Cardiac ryanodine receptor calcium release deficiency syndrome

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.This work was supported by research grants from the Canadian Institutes of Health Research (PJT-155940) to S.R.W.C. and (PJT 166105 and MOP 142486) to R.A.R.; the National Natural Science Foundation of China (81903611) to B.S.; the Spanish Ministry of Science Innovation and Universities SAF2017-88019-C3-R to L.H.-M. and R.B. and Marato-2015-20-30 to L.H.-M.; the Royal Netherlands Academy of Sciences (CVON 2012-10 PREDICT) to A.A.M.W.; the E-Rare Joint Transnational Call for Proposals 2015 “Improving Diagnosis and Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: Integrating Clinical and Basic Science” to S.R.W.C., S.S., and A.A.M.W.; the European Research Council Grant “EU-rhythmy” ERC-ADG-2014 (ID: 669387) to S.G.P.; the Novo Nordisk Foundation, Denmark (NNF18OC0031258) to H.K.J.; and the NIH (R01HL057832) to M.F. B.S. and J.Y. are recipients of the Alberta Innovates-Health Solutions (AIHS) Fellowship Award. J.W. is a recipient of the Libin Cardiovascular Institute of Alberta and Cumming School of Medicine Postdoctoral Fellowship Award. X.Z. and W.G. are recipients of the AIHS Studentship Award. S.R.W.C. holds the Heart and Stroke Foundation Chair in Cardiovascular Research.Peer reviewe