SK channels and ventricular arrhythmias in heart failure

Abstract

Small-conductance Ca(2+)-activated K(+) (SK) currents are important in the repolarization of normal atrial (but not ventricular) cardiomyocytes. However, recent studies showed that the SK currents are upregulated in failing ventricular cardiomyocytes, along with increased SK channel protein expression and enhanced sensitivity to intracellular Ca(2+). The SK channel activation may be either anti-arrhythmic or pro-arrhythmic, depending on the underlying clinical situations. While the SK channel is a new target of anti-arrhythmic therapy, drug safety is still one of the major concerns.

Figure 1

Effects of apamin (1μmol/L) on APD₈₀ and the differences between Ca²⁺ transient duration (Ca_iTD₈₀) and APD₈₀ in failing and normal rabbit hearts. Optical traces (top) of Vm (black line) and Ca_i (red line) were recorded from site marked by an asterisk in APD₈₀ map (bottom). A. Failing heart. Top subpanel shows epicardial optical traces of Vm and Cai and APD₈₀ map during sinus rhythm (SRm) before pacing-induced VF (left). Top right shows beats 1 and 2 had acute shortening of APD in the immediate post-shock period, resulting in the Ca_i elevation during late phase 3 and phase 4. Bottom right shows the corresponding APD₈₀ maps, and the maps of the difference between Ca_iTD₈₀ and APD₈₀ in beats 1 and 2. After apamin (bottom subpanel), the postshock beats 1 and 2 had longer APD₈₀ than those at baseline. The Ca_iTD80 was similar to that in A, and the differences between Ca_iTD₈₀ and APD₈₀ in beats 1 and 2 were reduced. B. Normal heart. As compared with the baseline, there were little changes of APD and Ca_iTD after defibrillation when the tissues were pretreated with apamin. Arrow indicates defibrillation. PI VF, pacing-induced VF; SRm indicates sinus rhythm. From Chua et al (Chua et al., 2011), with permission.

Figure 2

Apamin effect on QT interval and arrhythmias in failing rabbit hearts. A. Representative pseudoECG (pECG) traces of QT interval in a failing heart with complete atrioventricular (AV) block before and after 100 nmol/l apamin. B. Paired dot plot shows QTc at baseline and in the presence of apamin 100 nmol/L. There was significant prolongation of QTc. C. Representative traces at baseline and in the presence of apamin. Top panel, complete AV block developed during AV node cryoablation. Second panel, no polymorphic ventricular tachycardia was recorded at baseline. However, several episodes of spontaneous TdP polymorphic ventricular arrhythmia developed in the presence of apamin (bottom panels). From Chang et al (Chang et al., 2013b), with permission.

Figure 3

Effect of apamin on the percentage of action potential duration (APD) prolongation in normal and failing rabbit ventricles. A. APD₈₀ before (blue line) and after (red line) apamin infusion, and the percentage of APD₈₀ prolongation at pacing cycle length (PCL) 350, 300, 200, 180, and 160 ms in a normal and a HF ventricle. B. PCL and the percentage of APD₈₀ prolongation by apamin in all normal and HF ventricles. Note that the differences between HF and normal ventricles were significant only at very long (350–300 ms) and short (170–160 ms). PCLs (asterisks), but not with intermediate (280–180 ms) PCLs. From Hsieh et al (Hsieh et al., 2013), with permission.