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

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 CaBeat-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.