Calcium release near l-type calcium channels promotes beat-to-beat variability in ventricular myocytes from the chronic AV block dog

Abstract

Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca2+ handling. This remodeling process also leads to increased BVR. We aimed to determine the role that (local) Ca2+ handling plays in BVR.In isolated LV myocytes an exponential relationship was observed between BVR magnitude and action potential duration (APD) at baseline. Inhibition of Ca2+ release from sarcoplasmic reticulum (SR) with thapsigargin resulted in a reduction of [Ca2+]i, and of both BVR and APD. Increasing ICaL in the presence of thapsigargin restored APD but BVR remained low. In contrast, increasing ICaL with preserved Ca2+ release increased both APD and BVR. Inhibition of Ca2+ release with caffeine, as with thapsigargin, reduced BVR despite maintained APD. Simultaneous inhibition of Na+/Ca2+ exchange and ICaL decreased APD and BVR to similar degrees, whilst increasing diastolic Ca2+. Buffering of Ca2+ transients with BAPTA reduced BVR for a given APD to a greater extent than buffering with EGTA, suggesting subsarcolemmal Ca2+ transients modulated BVR to a larger extent than the cytosolic Ca2+ transient.In conclusion, BVR in hypertrophied dog myocytes, at any APD, is strongly dependent on SR Ca2+ release, which may act through modulation of the l-type Ca2+ current in a subsarcolemmal microdomain.