Cellular mechanisms of altered contractility in the hypertrophied heart - Big hearts, big sparks

To investigate the cellular mechanisms for altered Ca2+ homeostasis and con tractility in cardiac hypertrophy, we measured whole-cell L-type Ca2+ curre nts (I-Ca,I-L), whole-cell Ca2+ transients ([Ca2+](i)), and Ca2+ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) a nd from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contra ctility (increased fractional shortening) and no signs of heart failure. SH R cells had a voltage-dependent increase in peak [Ca2+](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,I-L density or kinetics, resting [ Ca2+](i), or Ca2+ content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca2+ sparks from SHR cells had larger averag e amplitudes (173+/-192 nmol/L [SHRs] versus 109+/-64 nmol/L [control]; P<0 .05), which was due to redistribution of Ca2+ sparks to a larger amplitude population. This change in Ca2+ spark amplitude distribution was not associ ated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca2+-ATPase, or phospholamban. Therefore, SHRs with car diac hypertrophy have increased contractility, [Ca2+](i) amplitude, time to relaxation, and average Ca2+ spark amplitude ("big sparks"). Importantly, big sparks occurred without alteration in the trigger for SR Ca2+ release ( I-Ca,I-L), SR Ca2+ content, or the expression of several SR Ca2+-cycling pr oteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in t he coupling of Ca2+ entry through L-type Ca2+ channels and the release of C a2+ from the SR, leading to big sparks and enhanced contractility. Alterati ons in the microdomain between L-type Ca2+ channels and SR Ca2+ release cha nnels may underlie the changes in Ca2+ homeostasis observed in cardiac hype rtrophy. Modulation of SR Ca2+ release may provide a new therapeutic strate gy for cardiac hypertrophy and for its progression to heart failure and sud den death.