Background: Transcatheter aortic valve implantation (TAVI) is increasingly being performed in very elderly patients, although its efficacy and validity remain unclear. This study evaluated real-world ...TAVI outcomes in Japanese nonagenarians with severe aortic stenosis.Methods and Results: This single-center study retrospectively assessed the early and long-term clinical outcomes of TAVI in nonagenarians (n=35) and in patients aged <90 years (group Y; n=171). There were no in-hospital deaths in either group. The device success rate and early safety were comparable between the 2 groups. The 5-year rates of freedom from cardiac events and deaths were equivalent in both groups. The cumulative survival rate at 5 years was non-significantly lower in nonagenarians (32.6% in nonagenarians vs. 57.5% in patients aged <90 years, P=0.49). There were no differences in the 5-year survival between nonagenarians after TAVI and the sex- and age-matched populations (P=0.18). The Cox regression model revealed that lower hemoglobin levels were associated with all-cause mortality (P=0.02), and age ≥90 years was not associated with all-cause mortality.Conclusions: The early and long-term clinical outcomes of TAVI for selected Japanese nonagenarians were comparable to those in patients aged <90 years. Nonagenarians who underwent TAVI achieved an acceptable prognosis compared to the sex- and age-matched population; thus, TAVI appears to be effective for treating aortic stenosis in Japanese nonagenarians.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca
homeostasis has been suggested as a common ...proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in App
mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from App
mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.
Background:Increased heart rate (HR) is an independent risk factor for cardiovascular outcomes in chronic heart failure (HF). Ivabradine, anIfinhibitor, improved outcomes in patients with HF and ...reduced ejection fraction (HFrEF) in the SHIFT study. We evaluated its efficacy and safety in Japanese HFrEF patients in a randomized, double-blind, placebo-controlled phase III study: the J-SHIFT study. The main objective was to confirm a hazard ratio of <1 in the primary composite endpoint of cardiovascular death or hospital admission for worsening HF.Methods and Results:Patients with NYHA functional class II–IV, left ventricular EF ≤35%, and resting HR ≥75 beats/min in sinus rhythm under optimal medical therapy received ivabradine (n=127) or placebo (n=127). Mean reduction in resting HR was significantly greater in the ivabradine group (15.2 vs. 6.1 beats/min, P<0.0001). However, symptomatic bradycardia did not occur. A total of 26 (20.5%) patients in the ivabradine group and 37 (29.1%) patients in the placebo group had the primary endpoint event (hazard ratio 0.67, 95% CI 0.40–1.11, P=0.1179) during median follow-up of 589 days. Mild phosphenes were reported in 8 (6.3%) patients in the ivabradine group and 4 (3.1%) patients in the placebo group (P=0.3760).Conclusions:The J-SHIFT study supported the efficacy and safety of ivabradine for Japanese HFrEF patients, in accord with the SHIFT study.
Background: Side branch (SB) occlusion during bifurcation stenting is a serious complication. This study aimed to predict SB compromise (SBC) using optical coherence tomography (OCT).Methods and ...Results: Among the 168 patients who enrolled in the 3D-OCT Bifurcation Registry, 111 bifurcation lesions were analyzed to develop an OCT risk score for predicting SBC. SBC was defined as worsening of angiographic SB ostial stenosis (≥90%) immediately after stenting. On the basis of OCT before stenting, geometric parameters (SB diameter SBd, length from proximal branching point to carina tip BP-CT length, and distance of the polygon of confluence dPOC) and 3-dimensional bifurcation types (parallel or perpendicular) were evaluated. SBC occurred in 36 (32%) lesions. The parallel-type bifurcation was significantly more frequent in lesions with SBC. The receiver operating characteristic curve indicated SBd ≤1.77 mm (area under the curve AUC=0.73, sensitivity 64%, specificity 75%), BP-CT length ≤1.8 mm (AUC=0.83, sensitivity 86%, specificity 68%), and dPOC ≤3.96 mm (AUC=0.68, sensitivity 63%, specificity 69%) as the best cut-off values for predicting SBC. To create the OCT risk score, we assigned 1 point to each of these factors. As the score increased, the frequency of SBC increased significantly (Score 0, 0%; Score 1, 8.7%; Score 2, 28%; Score 3, 58%; Score 4, 85%; P<0.0001).Conclusions: Prediction of SBC using OCT is feasible with high probability.
Background:In developed countries, the incidence of non-ST-segment elevation myocardial infarction (NSTEMI) has outpaced that of ST-segment elevation myocardial infarction (STEMI). However, whether ...this trend is observed in Japan, in which the aging of society is rapidly progressing, remains to be elucidated.Methods and Results:This study retrospectively investigated the trends over time in the incidence of acute coronary syndrome (ACS) between August 2009 and July 2019 at 2 institutions in Izumo City (in rural Japan), which has an elderly population. Crude and age-sex-adjusted incidences of total ACS, STEMI, and non-ST-segment elevation-ACS (NSTE-ACS; including NSTEMI and unstable angina pectoris) were calculated for each year. In the total population, factors associated with the development of NSTEMI were evaluated by multivariate analysis. In total, 1,087 patients were enrolled. The age-adjusted incidence of NSTE-ACS in male patients aged ≥75 years showed a significantly increasing trend. The proportion of NSTEMI per total ACS cases showed a significantly increasing trend over the entire study period. In the multivariate analysis, pre-development use of ≥3 medications for comorbidities was associated with the development of NSTEMI, independent of high-sensitivity cardiac troponin assay use.Conclusions:This study demonstrated an increasing trend in the incidence of NSTEMI in a rural high-aged Japanese population. In addition to the widespread use of high-sensitivity cardiac troponin assays, early medication use for comorbidities might have contributed to this trend.
Dantrolene inhibits Ca2+ leakage from destabilized ryanodine receptors and therefore may serve as a therapeutic agent against endoplasmic reticulum stress-associated diseases. However, its ...effectiveness in treating autoimmune diseases remains unclear. Here, we investigated the effect of dantrolene on collagen-induced arthritis (CIA) in mice. Oral administration of dantrolene resulted in significantly lower arthritic scores in both male and female CIA mice than in the control mice. Micro-computed tomographic and histological analyses showed that dantrolene suppressed bone and chondral destruction. The serum levels of anti-type II collagen (CII) IgG were positively correlated with the arthritic scores (r = 0.704, p < 0.01). In addition, the serum levels of anti-CII IgG were significantly lower in the dantrolene group than in the control group (p < 0.05). These results demonstrate that oral administration of dantrolene to CIA mice inhibits the production of serum anti-CII IgG and consequently prevents arthritis. Therefore, dantrolene may be a potential anti-rheumatic drug.
•Autoimmune arthritis is characterized by synovitis and autoantibody production.•Immunosuppressive effects of anti-rheumatic drugs increase the risk of infections.•Dantrolene inhibits bone and chondral destruction in collagen-induced arthritis mice.•Dantrolene administration reduces autoantibody production.•Dantrolene may be used as a potential anti-rheumatic drug.
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