Enhanced Ca2+ release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes -: Potential link between contractile adaptation and arrhythmogenesis

Background-Ventricular arrhythmias are a major cause of sudden death in patients with heart failure and hypertrophy. The dog with chronic complete atrioventricular block (CAVB) has biventricular hypertrophy and ventricular arrhythmias and is a useful model to study underlying cellular mechanisms. We investigated whether changes in Ca2+ homeostasis are part of the contractile adaptation to CAVE and might contribute to arrhythmogenesis. Methods and Results-In enzymatically isolated myocytes, cell shortening, Ca2+ release from the sarcoplasmic reticulum (SR), and SR Ca2+ content were enhanced at low stimulation frequencies; Ca2+ influx through L-type Ca2+ channels was unchanged, but Ca2+ influx via the Na/Ca exchanger was increased and contributed to Ca2+ loading of the SR. Inward Na/Ca exchange currents were also larger. Changes in Ca2+ fluxes were less pronounced in the right versus left ventricle. Conclusions-Enhanced Na/Ca exchange activity may improve contractile adaptation to CAVE but at the same time facilitate arrhythmias by (1) increasing the propensity to Ca2+ overload, (2) providing more inward current leading to (nonhomogeneous) action potential prolongation, and (3) enhancing (arrhythmogenic) currents during spontaneous Ca2+ release.