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(Circulation Research. 2005;96:e77.)
© 2005 American Heart Association, Inc.

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Bidirectional Ventricular Tachycardia and Fibrillation Elicited in a Knock-In Mouse Model Carrier of a Mutation in the Cardiac Ryanodine Receptor

Marina Cerrone^*, Barbara Colombi^*, Massimo Santoro^*, Marina Raffaele di Barletta, Mario Scelsi, Laura Villani, Carlo Napolitano, Silvia G Priori

From the Molecular Cardiology (M.C., B.C., M.S., M.R., C.N. S.G.P.) IRCCS Fondazione S. Maugeri, Pavia, Italy; the University of Pavia, Pavia (S.G.P.), Italy; and the Pathology Division (M.S., L.V.), IRCCS Fondazione S. Maugeri, Pavia, Italy.

Correspondence to Dr Silvia G Priori, Molecular Cardiology, Maugeri Foundation, University of Pavia, Via Ferrata 8, 27100- Pavia- Italy. E-mail spriori{at}fsm.it

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death. The autosomal dominant form of CPVT is caused by mutations in the RyR2 gene encoding the cardiac isoform of the ryanodine receptor. In vitro functional characterization of mutant RyR2 channels showed altered behavior on adrenergic stimulation and caffeine administration with enhanced calcium release from the sarcoplasmic reticulum. As of today no experimental evidence is available to demonstrate that RyR2 mutations can reproduce the arrhythmias observed in CPVT patients. We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT families, to evaluate if the animals would develop a CPVT phenotype and if beta blockers would prevent arrhythmias. Twenty-six mice (12 wild-type (WT) and 14RyR^R4496C) underwent exercise stress testing followed by epinephrine administration: none of the WT developed ventricular tachycardia (VT) versus 5/14 RyR^R4496C mice (P=0.02). Twenty-one mice (8 WT, 8 RyR^R4496C, and 5 RyR^R4496C pretreated with beta-blockers) received epinephrine and caffeine: 4/8 (50%) RyR^R4496C mice but none of the WT developed VT (P=0.02); 4/5 RyR^R4496C mice pretreated with propranolol developed VT (P=0.56 nonsignificant versus RyR^R4496C mice). These data provide the first experimental demonstration that the R4496C RyR2 mutation predisposes the murine heart to VT and VF in response caffeine and/or adrenergic stimulation. Furthermore, the results show that analogous to what is observed in patients, beta adrenergic stimulation seems ineffective in preventing life-threatening arrhythmias.

Key Words: arrhythmias • genetics • ion channels • transgenic mice • calcium • catecholamine

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