Cardiac ryanodine receptor calcium release deficiency syndrome

• DOI: 10.1126/scitranslmed.aba7287
• Publication Date: 2021-02-03T20:11:20Z
• Authors: Bo Sun; Jinjing Yao; Mingke Ni; Jinhong Wei; Xiaowei Zhong; Wenting Guo; Lin Zhang; Ruiwu Wang; Darrell Belke; Yong-Xiang Chen; Krystien V.V. Lieve; Anders K. Broendberg; Thomas M. Roston; Ivan Blankoff; Janneke A. Kammeraad; Johannes C. von A...; Julieta Lazarte; Alexander Vallmit...; Loryn J. Bohne; Robert A. Rose; Raul Benitez; Leif Hove-Madsen; Carlo Napolitano; Robert A. Hegele; Michael Fill; Shubhayan Sanatani; Arthur A.M. Wilde; Jason D. Roberts; Silvia G. Priori; Henrik K. Jensen; S. R. Wayne Chen
• Keywords: Disease mutation; Sarcoplasmic reticulum; 610; Electrònica en cardiologia; Arrhythmias, Cardiac; Ryanodine Receptor Calcium Release Channel; 3. Good health; Sudden cardiac death; :Enginyeria biomèdica::Electrònica biomèdica::Electrònica en cardiologia [Àrees temàtiques de la UPC]; Mice; 03 medical and health sciences; Death, Sudden, Cardiac; 0302 clinical medicine; Ryanodine receptor; Mutation; Tachycardia, Ventricular; Animals; Àrees temàtiques de la UPC::Enginyeria biomèdica::Electrònica biomèdica::Electrònica en cardiologia; Calcium; Ventricular fibrillation; Ventricular tachyarrhythmias; EMC COEUR-09

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged EST-negative individuals who loss-of-function (LOF) RyR2 mutations. The clinical relevance LOF including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed genetic evaluations suffered from SCD harbored an mutation. We carried out electrophysiological studies using programed electrical stimulation protocol consisting long-burst, long-pause, short-coupled (LBLPS) extra-stimulus. Linkage analysis six families revealed combined logarithm the odds ratio for linkage score 11.479 associated with negative EST. A mouse model exhibited no catecholamine-provoked arrhythmias as humans but did substantial remodeling increased propensity early afterdepolarizations. LBLPS pacing reliably induced mice having mutations, whose phenotype is otherwise concealed before SCD. Furthermore, quinidine flecainide abolished LBLPS-induced mice. Thus, underlie previously unknown disease entity normal EST that termed Ca