Discordant action potential alternans creates large gradients of refractoriness, which are thought to be the mechanisms linking T-wave alternans to cardiac arrhythmogenesis. Since intercellular coupling acts to maintain synchronization of repolarization between cells, we hypothesized that intercellular uncoupling, such as during
ischemia, would initiate discordant alternans and that restoration of intercellular coupling by the gap junction opener
rotigaptide may provide a novel approach for suppressing arrhythmogenic discordant alternans. Optical mapping was used to record action potentials from ventricular epicardium of Langendorff-perfused guinea pig hearts. Threshold for spatially synchronized (i.e., concordant) alternans and discordant alternans was determined by increasing heart rate step-wise during 1) baseline, 2) treatment with
rotigaptide or vehicle, and 3) global low-flow
ischemia +
rotigaptide or vehicle.
Ischemia reduced the threshold for concordant alternans in both groups from 362 +/- 8 to 305 +/- 9 beats/min (P < 0.01) and for discordant alternans from 423 +/- 6 to 381 +/- 7 beats/min (P < 0.01). Interestingly,
rotigaptide also increased the threshold for discordant alternans relative to vehicle both before (438 +/- 7 vs. 407 +/- 8 beats/min, P < 0.05) and during (394 +/- 7 vs. 364 +/- 9 beats/min, P < 0.05)
ischemia.
Rotigaptide increased conduction velocity and prevented conduction slowing and dispersion of repolarization during
ischemia. Confocal immunofluorescence revealed that total
connexin43 quantity and cellular distribution were unchanged before or after low-flow
ischemia, with and without
rotigaptide. However,
connexin43 dephosphorylation in response to low-flow
ischemia was significantly prevented by
rotigaptide (15.9 +/- 7.0 vs. 0.3 +/- 6.4%, P < 0.001). These data suggest that intercellular uncoupling plays an important role in the transition from concordant to discordant alternans. By suppressing discordant alternans, repolarization gradients, and connexinx43 dephosphorylation,
rotigaptide may protect against
ischemia-induced arrhythmias. Drugs that selectively open gap junctions offer a novel strategy for antiarrhythmic
therapy.