Background and Purpose: Isorhamnetin, a natural flavonoid, has strong antioxidant and anti-fibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). This study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Experimental Approach: Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII-and isorhamnetin-treated groups. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Key Results: Isorhamnetin decreased AF inducibility compared to the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. Conclusion and Implications: The findings of this study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling via modulating CaMKII-RyR2 and TRPC-mediated MAPK pathways, highlighting its potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

Introduction: To know whether cardiac pacemaker implantations improve the functional capacity (FC) and affect the prognosis. Methods and Results: We prospectively enrolled 621 de-novo pacemaker recipients (age 76±9 years, 50.7% male) between April 2015 and September 2016. The FC was assessed by the metabolic equivalents (METs) during the implantation and periodically thereafter. The patients were a priori classified into a poor FC (<2 METs, n=40 [6.4%]), moderate FC (24 METs, n=342 [55.1%]). Three months after the pacemaker implantation, poor FC or moderate FC patients improved to a good FC by 43%. The distribution of the three FCs remained at those levels by the end of the follow-up (p=0.18). During a median follow-up of 2.4 years, 71 patients (11%) had cardiovascular hospitalizations and 35 (5.6%) all-cause death. A multivariate Cox analysis revealed that a poor FC at baseline was an independent predictor of both a cardiovascular hospitalization (hazard ratio [HR] 2.494, 95% confidence interval [CI] 1.227-5.070, p=0.012) and all-cause death (HR 3.338, 95% CI 1.254-8.886, p=0.016). One year after the pacemaker implantation, the 19 patients whose poor FC improved to a good FC did not die, however, the 8 who remained with a poor FC had a high mortality rate of 37.5% (p<0.01). Conclusion: Approximately half of the poor or moderate FC patients improved to a good FC 3 months after the pacemaker implantation. The baseline FC predicted the prognosis, and patients with an improved FC after the pacemaker implantation had a better prognosis.