Recently it was reported in human end-stage HF that SK channel sensitivity to calcium was increased in ventricular myocytes, which could contribute in part to our findings. Of note, other proteins such as: protein kinase, calmodulin and protein phosphatase A, are also known to contribute to the regulation of SK channels, and thus may modulate IKCa during HF. Since IKCa is a calcium-activated potassium current, HFinduced changes in ventricular calcium handling should directly affect the current. We have previously reported that in our HF model, there is a significant reduction in SR calcium release and calcium transient amplitude, which would reduce rather than augment IKCa. In support of this interpretation, a Talazoparib 1207456-01-6 recent report indicates that SR release is necessary and sufficient for IKCa activation. Considering the HF-induced reduction in calcium cycling, and the lack of apamin effect in control cells where calcium cycling is robust, this suggests that altered calcium cycling is not responsible for the protective role of IKCa in heart failure. Reduced ventricular repolarization reserve may unmask the role of small currents such as IKCa. Decreased repolarization reserve is well-described in the ventricle during HF and attributed to reductions in repolarizing currents such as IK1,I Kr and IKs. These changes predispose to repolarization instability and/or arrhythmias. Since IKCa blockade prolonged the AP only during HF and not in controls, we suggest that the contribution of IKCa becomes evident only in settings of decreased repolarization reserve. Thus we suggest that increased channel expression, altered calcium sensitivity of SK channels, or altered repolarization reserve may contribute to the stabilizing role of IKCa. IKCa has been suggested as a therapeutic target for AF. IKCa is defined pharmacologically as apamin-sensitive current, as apamin blocks SK1, SK2 and SK3-encoded channels. One potential problem with this approach is non-selective effects on other ion currents. However, a recent paper surveying apamin effects on human ion channel protein function has demonstrated a high degree of specificity for SK-encoded IKCa, even at a concentration five-fold higher than in the present study. A potential limitation of previous studies evaluating IKCa blockade has been a focus on primarily one cardiac chamber; this is limiting since electrical remodeling during HF is chamber-dependent. Specifically during chronic HF, the atrial action potential is shortened while the ventricular action potential is prolonged.. Interest in IKCa as a therapeutic target for atrial arrhythmias followed reports of a genetic predisposition to lone AF attributed to a single nucleotide mutation in the gene KCNN3, which encodes for SK3. The exact mechanism by which a single mutation affects SK channel function remains unclear. Data supporting both loss of function and gain of function as possible mechanisms for AF have been reported in multiple models. Additionally, SK2 and SK3 down regulation have been associated with human AF.. One goal of this study was to elucidate the role of IKCa in atrial electrophysiology during HF and HF with superimposed AF.