Catecholaminergic-induced arrhythmias in failing cardiomyocytes associated with human HRC^sup S96A^ variant overexpression

The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers. In the present study, we assessed the molecular and cellular mechanisms underlying human arrhythmias by adenoviral expression of the human wild-type (HRCWT) or mutant HRC (HRCS96A) in adult rat ventricular cardiomyocytes. Total HRC protein was increased by ~50% in both HRCWT- and HRCS96A-infected cells. The HRCS96A mutant exacerbated the inhibitory effects of HRCWT on the amplitude of Ca2+ transients, prolongation of Ca2+ decay time, and caffeine-induced sarcoplasmic reticulum Ca2+ release. Consistent with these findings, HRCS96A reduced maximal sarcoplasmic reticulum calcium uptake rate to a higher extent than HRCWT. Furthermore, the frequency of spontaneous Ca2+ sparks, which was reduced by HRCWT, was increased by mutant HRCS96A under resting conditions although there were no spontaneous Ca2+ waves under stress conditions. However, expression of the HRCS96A genetic variant in cardiomyocytes from a rat model of postmyocardial infarction heart failure induced dramatic disturbances of rhythmic Ca2+ transients. These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca2+ waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers. [PUBLICATION ABSTRACT]