Abstract 3199: Remodeling of Repolarizing K+ Currents With Physiological Hypertrophy Maintains Cardiac Function
Background: Pathologic biomechanical stresses cause cardiac myocyte hypertrophy, which in turn is associated with QT prolongation and arrhythmias. Repolarizing K+ current densities are decreased markedly with pressure overload-induced left ventricular (LV) hypertrophy due to a failure to upregulate K+ channel expression levels in parallel with increased myocyte size. Cardiac hypertrophy also occurs with exercise, particularly in elite athletes, but this physiological hypertrophy is not associated with increased arrhythmia risk, leading us to hypothesize that electrical remodeling occurs in physiological hypertrophy to preserve normal cardiac rhythm.
Methods and Results: To explore this hypothesis directly, we examined the electrophysiological properties of LV myocytes isolated from a transgenic mouse model of physiological hypertrophy, produced by cardiac-specific expression of constitutively active phosphoinositide-3-kinase p110α (caPI3Kα), and from mice following 4 weeks of exercise (swimming) training. Whole cell voltage clamp recordings from caPI3Kα LV myocytes (n=25) revealed that the amplitudes of the repolarizing K+ currents, Ito,f, IKslow, Iss and IK1 were higher (P<0.01) than in control (non-transgenic) LV myocytes (n=20). Repolarizing K+ current densities, therefore, were maintained in spite of the marked increase in myocyte size. In LV myocytes from the exercised mice, Iss and IK1 amplitudes were also increased (P<0.01). Surface ECG recordings revealed normal QT intervals in both models of physiological hypertrophy, and ventricular action potential waveforms were indistinguishable from controls. Quantitative RT-PCR analyses revealed that the transcript expression levels of the subunits encoding myocardial K+ channels, including Kcnd2, Kcnip2 (Ito,f), Kcnb1(IKslow), as well as Kcnj2 and Kcnj12 (IK1), were increased (P<0.05) in caPI3Kα (n=6) compared to control (n=6) ventricles.
Conclusion: LV K+ currents and channel subunits are upregulated in physiological hypertrophy in proportion to the increase in myocyte size, suggesting that activation of physiological hypertrophy signaling pathway could be protective against increased risk of arrhythmia and sudden cardiac death in pathological hypertrophy.