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

Abstract

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 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 to undiseased hearts. Western-blot revealed identical SK-expression between undiseased and failing hearts. 100 nM apamin, 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. It was found weak coupling between SK2-channels and L-type Ca²⁺ channels. These results do not confirm the results of previous studies claiming an important role of SK-channels in the repolarization of human failing heart.