Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy
- 15 December 2010
- journal article
- Published by Wiley in Journal Of Physiology-London
- Vol. 588 (24), 5015-5032
- https://doi.org/10.1113/jphysiol.2010.197418
Abstract
Pathological biomechanical stresses cause cardiac hypertrophy, which is associated with QT prolongation and arrhythmias. Previous studies have demonstrated that repolarizing K(+) current densities are decreased in pressure overload-induced left ventricular hypertrophy, resulting in action potential and QT prolongation. Cardiac hypertrophy also occurs with exercise training, but this physiological hypertrophy is not associated with electrical abnormalities or increased arrhythmia risk, suggesting that repolarizing K(+) currents are upregulated, in parallel with the increase in myocyte size, to maintain normal cardiac function. To explore this hypothesis directly, electrophysiological recordings were obtained from ventricular myocytes isolated from two mouse models of physiological hypertrophy, one produced by swim-training of wild-type mice and the other by cardiac-specific expression of constitutively active phosphoinositide-3-kinase-p110α (caPI3Kα). Whole-cell voltage-clamp recordings revealed that repolarizing K(+) current amplitudes were higher in ventricular myocytes isolated from swim-trained and caPI3Kα, compared with wild-type, animals. The increases in K(+) current amplitudes paralleled the observed cellular hypertrophy, resulting in normalized or increased K(+) current densities. Electrocardiographic parameters, including QT intervals, as well as ventricular action potential waveforms in swim-trained animals/myocytes were indistinguishable from controls, demonstrating preserved electrical function. Additional experiments revealed that inward Ca(2+) current amplitudes/densities were also increased in caPI3Kα, compared with WT, left ventricular myocytes. The expression of transcripts encoding K(+), Ca(2+) and other ion channel subunits was increased in swim-trained and caPI3Kα ventricles, in parallel with the increase in myocyte size and with the global increases in total cellular RNA expression. In contrast to pathological hypertrophy, therefore, the functional expression of repolarizing K(+) (and depolarizing Ca(2+)) channels is increased with physiological hypertrophy, reflecting upregulation of the underlying ion channel subunit transcripts and resulting in increased current amplitudes and the normalization of current densities and action potential waveforms. Taken together, these results suggest that activation of PI3Kα signalling preserves normal myocardial electrical functioning and could be protective against the increased risk of arrhythmias and sudden death that are prevalent in pathological cardiac hypertrophy.This publication has 38 references indexed in Scilit:
- Moderate Exercise Training Improves Survival and Ventricular Remodeling in an Animal Model of Left Ventricular Volume OverloadCirculation: Heart Failure, 2009
- Reporting ethical matters in The Journal of Physiology: standards and adviceJournal Of Physiology-London, 2009
- Relation Between Training-Induced Left Ventricular Hypertrophy and Risk for Ventricular Tachyarrhythmias in Elite AthletesThe American Journal of Cardiology, 2008
- Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K + Currents With Left Ventricular HypertrophyCirculation Research, 2008
- Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure miceJournal of Applied Physiology, 2008
- A Conserved Role for Phosphatidylinositol 3-Kinase but Not Akt Signaling in Mitochondrial Adaptations that Accompany Physiological Cardiac HypertrophyCell Metabolism, 2007
- Protective effects of exercise and phosphoinositide 3-kinase(p110α) signaling in dilated and hypertrophic cardiomyopathyProceedings of the National Academy of Sciences of the United States of America, 2007
- QRS Duration and QT Interval Predict Mortality in Hypertensive Patients With Left Ventricular HypertrophyHypertension, 2004
- The consequences of disrupting cardiac inwardly rectifying K+ current (IK1) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genesJournal Of Physiology-London, 2001
- Left Ventricular Hypertrophy and QT Dispersion in HypertensionHypertension, 1996