Cardiac ryanodine receptor calcium release deficiency syndrome

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Gain-of-function RyR2 mutations cause catecholaminergic polymorphic ventricular tachycardia.
• Loss-of-function (LOF) RyR2 mutations are linked to sudden cardiac death (SCD) in individuals with normal exercise stress tests (EST).
• The clinical significance and mechanisms of RyR2 LOF mutations remain largely unknown.

Purpose of the Study:

• To investigate the clinical relevance and pathogenic mechanisms of RyR2 LOF mutations in individuals with SCD and negative EST.
• To identify diagnostic methods and potential therapeutic strategies for this condition.

Main Methods:

• Clinical and genetic evaluations of individuals with SCD and RyR2 LOF mutations.
• Electrophysiological studies using a novel long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus protocol.
• Linkage analysis in affected families and creation of a RyR2 LOF mouse model.

Main Results:

• RyR2 LOF mutations were linked to SCD with negative EST.
• A RyR2 LOF mouse model showed electrophysiological remodeling and propensity for early afterdepolarizations, but not catecholamine-induced arrhythmias.
• The LBLPS pacing protocol induced ventricular arrhythmias in both mice and humans with RyR2 LOF mutations.
• Quinidine and flecainide effectively abolished LBLPS-induced arrhythmias in model mice.

Conclusions:

• RyR2 LOF mutations cause a distinct syndrome, termed RyR2 Ca2+ release deficiency syndrome (CRDS), characterized by SCD and normal EST.
• The LBLPS pacing protocol serves as a specific diagnostic test for CRDS.
• Quinidine and flecainide represent potential therapeutic options for CRDS.