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-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 and membrane potential (Vm) 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 APD80 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 APD80 in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca sensitivity of IKAS in failing ventricles. The Kd 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 IKAS to intracellular Ca, leading to upregulation of IKAS, postshock APD shortening, and recurrent SVF.
- intracellular calcium
- ion channels
- ventricular fibrillation
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine