Abstract 16589: IK,ATP Gain-of-Function Decreases Transmural Ventricular Dispersion of Repolarization While Increasing Dispersion Between Chambers
Gain-of-function mutations in channel subunits responsible for the ATP-sensitive K+ current,IK,ATP, have recently been identified in patients with Early Repolarization Syndrome, which predisposes to deadly cardiac arrhythmias. Variability in currents between heart chambers and transmurally in the ventricles may cause differential action potential (AP) shortening by IK,ATP. To assess gain-of-function IK,ATP effects on cardiac myocyte APs, we applied a dynamic clamp via a custom analog circuit to simulate a progressively increasing linear K+ conductance (up to 8.5 pS/pF) in canine ventricular and atrial myocytes. Our results show that myocytes with prolonged AP duration (APD) are most susceptible to IK,ATP activation. This phenomenon is qualitatively reproduced in silico, using a recent, second generation, canine ventricular myocyte model (HRd2010). The modeling results indicate that increased shortening is caused by replenishment of repolarizing current that is otherwise lacking in cells with long APDs. In contrast to the expectation that arrhythmia in patients with IK,ATP mutations is promoted by ventricular heterogeneity, these results suggest that enhanced shortening of long APDs would tend to reduce dispersion of repolarization and may be protective. Direct measurements of maximum IK,ATP conductance (in response to 100 µM pinacidil) in myocytes isolated from epicardium and endocardium reveal no difference across the ventricular wall, indicating that heterogeneity in IK,ATP expression will not cause transmural variability in the ventricle. However, there is a significant difference between atrium (380±50 pS/pF) and ventricle (250±40 pS/pF, p<0.05). For the maximum IK,ATP conductance applied through the dynamic clamp, AP shortening to ~30 ms required 2.2% IK,ATP in atrium and 3.4% in ventricle. Our findings lead us to suggest that differences in IK,ATP channel expression between heart chambers rather than transmural ventricular differences are more likely to cause pro-arrhythmic dispersion of repolarization. The large magnitude of the IK,ATP conductance is likely to accentuate chamber-to-chamber variability upon activation either through ischemia or gain-of-function mutations.
- © 2011 by American Heart Association, Inc.