Heart Care Info - Heart Disease Prevention & Treatment

Enhanced Cardiac PI3Kα Signaling Mitigates Arrhythmogenic Electrical Remodeling in Pathological Hypertrophy and Heart Failure

KC Yang, PY Jay... - Cardiovascular ..., 2011 - Abstract Aims: Cardiac hypertrophy and heart failure are associated with QT prolongation and lethal ventricular arrhythmias, resulting from decreased K+ current densities and impaired repolarization. Recent studies in mouse models of physiological cardiac ...

Aims: Cardiac hypertrophy and heart failure are associated with QT prolongation and lethal ventricular arrhythmias, resulting from decreased K+ current densities and impaired repolarization. Recent studies in mouse models of physiological cardiac hypertrophy revealed that increased phosphoinositide-3-kinase-α (PI3Kα) signaling results in the upregulation of K+ channels and the normalization of ventricular repolarization. The experiments here were undertaken to test the hypothesis that increased PI3Kα signaling will counteract the adverse electrophysiological remodeling associated with pathological hypertrophy and heart failure.

Methods and Results: In contrast to wild-type mice, left ventricular (LV) hypertrophy, induced by transverse aortic constriction (TAC), did not result in prolongation of ventricular action potentials or QT intervals in mice with cardiac-specific expression of constitutively active PI3Kα (ca PI3Kα). Indeed, repolarizing K+ currents and K+ channel subunit transcripts were increased in ca PI3Kα+TAC LV myocytes in proportion to the TAC-induced cellular hypertrophy. Congestive heart failure in a transgenic model of dilated cardiomyopathy model is accompanied by prolonged QT intervals and ventricular action potentials, reduced K+ currents and K+ channel transcripts. Increased PI3Kα signaling, but not renin-angiotensin system blockade, in this model also results in increased K+ currents and improved ventricular repolarization.

Conclusion: In the setting of pathological hypertrophy or heart failure, enhanced PI3Kα signaling results in the upregulation of K+ channel subunits, normalization of K+ current densities and preserved ventricular function. Augmentation of PI3Kα signaling, therefore, may be a useful and unique strategy to protect against the increased risk of ventricular arrhythmias and sudden death associated with cardiomyopathy.