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

Abstract

Abstract-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 , 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 (Pϭ0.02); 4/5 RyR R4496C mice pretreated with propranolol developed VT (Pϭ0.56 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. (Circ Res. 2005;96:e77-e82.) Key Words: arrhythmias Ⅲ genetics Ⅲ ion channels Ⅲ transgenic mice Ⅲ calcium Ⅲ catecholamine C atecholaminergic polymorphic ventricular tachycardia (CPVT; OMIM: 604772) is a highly malignant cardiac disease manifesting in childhood and adolescence. It is characterized by adrenergically-mediated bidirectional or polymorphic ventricular tachycardia leading to syncope and/or sudden cardiac death. 1,2 Based on previously reported linkage data that had mapped the disease to chromosome 1q42-43, 3 we reported that the gene for the autosomal dominant variant of CPVT was RyR2; ie, the gene encoding for the cardiac isoform of the ryanodine receptor. 4 The first family in which a RyR2 mutation was identified was affected by a highly malignant form of the disease that was resistant to beta blockers; the mutation present in the family (R4497C) is a hot spot that we subsequently identified in other CPVT patients unrelated to the first kindred. The R4497C mutation has been extensively investigated in different in vitro models that demonstrated that it enhances the release of calcium from the sarcoplasmic reticulum. [5][6][7][8] It has therefore been inferred that arrhythmias may develop as a consequence of abnormal calcium release from intracellular stores. However, experimental evidence linking this mutation to the development of life-threatening arrhythmias is still lacking. Here we report on a conditional knock-in mouse-model carrier of the R4496C mutation that is the mouse equivalent of the human mutation R4497C. The objectives of the present study were to evaluate if the R449...

Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function

“…This may explain the absence of significant alteration in the QT interval, as expected if the prolonged phase of Ca 2+ release were to cause uniform and constant prolongation of the APD. Mouse hearts are remarkably resilient to VF even if harboring CPVT mutations, hence necessitating the RyR2 sensitizer caffeine as part of a standard arrhythmogenic mixture (7,12,27). Interestingly, caffeine was unable to trigger tachyarrhythmias in RyR2-A4860 +/− hearts, which is in line with its rather modest activation of recombinant RyR2-A4860 channels (Fig.…”

“…There were no spontaneous arrhythmias in either group under baseline conditions. Surprisingly, coadministration of caffeine (1 mM), a reliable trigger of arrhythmias in other CPVT mouse models (7,12,27), failed to induce arrhythmias in both groups (n = 2 and n = 3 hearts, respectively). However, increasing the extracellular [Ca 2+ ] from 1.8 to 3.6 mM during adrenergic stress induced spontaneous longlasting (>15 s average) VF in RyR2-A4860G +/− , which, in the optical movies, showed as meandering rotors, some of which lasted only one or more rotations (Fig.…”

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…This intervention induced ventricular tachycardia (VT) in 1 of the 7 Ctrl mice, whereas in the majority of diabetic animals (6 of 7), it elicited a bidirectional pattern of ventricular activation (Figure 4A through 4C), previously identified as bidirectional VT (BVT) 28, 29, 42. BVT was associated with a reduction in RR interval (Figure 4D) coupled with enhanced sinus discharge.…”

Suppression of canonical Wnt/ -catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy

“…Finally, a mouse model of catecholaminergic polymorphic ventricular tachycardia has been developed through conditional expression of a mutant ryanodine receptor in the heart (41). The model does not exhibit histological phenotype of ARVC and is a distinct phenotype (41). Thus cardiac-restricted DP-deficient mice provide for a genetically defined animal model of ARVC that could prove essential for further elucidating the molecular pathogenesis of ARVC and identification of novel diagnostic markers and therapeutic targets.…”