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    • HF is associated with the down regulation of multiple potass

    2019-06-24

    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 after-hyperpolarization (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 Costunolide molecular 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. In HF patients and animal models, the APD shortens more rapidly than in normal ventricles during rapid pacing, leading to an increased slope of the APD restitution (APDR) curve. A steep APDR curve promotes dynamic instability, wave breaks, and VF. Because rapid pacing causes Cai accumulation, IKAS activation in failing ventricles might lead to increased APD shortening during a rapid pacing rate, and further steepen the APDR curve. This hypothesis was confirmed by Hsieh et al., who showed that, in failing rabbit ventricles, apamin flattens the APDR curve at fast pacing rates [4]. Apamin also decreases wave breaks, reduces the dominant frequency, and shortens the duration of VF. On the contrary, apamin lengthens the APD, steepens the APDR curve, and abolishes repolarization heterogeneity during slow pacing rate (cycle length, CL 300–350ms). This finding also suggests that IKAS activation is a major factor that underlies the repolarization heterogeneity and preservation of repolarization reserve in HF ventricles. In Hsieh׳s study, a secondary rise in Cai during the late AP plateau was observed in 9–19% of the epicardial area during slow heart rate in failing ventricles. The prolonged availability of Ca2+ during secondary Cai rise might activate IKAS to shorten the APD, thereby maintaining repolarization reserve and preventing ventricular arrhythmias in HF. Because slower heart rates (longer diastolic intervals) are associated with higher availability of L-type Ca2+ current (ICa,L) and longer Cai transient duration that might maximize IKAS activation, an experimental model with extremely slow heart rate (CL>500ms) might better elucidate the role of IKAS in maintaining repolarization reserve. Chang et al. therefore performed cryoablation of the atrioventricular node in failing rabbit hearts to reduce the ventricular rate [5]. In that extremely slow heart rate (CL>500ms) model, apamin induced EAD, premature ventricular beats (PVBs) and torsades de pointes (TdPs) in failing ventricles. Interestingly, the earliest activation site of the EAD and PVB always occurred at the area with long APD and large amplitude of the secondary rise of Cai. This study further confirmed the importance of IKAS in maintaining repolarization reserve and preventing TdP in HF ventricles.