Cellular Mechanisms of Altered Contractility in the Hypertrophied Heart

To investigate the cellular mechanisms for altered Ca homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca currents (ICa,L), whole-cell Ca 21 transients ([Ca]i), and Ca 21 sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from ageand 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]i amplitude (at 0 mV, 1330662 nmol/L [SHRs] versus 836648 nmol/L [controls], P,0.05) that was not associated with changes in ICa,L density or kinetics, resting [Ca ]i, or Ca 21 content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca sparks from SHR cells had larger average amplitudes (1736192 nmol/L [SHRs] versus 109664 nmol/L [control]; P,0.05), which was due to redistribution of Ca sparks to a larger amplitude population. This change in Ca spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca-ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca]i amplitude, time to relaxation, and average Ca 21 spark amplitude (“big sparks”). Importantly, big sparks occurred without alteration in the trigger for SR Ca release (ICa,L), SR Ca content, or the expression of several SR Ca-cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca entry through L-type Ca channels and the release of Ca from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca channels and SR Ca release channels may underlie the changes in Ca homeostasis observed in cardiac hypertrophy. Modulation of SR Ca release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death. (Circ Res. 1999;84:424-434.)