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Dear Editor,We performed a comprehensive study to assess the pathogenicity of a cardiac myosin binding protein C3 (MYBPC3) variant (L460fs) and to pinpoint underlying molecular mechanisms by utilizing human-induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model. L460fs iPSC-CMs exhibited a variety of deleterious phenotypes in response to angiotensin II (Ang II), including reduced MYBPC3 expression, hypertrophy, arrhythmia and elevated diastolic intracellular Ca 2+ [Ca 2+ ] i . Mechanistically, heat shock protein family A (HSP70) member 8 (HSC70) accelerated MYBPC3 degradation via lysosomal pathway under Ang II stress. The reduced MYBPC3binding ryanodine receptor 2 (RYR2) caused by insufficiency of MYBPC3 protein may give rise to excessive free destabilized RYR2, which in turn promoted RYR2mediated Ca 2+ leak. The resultant elevated Ca 2+ loading may trigger the development of both hypertrophy and arrhythmogenesis, particularly under stress conditions. 1 Hypertrophic cardiomyopathy (HCM), featured by asymmetric ventricular hypertrophy, arrhythmias and sudden cardiac death (SCD), is the most common form of inherited cardiac disease. 2,3 To note, HCM has been repeatedly regarded as a major cause of SCD in young people. 4 MYBPC3, which encodes cardiac myosin-binding protein C, is the most frequent HCM-associated gene, accounting for more than 50% of the HCM patients. 5 However, the exact mechanism of MYBPC3-related HCM remains to be resolved. 6,7 In this study, a MYBPC3 variant (c.1377delC; p.L460fs) was identified in four-unrelated individuals who developed HCM in middle age (Figure 1A,B). The echocardiography and cardiac magnetic resonance imaging exhibited normal ventricular function, severe interventricular septum hypertrophy but without left ventricular outflow tract obstruction (Figure 1C, Figure S1A-D and Table S1). With treatment of β blockers or Ca 2+ channel blockers,This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Background Contraction of the esophagus was observed during cryoablation for paroxysmal atrial fibrillation (PAF). The purpose of this study is to investigate the mechanism of esophageal contraction and the correlation between the contraction and esophageal thermal lesions. Methods This prospective study enrolled 64 patients with PAF undergoing second‐generation cryoballoon (CB2) ablation for pulmonary vein isolation (PVI). During PVI for the left inferior pulmonary vein, contrast esophagography was performed before and during cryoablation. The sample population was divided into two groups: A (31 patients) and B (33 patients). Group A consisted of patients in whom the distal half of the CB was in proximity to the esophagus, while for group B the esophagus was away from the distal half of the CB. Esophageal contraction was recorded as a variation in the width of the esophageal lumen during PVI. Postablation esophageal endoscopy was done on all patients. Results The reduction in the width of the esophageal lumen in group A was greater than in group B during freezing (40.12 ± 23.24% vs 8.14 ± 10.35%, P < .001). Following endoscopy, no apparent esophageal lesion was detected in all patients. Conclusion The extent of esophageal contraction is correlated with the positioning of the esophagus at the distal half of the CB. The findings of this study indicate that esophageal contraction during freezing may be a self‐protective mechanism.