Do small-conductance Ca2+-activated K+-channels contribute to ventricular repolarization in human heart failure?

Chronic heart failure constitutes a clinical syndrome characterized by substantial attenuation of repolarization reserve resulting from electrical remodeling. The small-conductance Ca2+-activated K+ channel (SK) has been reported to undergo upregulation in animal heart failure models and in human preparations; however, its exact function is not fully understood. This study aims to elucidate the functional role of SK channels in end-stage human heart failure. SK-protein expression of undiseased and failed human ventricular tissue was investigated by Western blot technique. Action potentials were measured by the standard microelectrode technique from right ventricular papillary muscles of undiseased hearts and from right and left papillary muscles and from left midmyocardial tissue slices of failing hearts. Ionic currents were recorded by the whole cell configuration of the patch-clamp technique on isolated cells obtained from left ventricles of failing hearts. Failing hearts exerted consistent action potential lengthening and lacked spike-and-dome compared with undiseased hearts. Western blot revealed identical SK expression between undiseased and failing hearts. Apamin (100 nM), a commonly used selective SK channel inhibitor, failed to alter action potential duration values of the failing hearts in left and right endocardial preparations and in left midmyocardium. Furthermore, no apamin-sensitive current was identified in isolated cells. Week coupling between SK2 channels and L-type Ca2+ channels was found. These results do not confirm the results of previous studies claiming an important role of SK channels in the repolarization of the human failing heart.NEW & NOTEWORTHY This study re-evaluates the role of small-conductance Ca2+-activated K+ (SK) channels in ventricular repolarization in terminal human heart failure. Although SK protein is present and pharmacological activation causes only minor AP shortening, apamin does not affect action potentials or membrane currents, even with enhanced intracellular Ca2+. Partial IKr block alone induces repolarization failure, indicating severely reduced repolarization reserve and negligible compensatory SK current, questioning the therapeutic relevance of SK channels in end-stage heart failure.