Li, Yi‐Gang

Background Sorbs2b (sorbin and SH3 domain‐containing 2b) was recently identified as a cardiomyopathy gene from a zebrafish mutagenesis screen. However, cardiac functions of its mammalian ortholog remain elusive. Methods and Results We conducted a detailed expression and subcellular localization analysis of Sorbs2 ortholog in mice and a phenotypic characterization in Sorbs2 knockout mice. Sorbs2 is highly expressed in the mouse heart and encodes an adhesion junction/desmosome protein that is mainly localized to the intercalated disc. A mutation with near complete depletion of the Sorbs2 protein in mice results in phenotypes characteristic of human arrhythmogenic cardiomyopathy (ACM), including right ventricular dilation, right ventricular dysfunction, spontaneous ventricular tachycardia, and premature death. Sorbs2 is required to maintain the structural integrity of intercalated disc. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Targeted sequencing of human patients with ACM identified 2 rare splicing variants classified as likely pathogenic were in 2 unrelated individuals with ACM from a cohort of 59 patients with ACM. Conclusions The Sorbs2 knockout mouse manifests several key features reminiscent of human ACM. Although the candidacy of SORBS2 as a new ACM‐susceptibility gene is supported by preliminary human genetics study, future validation in larger cohorts with ACM is needed.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear. Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 349 patients (26.5%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was associated with a greater all-cause mortality than euthyroidism (hazard ratio, 1.19; 95% CI, 1.01-1.38; P=0.04). In this group, the risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level (hazard ratio, 1.27 per 5 mIU/L increase, 95% CI, 1.00-1.53, P=0.04). Conclusions Cardiac resynchronization therapy improves cardiac function in hypothyroid patients. Hypothyroidism has adverse effects on cardiac resynchronization therapy outcomes with reduced survival and increased implantable cardioverter-defibrillator therapies for ventricular arrhythmic events.

Background: Hydrogen peroxide (H2O2)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations. Methods: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H2O2 (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, Gö 6983 (1 μM), was applied to test the involvement of PKC. Results: H2O2 perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Gö 6983 prevented the emergence of H2O2-induced afterdepolarizations. Additional application of Gö 6983 with H2O2 effectively suppressed H2O2-induced afterdepolarizations. H2O2 increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by Gö 6983 (p < 0.01). H2O2 also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, Gö 6983 showed little effect on H2O2-induced enhancement of Ito. Conclusions: H2O2 induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.