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 Ca(2+) activated K(+) (SK2) channel and apamin‐sensitive K(+) currents (I(KAS)) are upregulated in failing human ventricles. METHODS AND RESULTS: We studied 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 μmol/L Ca(2+) 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 Ca(2+) 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 Ca(2+) sensitivity and SK2 protein expression contributes to the I(KAS) upregulation.