Histidine-Rich Calcium Binding Protein

The histidine-rich Ca binding protein (HRC), a 165 kD SR protein, may regulate SR Ca cycling during excitation-contraction coupling. Adenoviral-mediated HRC transfer in primary cultured rat ventricular myocytes was associated with an increase in SR Ca load, but decreased Ca release, resulting in depressed myocyte shortening and relengthening. Furthermore, isolated cardiomyocytes from transgenic mice with HRC overexpression revealed depressed SR Ca sequestration and delayed Ca decline as well as relaxation rates, which triggered hypertrophy during the aging process. Collectively, these findings suggest that HRC may play a regulatory role in both SR Ca release and uptake. Recently, we screened the HRC gene coding region in 96 healthy individuals and a well-characterized cohort of 123 nonischemic DCM patients, with a long follow-up period. Although the identified HRC genetic alterations occur in both DCM patients and controls with similar frequencies, we demonstrated that the Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of dilated cardiomyopathy (Fig 1).

Fig 1. Kaplan-Meier plots for the probability of survival from life-threatening ventricular arrhythmic events including sudden cardiac death and episodes of unstable VT (>180 b.p.m.) or ventricular fibrillation, which were recorded by an implantable cardioverter-defibrillator device. Each event is depicted as a step down. Each censored case [due to death from other causes except sudden cardiac death, heart transplantation, and study termination] is marked with a cross. The table at the bottom of the plots indicates the number of dilated cardiomyopathy patients in risk for each year of the follow-up study. The Ala/Ala homozygotes for the Ser96Ala polymorphism were statistically more susceptible to ventricular arrhythmic events, compared with Ser/Ala heterozygotes and Ser/Ser homozygotes.