Cardiomyocytes hypertrophic status after myocardial infarction determines distinct types of arrhythmia: Role of the ryanodine receptor

The mechanisms responsible for sudden cardiac death in heart failure (HF) are unclear. We investigated early and delayed afterdepolarizations (EADs, DADs) in HF. Cardiomyocytes were enzymatically isolated from the right ventricle (RV) and the septum of rats 8 weeks after myocardial infarction (MI) and sham-operated animals. Membrane capacitance, action potentials (AP) and ionic currents were measured by whole-cell patch-clamp. The [Ca2+]i transients and Ca2+ sparks were recorded with Fluo-4 during fluorescence measurements. Arrhythmia was triggered in 40% of MI cells (not in sham) using trains of 5 stimulations at 2.0 Hz. EADs and DADs occurred in distinct cell populations both in the RV and the septum. EADs occurred in normal-sized PMI cells (<230 pF), whereas DADs occurred in hypertrophic PMI cells (>230 pF). All cells exhibited prolonged APs due to reduced Ito current. However, additional modifications in Ca2+-dependent ionic currents occurred in hypertrophic cells: a decrease in the inward rectifier K+ current IK1, and a slowing of L-type Ca2+ current inactivation which was responsible for the lack of adaptation of APs to abrupt changes in the pacing rate. The occurrence of spontaneous Ca2+ sparks, reflecting ryanodine receptor (RyR2) diastolic activity, increased with hypertrophy. The [Ca2+]i transient amplitude, sarcoplasmic reticulum (SR) Ca2+ load and Ca2+ sparks amplitude were all inversely correlated with cell size. We conclude that the trophic status of cardiomyocytes determines the type of cellular arrhythmia in MI rats, based on differential electrophysiological remodeling which may reflect early-mild and late-severe or differential modifications in the RyR2 function.