Abstract 19749: Cardiac-specific Deletion of Caveolin-3 Delays Repolarization and Increases Susceptibility to Ventricular Arrhythmia

Abstract

Caveolin-3 (Cav-3) is an essential scaffolding protein for formation of caveolae in muscle cells. Cav-3 is part of a macromolecular complex including several ion channels. Mutations in Cav-3 have been associated with the inherited long QT syndrome as well as a variety of skeletal myopathies. To investigate the role of Cav-3 in heart and whether loss of function of Cav-3 explains the long QT phenotype, we generated cardiac-specific, inducible Cre-lox Cav-3 knockout mice. 8 week old mice were treated with tamoxifen in the chow to induce cardiac-specific recombination. Western blot analysis and transmitted electron microscopy demonstrated a graded loss of Cav-3 and caveolae in Cav-3 KO heterozygous mice (Cav-3-/+), Cav-3 KO homozygous mice (Cav-3-/-) relative to the littermate controls mice (WT). Echocardiography revealed no significant difference in %EF, %FS, LV chamber dimensions, and LV wall thickness between the different genotypes. Histopathological examination demonstrated no significant difference in HW/BW ratio, cardiac structure or fibrosis comparing Cav-3-/- and WT mice. Telemetry ECG recordings revealed a significant increase in QTc interval Cav-3-/- (68.5±7 ms) compared to WT (54.83±6 ms). Whole cell patch clamp analysis from isolated ventricular myocytes indicated a progressive increase in action potential duration (APD) with loss of Cav-3: WT (APD50: 4.7 ± 1ms; APD90: 28.0±3 ms; n=9); Cav-3-/+(APD50: 10.3±2 ms; APD90: 42.4±3 ms; n=13), Cav-3-/- (APD50: 32.4±6ms; APD90: 97.4±7ms; n=12). Whole cell voltage clamp measurements from Cav-3-/- revealed increased late INa, decrease in ICa,L, Ito,Iss current density without altering peak INa compared to WT cells, and these current changes were adequate to explain the increased APD based on computational representation using the Morotti et al. mouse ventricular cell model. Intracardiac programmed electrical stimulation (ventricular burst pacing) induced VT/Vfib in 8 out of 9 Cav3-/- but none of WT mice (0/5). Our results demonstrate that loss of Cav-3 and caveolae in adult mice does not alter cardiac structure or contractile function but leads to prolonged APD, an increased in QTc, and increased susceptibility to ventricular arrhythmias.