Kenya Saji

Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension

We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, as a more feasible option to locally deliver the drug for PAH. We examined 15 patients with PAH (13 women and 2 men, 45 ± 4 years old), including idiopathic PAH (n = 5), PAH associated with connective tissue disease (n = 6), PAH with congenital heart disease (n = 3), and portal PAH (n = 1). In those patients, we performed right heart catheterization with a Swan-Ganz catheter in the two protocols with inhalation of nitric oxide (NO) (40 ppm, 10 min) and fasudil (30 mg, 10 min) with a sufficient interval (>30 min). Both NO and fasudil inhalation significantly reduced mean pulmonary arterial pressure (PAP) (NO: P < 0.01, fasudil: P < 0.05) and tended to decrease pulmonary vascular resistance (NO: P = 0.07, fasudil: P = 0.1), but did not affect cardiac index. The ratio of pulmonary to systemic vascular resistance was significantly reduced both in NO and fasudil inhalation (NO: P < 0.01, fasudil: P < 0.05), indicating that both NO and fasudil inhalation selectively affect lung tissues. Interestingly, there was no correlation in the vasodilator effects between NO and fasudil, and a positive correlation with serum levels of high-sensitivity C-reactive protein was noted for fasudil but not for NO. These results suggest that inhalation of fasudil is as effective as NO in patients with PAH, possibly through different mechanisms.

Long-term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats.

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.

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30 mg kg−1 i.p.), HT+DM; a high-salt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1 mg kg−1 day−1). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-β2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin–angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.

The systemic inflammation-based Glasgow Prognostic Score as a prognostic factor in patients with acute heart failure.

Aims By combining C-reactive protein and serum albumin concentrations, the Glasgow Prognostic Score (GPS) provides valuable predictions of prognosis in patients with cancer. Both systemic inflammatory response and malnutrition are also common in patients with heart failure. We evaluated the efficacy of the GPS for predicting the prognoses of patients with acute decompensated heart failure (ADHF). Methods We investigated 336 patients who were admitted with ADHF. The GPS (0, 1, and 2) was defined as follows: patients with both elevated C-reactive protein (>1.0 mg/dl) and hypoalbuminemia (<3.5 g/dl) were allocated a score of 2, patients with only one of these biochemical abnormalities were allocated a score of 1, and patients with neither of these abnormalities were allocated a score of 0. Results During the follow-up period (mean ± SD: 504 ± 471 days), 71 patients (21.1%) died. Relative to a GPS of 0, the hazard ratios for all-cause death were 3.40 (95% confidence interval 1.81–6.45) for a GPS of 2 and 1.97 (95% confidence interval 1.06–3.66) for a GPS of 1, as determined using adjusted Cox proportional-hazards analysis. Conclusions The GPS, which is based on systemic inflammation, is useful for predicting the prognoses of hospitalized patients with ADHF.

Epidemiology of Pulmonary Embolism in Japan

The incidence of PE is low in Japan compared with Western countries, but it has been increasing in recent years. The reasons for the low incidence may be genetic predisposition, lifestyle, and diagnostic power. On the other hand, the recent increment in incidence may result from changes in lifestyle and improvement in the diagnostic power.