TY - JOUR
T1 - Cardiac ryanodine receptor calcium release deficiency syndrome
AU - Sun, Bo
AU - Yao, Jinjing
AU - Ni, Mingke
AU - Wei, Jinhong
AU - Zhong, Xiaowei
AU - Guo, Wenting
AU - Zhang, Lin
AU - Wang, Ruiwu
AU - Belke, Darrell
AU - Chen, Yong-Xiang
AU - Lieve, Krystien V. V.
AU - Broendberg, Anders K.
AU - Roston, Thomas M.
AU - Blankoff, Ivan
AU - Kammeraad, Janneke A.
AU - von Alvensleben, Johannes C.
AU - Lazarte, Julieta
AU - Vallmitjana, Alexander
AU - Bohne, Loryn J.
AU - Rose, Robert A.
AU - Benitez, Raul
AU - Hove-Madsen, Leif
AU - Napolitano, Carlo
AU - Hegele, Robert A.
AU - Fill, Michael
AU - Sanatani, Shubhayan
AU - Wilde, Arthur A. M.
AU - Roberts, Jason D.
AU - Priori, Silvia G.
AU - Jensen, Henrik K.
AU - Chen, S. R. Wayne
N1 - Funding Information: Funding: This work was supported by research grants from the Canadian Institutes of Publisher Copyright: Copyright © 2021 The Authors.
PY - 2021/2/3
Y1 - 2021/2/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85101018163&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/scitranslmed.aba7287
DO - https://doi.org/10.1126/scitranslmed.aba7287
M3 - Article
C2 - 33536282
SN - 1946-6234
VL - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 579
M1 - eaba7287
ER -