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

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 Ca2+-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 Ca2+ 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 mu mol/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 degrees 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 Ca2+ response of I-KAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca2+ 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 Ca2+, leading to upregulation of I-KAS, postshock APD shortening, and recurrent SVF. (Circ Res. 2011;108:971-979.)