Research ArticleCardiology

Cardiac ryanodine receptor calcium release deficiency syndrome

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Science Translational Medicine  03 Feb 2021:
Vol. 13, Issue 579, eaba7287
DOI: 10.1126/scitranslmed.aba7287

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Calcium and cardiac arrhythmia

Calcium signaling couples cardiac electrical excitation and contraction and is tightly controlled within myocytes via the ryanodine receptor (RyR2). Sun et al. investigated loss-of-function mutations in RyR2 identified in families of individuals who experienced sudden cardiac death. RyR2 mutations were linked to cardiac arrhythmias due to prolonged calcium release refractoriness and electrophysiological and structural remodeling. The authors developed a cardiac stimulation protocol that induced ventricular arrhythmias in mice harboring a RyR2 mutation, and similar electrical patterns were seen in patients, which could be used to diagnose the RyR2 calcium release deficiency syndrome. Quinidine and flecainide could suppress arrhythmias in mice, suggesting possible treatments for this disease.


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.

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