Small-Conductance Calcium-Activated Potassium Channel and Recurrent Ventricular Fibrillation in Failing Rabbit Ventricles

Abstract

Rationale: Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). Objective: We hypothesized that activation of apamin-sensitive small-conductance Ca 2+ -activated K + (SK) channels is responsible for the postshock APD shortening in failing ventricles. Methods and Results: A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca 2+ and membrane potential ( V m ) was performed in failing and nonfailing ventricles. Three failing ventricles developed SVF (SVF group); 9 did not (no-SVF group). None of the 10 nonfailing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF and increased postshock APD 80 in the SVF group from 126±5 to 153±4 ms ( P <0.05) and from 147±2 to 162±3 ms ( P <0.05) in the no-SVF group but did not change APD 80 in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K + current ( I KAS ) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial I KAS density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca 2+ response of I KAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca 2+ sensitivity of I KAS in failing ventricles. The K d was 232±5 nmol/L for failing myocytes and 553±78 nmol/L for normal myocytes ( P =0.002). Conclusions: Heart failure heterogeneously increases the sensitivity of I KAS to intracellular Ca 2+ , leading to upregulation of I KAS , postshock APD shortening, and recurrent SVF.