Abstract 2270: Age-dependent Electrical Remodelling in R33Q Catecholaminergic Ventricular Tachycardia Knock-in Mouse Model
Recessive Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by homozygous mutations in the calsequestrin gene (CASQ2). We previously developed a knock in mouse model (CASQ2R33Q/R33Q ) and demonstrated that it closely mimics the features of human CPVT phenotype. Here we studied the influence of ageing in the development of arrhythmogenic substrate. We analyzed the electrophysiological properties of ventricular myocytes isolated by enzymatic digestion from 3, 9 and 12 months old (mo) wild-type (WT) and homozygous CASQ2R33Q/R33Q (HO) mice. Quantitative results are summarized in the table⇓. Comparison of 3-, 9- and 12-mo old HO mice showed an increased incidence of triggered activity (TA) with ageing which was not present in WT. Furthermore, significantly prolonged APD50 but not APD90 was observed. By means of whole cell voltage clamp we observed marked reduction of the fast recovery of transient outward potassium current densities (Ito,f) with an acceleration of the steady-state and close-state inactivation. We also found an increase of L-type calcium current densities (ICa,L) with shorter recovery from inactivation. No changes in ultrarapid delayed rectifier K+ current (IKur), and inward rectifier K+ current (IK1) were detected. Interestingly such changes of the electrophysiological substrate were not associated with echo abnormalities: left ventricular diameter (12-mo: WT 3.6±02mm vs. HO 3.7±0.3mm; p = ns), left ventricular mass (12-mo: WT 121±24mg vs. HO 120±24mg; p = ns). In summary combined electrophysiological and morphological assay in CASQ2R33Q/R33Q ageing mice show extensive electrical remodelling in the absence of echocardiographic changes. This suggests that CASQ2-CPVT mutations may be associated with progressive worsening of the arrhythmogenic substrate in the absence of structural cardiomyopathy.