A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

Medical Doctors' Work-Life Balance and the Use of Household Chore Support Services.

Background: Achieving an optimal work-life balance (WLB) is an important social issue not only for workers in general but also for doctors due to the shortage of women doctors. The present study aims to survey doctors' WLB and their use of household chore support services (HCSS). Methods: A questionnaire survey was conducted with doctors working in Tottori Prefecture and a total of 289 responses (212 men, 77 women) were obtained and analyzed. To examine the relationship between gender and satisfaction with working patterns or with life for WLB, as well as the use of HCSS, a chi-squared test was conducted. Furthermore, a chi-squared test was conducted including age, marital status, whether or not they have preschool-aged children, and type of institution the participant worked. Results: A significant difference was found in type of institution the participant worked regarding satisfaction with work patterns and life. The proportion of those who have used HCSS was 12.5% of the total sample and was significantly higher for women than men (men: 8.5%; women: 23.4%). Regarding the reason to use HCSS, "to reduce the burden of household chores and childcare" and "to secure time for work" were most common with the same proportions, and amongst women, "to secure time for work" was the highest. Conclusion: Doctors working at a university hospital could have different work patterns and satisfaction with life compared to those working at other types of medical institutions. Additionally, the demand for HCSS was particularly high among women doctors, which suggests that HCSS may be used to reduce the burden of household chores and childcare, as well as to create time for work.

Protective effect of K201 on isoproterenol-induced and ischemic-reperfusion-induced ventricular arrhythmias in the rat: comparison with diltiazem.

AIM: Ventricular arrhythmia (VA) is a risk for sudden death. Polymorphic ventricular tachycardia (VT) degenerating to ventricular fibrillation occurs subsequent to the prolongation of the QT interval following administration of catecholamines under Ca(2+) loading. Fatal VA also occurs in ischemia and ischemic-reperfusion. We compared the suppressive effect of K201 (JTV519), a multiple-channel blocker and cardiac ryanodine receptor-calcium release channel (RyR2) stabilizer, with that of diltiazem, a Ca(2+ )channel blocker, in 2 studies of isoproterenol-induced (n = 30) and ischemic-reperfusion-induced VAs (n = 38) in rats. METHODS: Adult male Wistar rats were administered 12 mg/kg/min calcium chloride (CaCl(2)) for 20 minutes and then 6 µg/kg/min isoproterenol was infused with CaCl(2) for a further 20 minutes. In other rats, the left coronary artery was ligated for 5 minutes followed by reperfusion for 20 minutes. K201 or diltiazem (both 1 mg/kg) was administered before infusion of the isoproterenol or induction of ischemia. RESULTS: After administration of isoproterenol under Ca(2+) loading, fatal VA frequently occurred in the vehicle (9 of 10 animals, 90%) and diltiazem (8 of 10, 80%) groups, and K201 significantly suppressed the incidences of arrhythmia and mortality (2 of 10, 20%). In the reperfusion study, the incidence and the time until occurrence of reperfusion-induced VA and mortality were significantly suppressed in the K201 (2 of 15 animals, 13%) and diltiazem (1 of 9 animals, 11%) groups compared to the vehicle group (8 of 14 animals, 57%). SIGNIFICANCE: Induction of VA in an experimental model was achieved with a low dose of isoproterenol under Ca(2+) loading. K201 markedly suppressed both the isoproterenol-induced and the reperfusion-induced VAs, whereas diltiazem did not suppress the isoproterenol-induced VA. The results suggest that both VAs are related to early after depolarization (EAD) and indicate that K201 has the potential to suppress EAD by stabilizing RyR2 to mediate Ca(2+) release from the sarcoplasmic reticulum and acting as a multiple-channel blocker.

Campylobacter fetus as cause of prosthetic valve endocarditis.

A 65-year-old woman who had previously undergone aortic root replacement with a bioprosthetic valve (Bentall operation) in treatment of annuloaortic ectasia became feverish after developing dental caries and was admitted to our hospital. Transesophageal echocardiography showed an 18 × 4-mm vegetation on her prosthetic valve. Campylobacter fetus was isolated on blood cultures, and she was diagnosed with infectious endocarditis. Aggressive combined antibiotic treatment was effective for her recovery. C. fetus infection is a rarely reported cause of prosthetic valve endocarditis.

Three-dimensional reconstruction of the human capillary network and the intramyocardial micronecrosis.

Three-dimensional reconstruction of the human heart was performed to define the structure of the intramyocardial microvasculature. A total of 200 consecutive serial sections of 6 µm each were prepared from the left ventricular tissue of an autopsied human heart with normal coronary arteries. The corresponding arteriole, venule, and all capillaries were reconstructed using three-dimensional software. The capillary network extended right and left along the cardiomyocyte with major and minor axes of about 130 and 120 µm, respectively. The capillary length from an arteriole to an adjacent venule was about 350 µm. Two types of sack-like structures, the precapillary sinus and the capillary sinus, were present in the capillary network, and many capillaries diverged from these sinuses. The cardiomyocytes were covered with reticular capillaries. In contrast, the precapillary and capillary sinuses were surrounded by many cardiomyocytes. The arterial and venous capillaries were positioned alternately, forming a lattice pattern. Intramyocardial microcirculatory units forming a capillary network from an arteriole to adjacent venules on both sides were present. The sizes of myocardial micronecroses corresponded to that of the intramyocardial microcirculatory unit. These results show that the capillary network is an ordered and anatomically regulated structure and that the microcirculatory unit and the precapillary and capillary sinuses may play an important role in maintaining the intramyocardial microcirculation during contraction and relaxation.

Early effect of lipid-lowering therapy with pitavastatin on regression of coronary atherosclerotic plaque. Comparison with atorvastatin.

BACKGROUND: Virtual histology intravascular ultrasound (VH-IVUS) is used to diagnose coronary plaques and evaluate statin therapy. However, in most cases, quantitative changes in plaques have been evaluated in the chronic stage. We evaluated the quantitative and qualitative early effects of 2 statins on coronary lesions using VH-IVUS. METHODS AND RESULTS: Patients with acute coronary syndrome who underwent emergency percutaneous coronary intervention (PCI) were randomly assigned to receive pitavastatin (n=80; 2 mg/day) or atorvastatin (n=80; 10 mg/day) immediately after PCI. All patients underwent a blood lipid test and VH-IVUS evaluation of non-PCI lesions at admission and after 2-3 weeks of statin administration. After treatment, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) showed significant decreases to similar levels in each group (P<0.001). In the pitavastatin group, the plaque volume index and fibrofatty volume index (FFVI) also decreased significantly. In patients from the pitavastatin group with a dense calcium ratio of < or =10% (n=61), the percentage changes in FFVI and LDL-C were correlated positively (r=0.305, P=0.017), whereas no significant changes were found after treatment in the atorvastatin group. CONCLUSIONS: Fibrofatty composition and plaque volume decreased significantly following treatment with pitavastatin, which suggests that pitavastatin might have a higher affinity for fibrofat compared with atorvastatin.

Pharmacological characteristics and clinical applications of K201.

K201 is a 1,4-benzothiazepine derivative that is a promising new drug with a strong cardioprotective effect. We initially discovered K201 as an effective suppressant of sudden cardiac cell death due to calcium overload. K201 is a non-specific blocker of sodium, potassium and calcium channels, and its cardioprotective effect is more marked than those of nicorandil, prazosine, propranolol, verapamil and diltiazem. Recently, K201 has also been shown to have activities indicated for treatment of atrial fibrillation, ventricular fibrillation, heart failure and ischemic heart disease, including action as a multiple-channel blocker, inhibition of diastolic Ca(2+) release from the sarcoplasmic reticulum, suppression of spontaneous Ca(2+) sparks and Ca(2+) waves, blockage of annexin V and provision of myocardial protection, and improvement of norepinephrine-induced diastolic dysfunction. Here, we describe the pharmacological characteristics and clinical applications of K201.

Risk of heart failure due to a combination of mild mitral regurgitation and impaired distensibility of the left ventricle in patients with old myocardial infarction.

BACKGROUND: Ischemic mitral regurgitation (MR) is a serious complication after myocardial infarction, and the incidence of heart failure (HF) increases as the severity of MR increases. However, little is known about the relationship between mild MR and HF in the patients with old myocardial infarction (OMI) and a normal ejection fraction (EF). HYPOTHESIS: We hypothesized that a combination of mild MR and impaired distensibility of the left ventricle may increase the risk of diastolic HF in the patients with OMI and a normal EF. METHODS: The relationship between HF and mild MR was retrospectively investigated in 62 patients with OMI and EF of > 50% on echocardiography. RESULTS: Of the 62 patients, 47 (76%) did not have HF and 15 (24%) had HF. There was a significant difference in the incidence of mild MR between the patients with and without HF (p < 0.0001): of the 47 patients without HF, mild MR was detected in 19, but all 15 patients with HF had mild MR. However, there were no significant differences in age, gender, infarct sites, diseased coronary vessels, peak CK level, and observation period between the 2 groups. An increased E-wave and the ratio of the E-wave to the A-wave (E/A), a reduction of the E-wave deceleration time, and an increased brain natriuretic peptide (BNP) level were significantly noted in HF patients with mild MR compared with patients without HF. CONCLUSIONS: Even a mild MR may cause diastolic HF in patients with impaired distensibility of the left ventricle due to ischemic heart disease.

[Right coronary artery to left ventricle fistula associated with three-vessel coronary artery disease: a case report].

Right coronary artery to left ventricle fistula is a rare type of coronary artery fistula among congenital coronary artery anomalies. Most patients exhibit no symptoms and some experience chest pain. Coronary angiography sometimes detects the presence of coronary artery fistula, but not coronary arteriosclerosis. A 76-year-old man with unstable angina was admitted because he did not respond to drug therapy. Coronary angiography showed three-vessel coronary artery disease and the contrast agent entered the left ventricle from the terminal of the right coronary artery during diastole. Multidetector-row computer tomography showed similar findings. The patient subsequently underwent coronary artery bypass grafting and obliteration of the coronary artery fistula. The chest pain was relieved and he is now in good condition.

K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes and attenuates an increase in repolarization.

K201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong cardioprotective action and acts as a multiple-channel blocker, including as a K+ channel blocker. An experimental model of prolongation of the QT interval and torsades de pointes can be induced in rabbits by treatment with clofilium in the presence of the alpha1-adrenoreceptor agonist methoxamine. In this study we examined the effects of K201 with and without methoxamine on the QT and QTc intervals, and determined whether K201 inhibits clofilium-induced torsades de pointes in the presence of methoxamine (15 microg/kg/min) in rabbits (n=74). Administration of K201 (0, 40, 100, 200 and 400 microg/kg/min) with and without methoxamine prolonged the QT interval in a dose-dependent manner, and torsades de pointes did not occur in any animals. However, clofilium (50 microg/kg/min) with methoxamine induced torsades de pointes in all animals (6/6). Torsades de pointes occurred at rates of 100%, 67%, 40% and 0% at K201 concentrations of 0, 50, 200 and 400 microg/kg/min, respectively, in the clofilium-infused torsades de pointes model. Therefore, 400 microg/kg/min of K201 completely inhibited clofilium-induced torsades de pointes and attenuated the increase of repolarization caused by clofilium; the inhibitory effects of K201 may be related to its pharmacological properties as an alpha1-adrenoceptor blocker. Overall, our results show that K201 causes prolongation of the QT and QTc intervals, but does not induce torsades de pointes, with and without alpha1-adrenoceptor stimulation. Furthermore, K201 inhibits clofilium-induced torsades de pointes, despite QT prolongation, suggesting that QT prolongation alone is not a proarrhythmic signal.

Effects of enhanced external counterpulsation on hemodynamics and its mechanism.

BACKGROUND: The hemodynamic effects of enhanced external counterpulsation (EECP) and its mechanism(s) were investigated in relation to neurohumoral factors in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Twenty-four patients with AMI were studied before, during and after EECP treatment for 60 min. Heart rate (HR), right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) were determined. In addition, circulating concentrations of neurohumoral factors were determined at each time point. HR did not change following EECP treatment. However, RAP and PCWP increased significantly and CI was significantly elevated during EECP and thereafter. Blood atrial natriuretic peptide (ANP) concentration was significantly increased 15 and 60 min after the start of EECP treatment, but brain natriuretic peptide (BNP) did not change. Renin, aldosterone and catecholamine concentrations also did not change. CONCLUSION: Treatment with EECP resulted in an increased preload because of increased venous return, and CI was increased thereafter. In patients with AMI, EECP increased blood ANP concentration, but not BNP, which suggests that an increase in ANP without an increase in BNP is an important mechanism for the effects of EECP treatment.

Clinical significance of measurement of plasma annexin V concentration of patients in the emergency room.

Annexin V, a calcium-binding protein, is widely present in various organs and tissues. In the present study, plasma annexin V concentration was measured in 158 patients who were brought to the emergency room, including 25 patients suffering from acute myocardial infarction (AMI), 14 with cerebrovascular disease, 11 with trauma of the extremities, 11 with severe trauma associated with visceral damage, and 35 with witnessed cardiac arrest. Annexin V concentration in normal healthy individuals (n=110) was 1.9+/-0.7 ng/ml. Annexin V concentration in AMI and cardiac arrest patients was 11.0+/-4.9 and 15.3+/-7.9 ng/ml, respectively, being significantly higher than that in patients with cerebrovascular disease (5.4+/-2.7 ng/ml). The value in severe trauma patients was 15.9+/-9.4 ng/ml, being significantly higher than that in patients with trauma of the extremities (5.6+/-1.2 ng/ml). Annexin V concentrations in the cardiac arrest and AMI patients who survived more than 24 h after admission were lower than those in patients who died within 24 h after the onset of symptoms. Annexin V content in the lungs and myocardium in normal rats was extremely high in comparison to that in brain and skeletal muscle. These results suggest that the high levels of plasma annexin V in patients with AMI, cardiac arrest and severe trauma reflect the severity of damage of the myocardium and/or other visceral organs, and measurement of plasma annexin V concentration may help to assess the prognosis of patients brought to the emergency room.