Abstract 14182: A Missense Mutation in Ryanodine Receptor 2 Leads to Structural Remodeling of the Heart and Cardiac Arrhythmia in a Rabbit Model

Ryanodine receptor 2 (RyR2) is the Ca 2+ release channel of sarcoplasmic reticulum that provides the majority of Ca 2+ necessary for contractions of the heart. RyR2 mutations are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disorder with normal heart structure. There are reports suggesting that RyR2 mutations can also lead to structural heart disease, notably arrhythmogenic right ventricular cardiomyopathy (ARVC); however, additional research is required to support this association. We generated a rabbit model carrying the missense mutation RyR2-V2475F, linked to CPVT in humans. Heterozygous (V2475F +/- ) rabbits show a CPVT-like syndrome and display arrhythmia under pharmacological stress. Homozygotes (V2475F +/+ ) show a stronger phenotype, with 37% of the animals (13/35) experiencing sudden death at 22.5±3.8 weeks old during regular housing. Remarkably, gross examination of V2475F +/+ hearts showed significant structural remodeling, characterized by fibrous infiltrations and thinning of the right ventricle with or without left ventricle involvement. This phenotype is reminiscent of ARVC. Lead II ECG obtained in conscious rabbits by telemetry showed that V2475F +/+ animals have significant bradycardia (144.6±11.1 bpm) with prolonged QT interval (QTc: 180.4±8.2 ms, n=6) compared to WT (HR: 224.9±4.2 bpm, p=0.04; QTc: 157.4±5.3 ms, p=0.02, n=5). After subcutaneous injection of 0.5 mg/kg of isoproterenol, WT rabbits showed the expected positive chronotropic response (HR, 367±10 bpm, n=3) while V2475F +/+ animals developed bouts of ventricular tachycardia. Mild emotional stress applied by transporting the animal around the laboratory, also induced ventricular arrhythmia in 100% (5/5) V2475F +/+ rabbits, while WT littermates were unaffected. RyR2-V2475F expressed in a rabbit model triggers remarkably different phenotypes based on the zygosity of the animals, ranging from a purely arrhythmogenic syndrome (CPVT) in V2475F +/- animals to severe structural disease compatible with ARVC in V2475F +/+ rabbits. The RyR2-V2475F rabbit model is therefore an excellent model to dissect the intersection of arrhythmic and structural phenotypes due to RyR2 dysfunction.