidence of thrombotic PE was high in those with adenocarcinoma, leukemia and large cell carcinoma, and was low in those with hepatic cell carcinoma. The incidence of PE was high when tumor was present in hematogenous tissue, lungs, ovaries, pancreas and the biliary system, and was low when tumor was present in the liver. The incidence of tumor PE was high with large cell carcinoma, hepatic cell carcinoma and adenocarcinoma, and was also high when tumor was present in the lungs, ovaries, kidneys and liver. There was a significant correlation between the incidence of tumor PE and the incidence of tumor invasion into large veins. CONCLUSION: The incidence of thrombotic PE, tumor PE and tumor invasion into large veins varies significantly according to tumor histopathology and tumor site.

BACKGROUND: The diagnostic and therapeutic strategy for acute pulmonary thromboembolism (APTE) was published by the Japanese Circulation Society. But in Japan, there has been no report on how to improve the pre-test probability in APTE-suspected cases, to determine a practically available diagnostic strategy, nor has been a report that compares diagnostic methods and therapies for APTE by decision analysis. METHODS AND RESULTS: APTE was found in 66.7% before using diagnostic imaging techniques. Compared with the absence of APTE, prolonged immobilization, cancer, tachycardia, unilateral leg swelling and inverted T-wave in V(1-3) were found more often in the presence of APTE. The rate of obtaining the result on the day of ordering the examination test was 100% with arterial blood gas analysis, trans-thoracic echocardiography and computed tomography (CT), 78.2% in D-dimer, 85.5% in pulmonary angiography, and 54.5% in perfusion lung scan. Decision analysis showed that the highest expected utility was anticoagulant over 0.51 in pre-test probability, with CT between 0.13 and 0.51. CONCLUSIONS: The pre-test probability of APTE has already been high before using specific diagnostic imaging techniques in Japan. Our results showed that the diagnostic strategy for APTE made by the Japanese Circulation Society was available in most hospitals in Japan.

BACKGROUND: The goal of the present study was to examine the cardiac configuration and pulmonary vascular changes in patients with portopulmonary hypertension (PPHTN) and compare them with those of idiopathic pulmonary arterial hypertension (IPAH). METHODS AND RESULTS: The subjects were 10 patients with PPHTN and 18 with IPAH. In PPHTN, the increases in the right ventricular end-diastolic volume index (89+/-19 vs 128+/-50 ml/m2; p=0.04), right end-systolic volume index (50+/-19 vs 95+/-47 ml/m 2; p=0.02) and right ventricular mass index (47+/-18 g/m2 vs 79+/-31; p=0.04) were low compared with IPAH. The decrease in the right ventricular ejection fraction was also low in PPHTN (45+/-10 vs 28+/-13%; p=0.01). The degree of sparse arborization and abrupt narrowing on wedged pulmonary angiography was moderate in PPHTN compared with IPAH. In PPHTN, the proximal pulmonary arteries were dilated near the segmental arteries, which were narrow in IPAH. CONCLUSION: Changes in the configuration of the heart were moderate in PPHTN compared with those in IPAH. The degree of sparse arborization and abrupt narrowing were also moderate in PPHTN.

BACKGROUND: There have only been a few reports published on combination therapy for patients with primary pulmonary hypertension (PPH). METHODS AND RESULTS: Fifteen patients with PPH (4 men and 11 women, 34.5+/-12.1 years old) had received chronic administration of epoprostenol and the additive effects of inhaled nitric oxide (NO) and the hemodynamic changes were evaluated. In addition, the difference in the effect of acute NO loading before and after the epoprostenol therapy was compared in 6 of these patients. Under chronic use of epoprostenol, mean pulmonary arterial pressure, mean right atrial pressure and pulmonary vascular resistance were decreased with acute inhalation of NO. However, cardiac output, mean aortic pressure and systemic vascular resistance were unchanged. As a result, the pulmonary to systemic vascular resistance ratio was reduced. Moreover, after chronic use of epoprostenol, the change (delta) in cardiac output with NO inhalation was increased and the NO-induced decrease in pulmonary vascular resistance was augmented compared to those before the induction. CONCLUSION: Nitric oxide inhalation further improved the hemodynamics when combined with chronic use of epoprostenol in PPH patients. These results suggest the possibility that combination therapies can be used in the treatment for PPH patients.