Our findings are different from a recent report where IKCa blockade prolonged the atrial action potential in a whole atrial preparation in a reverse rate-dependent fashion; however this only occurred at rates slower than those used in the present study.. The atrial action potential was not prolonged with IKCa block in HF despite increased both SK2 and SK3 expression. Possible explanations include altered protein trafficking, altered channel calcium sensitivity or altered myocyte calcium handling. We previously reported that HF causes a decrease in calcium current in our 4 months HF tachypacing induced canine model, and in the present study we report PF-4217903 reduced calcium transient amplitude. Surprisingly, even in control myocytes where the calcium transient and current are normal, apamin failed to prolong the action potential. Since a role for IKCa blockers in the treatment of AF has been suggested we also evaluated a HF model with superimposed AF. In a recent report in a canine atrial tachypacing AF model, with preserved LV function, IKCa reduction via a drug which reduced calcium sensitivity of the channel caused a significant prolongation of left atrial action potentials. This contrasts with our AF results in the setting of chronic HF, where IKCa blockade failed to prolong the action potential. Notably, we observed that atrial HF myocytes had similar calcium transient amplitudes whether or not AF was superimposed, suggesting that calcium cycling in HF may be insufficient to activate the current. In agreement with a previous study of patients with chronic AF who had decreased expression of SK proteins, we found that AF superimposed on HF caused a decrease in the SK2 and SK3 protein expression relative to HF alone. Thus, the lack of apamin effect in the 4 months HF+AF atrial cells may be explained by a decrease in protein expression and/or a decrease in the calcium available for current activation. Since IKCa is a very small current and repolarization is accelerated in AF, it may be less likely that a change in IKCa would affect the overall AP duration. The same logic might apply in chronic HF, where atrial repolarization is also accelerated.. While we did not find a beneficial role for IKCa block in HF or AF, IKCa blockade might have utility in disease states where atrial repolarization is prolonged, or if there is spatial dispersion of atrial repolarization. Additionally, a recent study shows that IKCa blockade in pulmonary veins terminates AF suggesting a potential role for IKCa blockers in paroxysmal AF.. One confounding variable in studying IKCa is that the activity varies during the cardiac cycle in a calcium concentrationdependent manner. To assess the role of IKCa in an integrated system, we used perforated patch action potential recordings to permit maintenance of intrinsic calcium cycling, rather than conducting voltage clamp studies to assess the current. We relied on a pharmacologic approach to define IKCa. As with any pharmacologic approach there is a concern about non-specific effects. A recent report evaluated apamin selectivity in multiple human cardiac ion channels including L-type calcium channels.