Heterogeneous Upregulation of Apamin-Sensitive Potassium Currents in Failing Human Ventricles

Background-We previously reported that I-KAS are heterogeneously upregulated in failing rabbit ventricles and play an important role in arrhythmogenesis. This study goal is to test the hypothesis that subtype 2 of the small-conductance Ca2+ activated K+ (SK2) channel and apamin-sensitive K+ currents (I-KAS) are upregulated in failing human ventricles. Methods and Results-We stud(i)ed 12 native hearts from transplant recipients (heart failure [HF] group) and 11 ventricular core biopsies from patients with aortic stenosis and normal systolic function (non-HF group). I-KAS and action potential were recorded with patch-clamp techniques, and SK2 protein expression was studied by Western blotting. When measured at 1 mu mol/L Ca2+ concentration, I-KAS was 4.22 (median) (25th and 75th percentiles, 2.86 and 6.96) pA/pF for the HF group (n=11) and 0.98 (0.54 and 1.72) pA/pF for the non-HF group (n=8, P=0.008). I-KAS was lower in the midmyocardial cells than in the epicardial and the endocardial cells. The Ca2+ dependency of I-KAS in HF myocytes was shifted leftward compared to non-HF myocytes (K-d 314 versus 605 nmol/L). Apamin (100 nmol/L) increased the action potential durations by 1.77% (-0.9% and 7.3%) in non-HF myocytes and by 11.8% (5.7% and 13.9%) in HF myocytes (P=0.02). SK2 protein expression was 3-fold higher in HF than in non-HF. Conclusions-There is heterogeneous upregulation of I-KAS densities in failing human ventricles. The midmyocardial layer shows lower I-KAS densities than epicardial and endocardial layers of cells. Increase in both Ca2+ sensitivity and SK2 protein expression contributes to the I-KAS upregulation.