Calcium-Activated Potassium Current Modulates Ventricular Repolarization in Chronic Heart Failure

Abstract

The role of IKCa in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of IKCa blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The IKCa blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by IKCa blockade in all of the groups studied. IKCa blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. IKCa blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, IKCa blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for IKCa in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.

SK channels and ventricular arrhythmias in heart failure

“…The heterogeneity might also contribute to the arrhythmogenecity in failing hearts. More recently, Bonilla et al and Ni et al confirmed these observations by showing that apamin significantly prolonged APD in failing human and canine ventricular cardiomyocytes, along with increased expression of SK channel protein in failing ventricles (Bonilla et al, 2014; Ni et al, 2013). The authors further demonstrated that there was a trend for more ventricular SK protein expression and greater APD prolongation in dogs with 4 months than with 1 month of HF.…”

“…In neuronal cells, the SK channels account for the slow component of afterhyperpolarization, which regulates neuronal discharges. SK channels contribute to repolarization of action potential in atrial cardiomyocytes and diseased ventricular cells (Bonilla et al, 2014; Chang et al, 2013a; Chua et al, 2011; Lee et al, 2013; Xu et al, 2003). The activation of SK channels also plays important roles in the function of a range of other tissues, such as the endothelium, intestine and urinary bladder (Feher et al, 2014; Hougaard et al, 2009; Ro et al, 2001).…”

“…In addition to safety concerns, the SK channel blockers may not be effective in treating atrial arrhythmias associated with HF. A recent study showed that the atrial myocyte action potentials were unchanged by SK current blockade in a canine model of HF (Bonilla et al, 2014). Induction of bradycardia is another concern of chronic SK channel therapy.…”

Ca²⁺-Activated K⁺ Channels as Therapeutic Targets for Myocardial and Vascular Protection

“…21 However, in HF, the contribution of ISK to repolarization during AP was demonstrated; and both an increase in expression levels and sensitivity to [Ca 2+ ] of SKCa channels in animal models and human HF have been established. 21,58, 59 Enhanced propensity to ventricular tachyarrhythmia is a major contributor to the death of patients with HF. Experiments using a rabbit model of tachypacing-induced cardiomyopathy demonstrated heterogeneous upregulation of SK channels, which can contribute to shortening of the APD and the development of ventricular fibrillation at fast rates.…”

“…29 In line with our findings, single-cell electrophysiology studies of ventricular myocytes from a chronic canine model of HF demonstrated that SKCa inhibition effectively evokes AP instability. 59 Underscoring a protective role of SKCa channels in diseased hearts, blockade of SKCa channels in rabbit failing hearts was shown to enhance predisposition to Ca 2+ -dependent triggers exacerbating arrhythmic potential. 60 IR Injury/MI Recent findings from a rat model of acute MI indicate that SKCa channels in ventricular myocytes can be functionally recruited nearly instantaneously and subsequently evoke APD shortening in the MI zone within 10 min after ligation of the left anterior descending coronary artery.…”