Keiichi Odagiri

Local control of mitochondrial membrane potential, permeability transition pore and reactive oxygen species by calcium and calmodulin in rat ventricular myocytes

Calmodulin (CaM) and Ca(2+)/CaM-dependent protein kinase II (CaMKII) play important roles in the development of heart failure. In this study, we evaluated the effects of CaM on mitochondrial membrane potential (DeltaPsi(m)), permeability transition pore (mPTP) and the production of reactive oxygen species (ROS) in permeabilized myocytes; our findings are as follows. (1) CaM depolarized DeltaPsi(m) dose-dependently, but this was prevented by an inhibitor of CaM (W-7) or CaMKII (autocamtide 2-related inhibitory peptide (AIP)). (2) CaM accelerated calcein leakage from mitochondria, indicating the opening of mPTP, however this was prevented by AIP. (3) Cyclosporin A (an inhibitor of the mPTP) inhibited both CaM-induced DeltaPsi(m) depolarization and calcein leakage. (4) CaM increased mitochondrial ROS, which was related to DeltaPsi(m) depolarization and the opening of mPTP. (5) Chelating of cytosolic Ca(2+) by BAPTA, the depletion of SR Ca(2+) by thapsigargin (an inhibitor of SERCA) and the inhibition of mitochondrial Ca(2+) uniporter by Ru360 attenuated the effects of CaM on mitochondrial function. (6) CaM accelerated Ca(2+) extrusion from mitochondria. We conclude that CaM/CaMKII depolarized DeltaPsi(m) and opened mPTP by increasing ROS production, and these effects were strictly regulated by the local increase in cytosolic Ca(2+) concentration, initiated by Ca(2+) releases from the SR. In addition, CaM was involved in the regulation of mitochondrial Ca(2+) homeostasis.

The usefulness of delayed enhancement magnetic resonance imaging for diagnosis and evaluation of cardiac function in patients with cardiac sarcoidosis

OBJECTIVES Cardiac involvement is an important prognostic factor in patients with sarcoidosis. We evaluated the usefulness of delayed enhancement MRI (DE-MRI) for diagnosing cardiac sarcoidosis by comparing with nuclear imaging and studying the correlation between DE area and left ventricular (LV) function. METHODS Twelve patients (male:female 3:9) diagnosed as having sarcoidosis underwent Gd-MRI, myocardial perfusion SPECT (Tl-201, Tc-99m sestamibi), Ga-67 scintigraphy, and/or F-18 FDG-PET. RESULTS DE was observed in 5 patients, and was positive in 39 (39%) of 100 LV segments. The corresponding perfusion defects in myocardial perfusion SPECT were undetectable in 14 (36%) segments. DE distributed mainly in mid- to epi-myocardium, and the lack of perfusion defects in myocardial perfusion SPECT was more prominent in less transmural DE segments. Two patients with diffuse DE and 1 case with focal DE exhibited positive cardiac uptake in Ga-67 scintigraphy, and 2 other cases with focal DE showed cardiac uptake in F-18 FDG-PET. In 7 patients without DE, there were no significant findings in nuclear imaging. Both LV end-diastolic and end-systolic volume were positively and LV ejection fraction was negatively correlated with the extent of DE area. Four patients treated with corticosteroid showed improvement in nuclear imaging and slight decreases in DE area but no recovery in LV function. CONCLUSIONS DE-MRI is useful to diagnose the cardiac involvement of sarcoidosis and to evaluate cardiac function. It is likely that the distribution of DE in mid- to epi-myocardium is the characteristic of cardiac sarcoidosis, and the larger DE area may be correlated with poor LV function.

Waist to Height Ratio Is an Independent Predictor for the Incidence of Chronic Kidney Disease

Objective Obesity is a risk factor for chronic kidney disease (CKD) and cardiovascular disease. The association between waist to height ratio (WheiR) and CKD is unclear. This study evaluated the association between WheiR and CKD. Design and Methods In this longitudinal cohort study, 4841 Japanese workers (3686 males, 1155 females) 18 to 67 years of age in 2008 were followed up until 2011. CKD was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 (by the Modification of Diet in Renal Disease equation for Japanese) or dipstick proteinuria (≥1+). Cox proportional hazards models were used to examine the relationship between WheiR and development of CKD. Results A total of 384 (7.9%) participants (300 men and 84 women) were found to have new CKD. The incidence of CKD was 13.7, 24.2, 37.9 and 43.7 per 1000 person-years of follow-up in the lowest, second, third and highest quartiles of WheiR, respectively. After adjustment for potential confounders, the adjusted hazard ratios (95% confidence interval) for CKD were 1.00 (reference), 1.23 (0.85, 1.78), 1.59 (1.11, 2.26) and 1.62 (1.13, 2.32) through the quartiles of WheiR, respectively. WheiR had a significant predictive value for the incidence of both proteinuria and low estimated glomerular filtration rate. After subdivision according to gender, the relationship between WheiR and the incidence of CKD was statistically significant in the unadjusted model. However, after adjusting for potential confounders, WheiR was significantly associated with the incidence of CKD in females, whereas it was not significant in males. Conclusions WheiR, which is commonly used as an index of central obesity, is associated with CKD. There was a significant gender difference in the relationship between CKD and WheiR.

Delayed Enhancement on Cardiac Magnetic Resonance and Clinical, Morphological, and Electrocardiographical Features in Hypertrophic Cardiomyopathy

BACKGROUND The clinical, morphological, and electrocardiographical relevance of delayed enhancement (DE) in cardiac magnetic resonance (CMR) was studied in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS A total of 56 patients underwent both gadolinium-enhanced CMR and 12-lead electrocardiogram. The CMR demonstrated DE at the left ventricular (LV) wall in 39 patients. The patients with DE included more cases with dilated phase of HCM, higher New York Heart Association (NYHA) classes and incidence of ventricular tachyarrhythmias (VT), lower LV ejection fraction (LVEF) and mean LV wall thickness (WT), and a larger ratio of maximum to minimum LVWT. The QRS duration was prolonged and the QRS axis deviated toward left with increases in the DE volume (r = 0.58 and r = 0.41, P < .01). Abnormal Q waves were present in 5 patients and the location coincided with the DE segments in 4 patients, but the concordance was not significant. The amplitude of T waves correlated with the ratio of the apex to basal LVWT (r = 0.38, P < .01) and was more negative in cases with DE at the apex. CONCLUSIONS In HCM, the DE was associated with higher NYHA classes and prevalence of VT, impaired global LV function and asymmetrical hypertrophy, and conduction disturbance, abnormal Q waves, and giant negative T waves.

Evaluation of right and left ventricular function by quantitative blood-pool SPECT (QBS): Comparison with conventional methods and quantitative gated SPECT (QGS)

Though quantitative ECG-gated blood-pool SPECT (QBS) has become a popular tool in research settings, more verification is necessary for its utilization in clinical medicine. To evaluate the reliability of the measurements of left and right ventricular functions with QBS, we performed QBS, as well as first-pass pool (FPP) and ECG-gated blood-pool (GBP) studies on planar images in 41 patients and 8 healthy volunteers. Quantitative ECG-gated myocardial perfusion SPECT (QGS) was also performed in 30 of 49 subjects. First, we assessed the reproducibility of the measurements of left and right ventricular ejection fraction (LVEF, RVEF) and left and right ventricular end-diastolic volume (LVEDV, RVEDV) with QBS. Second, LVEF and RVEF obtained from QBS were compared with those from FPP and GBP, respectively. Third, LVEF and LVEDV obtained from QBS were compared with those from QGS, respectively. The intra- and inter-observer reproducibilities were excellent for LVEF, LVEDV, RVEF and RVEDV measured with QBS (r = 0.88 to 0.96, p < 0.01), while the biases in the measurements of RVEF and RVEDV were relatively large. LVEF obtained from QBS correlated significantly with those from FPP and GBP, while RVEF from QBS did not. LVEF and LVEDV obtained from QBS were significantly correlated with those from QGS, but the regression lines were not close to the lines of identity. In conclusion, the measurements of LVEF and LVEDV with QBS have good reproducibility and are useful clinically, while those of RVEF and RVEDV are less useful compared with LVEF and LVEDV. The algorithm of QBS for the measurements of RVEF and RVEDV remains to be improved.

Effects of the Rho-kinase inhibitor, fasudil, on pulmonary hypertension.

motility, migration, proliferation, differentiation, and apoptosis. Activation of Rho/ROCK is considered to play a major role in the pathogenesis of several cardiovascular diseases, including PH,5 and thus is a new therapeutic target for PH (Figure). Fasudil is one of the most frequently used ROCK inhibitors, and was approved as a therapeutic agent for vasospasm after arachnoid hemorrhage. Several studies reported that fasudil ameliorated PH in various animal models, including PH induced by monocrotaline (MCT), Sugen5416/hypoxia, and bleomycin.6–10 Oka et al demonstrated the effects of acute ROCK inhibition by intravenous administration of fasudil on Sugen5416/hypoxia-induced PH in rats.10 Intravenous fasudil was more effective in reducing right ventricular systolic pressure (RVSP) compared with ulmonary hypertension (PH) is a progressive, lifethreatening disease characterized by vasoconstriction, thrombosis, and vascular remodeling, leading to elevated pulmonary arterial pressure (PAP), right heart failure and death. Vasorelaxant agents, including prostanoids, phosphodiesterase-5 (PDE-5) inhibitors, and endothelin receptor antagonists (ERAs), have been shown to improve symptoms, exercise tolerance, and mortality in PH patients.1–3

Exercise myocardial perfusion scintigraphy is useful for evaluating myocardial ischemia even in the elderly

Pharmacologic stress testing is recommended to elderly patients as a valuable alternative to exercise testing. We examined whether exercise testing is as useful for evaluating myocardial ischemia in the elderly as in the young. The consecutive 1,508 patients who underwent exercise201Tl single-photon emission computed tomography (SPECT) were divided into six age groups: 6–29 years (n =56), 30–44 (n=143), 45–54 (n=311), 55–64 (n=498), 65–74 (n=402), and 75–88 (n=98). Both heart rate and rate-pressure product at peak exercise were significantly lower in patients aged 75–88 than in the other five groups. The frequency of ischemic ST depression was higher in patients aged 75–88 than in those aged 6–74, although the difference was not significant. Moreover, the frequency of201Tl transient defect was significantly higher in patients aged 75–88 than in those aged 6–74. On the other hand, the sensitivity of ischemic ST depression for201 Tl transient defect was similar among the six groups, but the specificity was significantly lower in patients aged 75–88 than in those aged 6–74. In conclusion, exercise201Tl SPECT is useful for evaluating myocardial ischemia even in the elderly, but exercise electrocardiography has limitations such as lower specificity in the elderly than201Tl SPECT.

Pharmacokinetic and Pharmacodynamic Comparison of Sildenafil-Bosentan and Sildenafil-Ambrisentan Combination Therapies for Pulmonary Hypertension.

To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4–5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration–time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.

In Vivo Drug Dissolution in Human Oral Cavity from Orally Disintegrating Tablet and Comparability with in Vitro Testing

We examined the amlodipine dissolution from orally disintegrating tablets (ODTs) in vivo in the human oral cavity. Additionally, 5 different in vitro short dissolution test methods (Tricorptester, magnetic stirrer, rotating injection syringe, paddle apparatus, shaking) were used to evaluate dissolution and the results were compared to those obtained with the human volunteers. Various amlodipine ODTs with different levels of physical masking effectiveness were manufactured using the RACTAB® technique. Quantitative findings showed that amlodipine dissolution from ODT was dependent on time in the oral cavity and the amount of coating applied for physical masking. We also found that dissolution in the oral cavity was best correlated to that in in vitro short dissolution tests with a time period of 30 s. For more detailed evaluations, mean prediction error, mean absolute error, and root mean square error values were calculated, each of which was lowest with the Tricorptester method among all of the investigated test methods. Our results indicate that mimicking of the inside of the human oral cavity is accurate with a testing time of 30 s, while the Tricorptester method was the most preferable of all in vitro tests investigated in this study.

Health-related behaviors associated with subjective sleep insufficiency in Japanese workers: A cross-sectional study

Sleep disturbances are related to somatic and mental disorders, industrial accidents, absenteeism, and retirement because of disability. We aimed to identify health‐related behaviors associated with subjective sleep insufficiency in Japanese workers.