KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels.

AIMS: As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models. METHODS AND RESULTS: Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca2+ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors. CONCLUSIONS: KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF.

Association between high-density lipoprotein cholesterol and all-cause mortality in the general population of northern China.

Recent studies proposed reasonable doubts about the good prognosis of very high levels of high-density lipoprotein cholesterol (HDL-c). We aimed to investigate the association between HDL-c levels and all-cause mortality using data from an observational cohort study in northern China from 2006 to 2015. The study population was stratified into six groups by HDL-c levels in mg/dl (<40, 40-49, 50-59, 60-69, 70-79, ≥80). Cox hazards regression models were used to estimate the association between HDL-c levels and all-cause mortality. In total, 100,070 participants (aged 51.9 ± 12.7 years) were included in the current analysis. During a mean follow-up of 8.76 years, 7,362 deaths were identified (mortality rate, 8.40 per 1000 person-years). There was a significant interaction effect between age and HDL-c levels (P for interaction < 0.001). Among individuals aged 65 and older, no significant association was found between HDL-c levels and total mortality. In contrast, HDL-c levels showed a U-shaped relationship with all-cause mortality in younger participants (<65 years old), and very high HDL-c levels (≥80 mg/dl) were independently associated with increased total mortality risk compared with the reference level (60 to 69 mg/dl). These findings suggest that very high HDL-c levels may not represent a good prognosis, especially in younger individuals.

Clinical Implications of Unmasking Dormant Conduction After Circumferential Pulmonary Vein Isolation in Atrial Fibrillation Using Adenosine: A Systematic Review and Meta-Analysis.

Purpose: Circumferential pulmonary vein isolation (CPVI) is a routine ablation strategy of atrial fibrillation (AF). The adenosine test can be used to unmask dormant conduction (DC) of pulmonary veins after CPVI, thereby demonstrating possible pulmonary vein re-connection and the need for further ablation. However, whether adenosine test could help improve the long term successful rate of CPVI is still controversial. This systemic review and meta-analysis was to determine the clinical utility of the adenosine test. Methods: PubMed, EMBASE, Web of Science and Cochrane Library database were searched through July 2016 to identify relevant studies using the keywords "dormant pulmonary vein conduction," "adenosine test," "circumferential pulmonary vein isolation," and "atrial fibrillation." A random-effects model was used to compare pooled outcomes and tested for heterogeneity. Results: A total of 17 studies including 5,169 participants were included in the final meta-analysis. Two groups of comparisons were classified: (1) Long-term successful rate in those AF patients underwent CPVI with and without adenosine test [Group A (+) and Group A (-)]; (2) Long-term successful rate in those patients who had adenosine test with and without dormant conduction [Group DC (+) and Group DC (-)]. The overall meta-analysis showed that no significant difference can be observed between Group A (+) and Group A (-) (RR 1.08; 95% CI 0.97-1.19; P = 0.16; I2 = 66%) and between Group DC (+) and Group DC (-) (RR 1.01; 95% CI 0.91-1.12; P = 0.88; I2 = 60%). Conclusion: Pooled meta-analysis suggested adenosine test may not improve long-term successful rate in AF patients underwent CPVI. Furthermore, AF recurrence may not be decreased by eliminating DC provoked by adenosine, even though adenosine test was applied after CPVI.