Apamin-sensitive potassium current and the Mechanisms of ventricular arrhythmia: Perspectives in heart failure treatment

Abstract

In patients with advanced heart failure (HF), recurrent spontaneous ventricular fibrillation (SVF)/electrical storm (ES) is a frequent complication requiring multiple defibrillation shocks within a short space of time. The mechanism underlying initiation of SVF/ES, spontaneously or immediately after defibrillation shocks, remains unclear. In 2009, Ogawa et al. developed a pacing-induced HF model, in which SVF occurred frequently in failing rabbit ventricles [1]. In that model, acute but reversible post-shock action potential duration (APD) shortening could induce recurrent SVF (Fig. 1, panel A) [1]. The induction of SVF was associated with persistent intracellular calcium (Cai) elevation during late phase 3 and/or phase 4 of the action potential (AP), indicating that APD shortening, in conjunction with persistent post-shock Cai elevation, is a novel mechanism of post-shock SVF/ ES [1]. However, the mechanisms underlying acute APD shortening after fibrillation/defibrillation episodes in HF ventricles remains to be determined. HF is associated with the down-regulation of multiple potassium (K) currents (i.e., Ito, IKs, IKr, IK1, and IKATP). The only K channel that is upregulated in HF is the small conductance Ca-activated K (SK) channel. The SK channel was originally found in most neurons. The increase in Cai evoked by the AP allows the SK channel to become activated, and generates a long-lasting afterhyperpolarization (AHP). Physiologically, the AHP can inhibit repetitive firing, and prevent deleterious tetanic activity in the nervous system. Previous studies show that the SK current is abundantly present in cardiac atrial cells, but not in normal ventricular cells. Because ventricular fibrillation (VF) is associated with Cai accumulation, especially in HF ventricles, Chua et al. hypothesized that SK channels might exist in HF ventricles and contribute to the post-shock APD shortening observed in Ogawa's study [1,2]. To test this hypothesis, they used apamin, a selective SK channel blocker that specifically inhibits apamin-sensitive K current (IKAS), to explore the roles of the SK channel in mediating ventricular arrhythmia of failing ventricles. Chua et al. found that apamin administration effectively prevented post-shock APD shortening, late phase 3 early after-depolarizations (EAD), and triggered activity and recurrent SVF in failing rabbit ventricles (see Fig. 1, panel B) [2]. Using a voltage-clamp technique, they reported that the IKAS current density was significantly larger in failing ventricular cardiomyocytes than in normal ones [2]. The IKAS sensitivity to Cai was increased in cardiomyocytes isolated from failing ventricles compared to those from normal ventricles [2]. Similar findings were reproduced in failing human ventricles by Chang et al. [3]. They also showed that the IKAS current density was lower in the mid-myocardial cells than in the epicardial and endocardial cells [3]. The subtype 2 of SK (SK2) protein expression was 3-fold higher in HF than in non-HF human ventricles [3]. These findings indicated for the first time that HF heterogeneously increases the sensitivity of IKAS to Cai, leading to the up-regulation of IKAS, post-shock APD shortening, late phase 3 EAD, triggered activity, and recurrent SVF in both animal models and failing human ventricles.