Cellular Mechanisms of Altered Contractility in the Hypertrophied Heart: Big Hearts, Big Sparks

Abstract

Abstract —To investigate the cellular mechanisms for altered Ca 2+ homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca 2+ currents ( I Ca,L ), whole-cell Ca 2+ transients ([Ca 2+ ] i ), and Ca 2+ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. SHR cells had a voltage-dependent increase in peak [Ca 2+ ] i amplitude (at 0 mV, 1330±62 nmol/L [SHRs] versus 836±48 nmol/L [controls], P <0.05) that was not associated with changes in I Ca,L density or kinetics, resting [Ca 2+ ] i , or Ca 2+ content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca 2+ sparks from SHR cells had larger average amplitudes (173±192 nmol/L [SHRs] versus 109±64 nmol/L [control]; P <0.05), which was due to redistribution of Ca 2+ sparks to a larger amplitude population. This change in Ca 2+ spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca 2+ -ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca 2+ ] i amplitude, time to relaxation, and average Ca 2+ spark amplitude (“big sparks”). Importantly, big sparks occurred without alteration in the trigger for SR Ca 2+ release ( I Ca,L ), SR Ca 2+ content, or the expression of several SR Ca 2+ -cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca 2+ entry through L-type Ca 2+ channels and the release of Ca 2+ from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca 2+ channels and SR Ca 2+ release channels may underlie the changes in Ca 2+ homeostasis observed in cardiac hypertrophy. Modulation of SR Ca 2+ release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death.