Late Ca2+Spark Arrhythmogenesis in Failing Cardiac Myocytes

Abstract

Heart failure (HF) is associated with diminished amplitude and slower kinetics of the Ca2+ transient in ventricular myocytes. Loss of t-tubules geometrically uncouples voltage gated Ca2+ channels (which carry the Ca2+ current -ICa) from RyR2 Ca2+ release channels on the sarcoplasmic reticulum. Changes in action potential (AP) morphology, due to altered K+ currents, further reduce peak ICa and increase heterogeneity in Ca2+ release. We recently reported that partially inhibiting ICa in non-failing cardiac myocytes increased the occurrence of “late Ca2+ sparks” (LCS) which prolonged the Ca2+ transient decay. Here we tested the hypothesis that LCS are similarly increased in HF by changes in t-tubules and/or altered AP morphology, and that they may contribute to arrhythmogenesis via inward Na+/Ca2+ exchange (NCX) current. HF was developed in rabbits after coronary artery ligation. Myocytes were isolated by collagenase digestion of the heart and whole cell patch-clamped using pipettes containing Fluo-4 (50 µM). Myocytes were imaged on a laser scanning confocal microscope (LSM880) in line-scanning mode. Ca2+ release was more dyssynchronous and more LCS were detected during the Ca2+ transient decay in cells from HF rabbits compared to non-failing control rabbits. Early afterdepolarizations (EADs) occurred in some HF cells, coinciding with greatly increased LCS frequency. Consistent with experimental data, a multiscale ventricular myocyte computer model showed that the increased LCS could increase inward NCX current sufficiently to drive membrane oscillations. These data indicate LCS are an arrhythmogenic substrate in failing cardiac myocytes and that controlling repolarization abnormalities may be beneficial for rescuing contractility and decreasing arrhythmias.