Abstract 15134: Myocardial Restoration of Casq2 Protein in Adult Casq2 Null Mice Reverses Myocyte Remodeling and Completely Prevents CPVT Phenotype
Background: Casq2 null mutations cause a recessive arrhythmia disorder known as catecholaminergic polymorphic ventricular tachycardia (CPVT). Casq2 null mouse myocytes show structural remodeling (ie. sarcoplasmic reticulum (SR) remodeling and near complete loss of triadin and junctin protein) that contributes to the arrhythmia risk. Casq2 viral gene transfer in neonatal Casq2 null mice can prevent structural remodeling and development of CPVT, but whether gene therapy is effective in adult mice with fully-established disease is not known.
Objective: To test whether Casq2 restoration in adult Casq2 null mice can reverse myocyte remodeling and prevent CPVT.
Methods and Results: To achieve complete restoration of Casq2 protein in the adult myocardium, we generated a “rescueable” Casq2 null allele, where treatment with Cre recombinase restores the wild-type Casq2 gene. Mice homozygous for this rescuable Casq2 null allele were crossed with mice expressing tamoxifen (TAM) inducible Cre in the heart (“rescue”). Before TAM treatment, 3-4 month old “rescue” Casq2 mice lack myocardial Casq2 protein (FIGURE) and exhibit a full-blown CPVT phenotype. 7 days after TAM, Casq2 protein expression reached wild-type levels and was homogeneously expressed throughout the heart (FIGURE). Triadin and junctin protein levels were restored. Electron microscopy showed normal-appearing junctional SR containing newly expressed Casq2. Restoration of Casq2 by TAM completed prevented ventricular arrhythmia (VA) during isoproterenol/caffeine challenge (8/12 with VA before TAM vs 0/12 after TAM, p<0.01). Telemetry recordings confirmed complete absence of VA during exercise stress after TAM (FIGURE). TAM had no effect in Casq2KO mice lacking the rescue allele (FIGURE).
Conclusions: Our results provide proof-of-concept that successful gene therapy in the adult can reverse myocardial remodeling and prevent arrhythmias in a mouse model of severe homozygous recessive CPVT.
- © 2013 by American Heart Association, Inc.