Marked activation delay caused by ischemia initiated after regional K+ elevation in in situ pig hearts

Conduction mediated by the slow inward (Ca2+) current occurs in vitro under specific experimental conditions but has not been documented in ventricular muscle in vivo during regional myocardial ischemia, perhaps because certain constituents of ischemia (including hypoxia and acidosis) may inhibit the Ca2+ current in this setting. We hypothesized that slow conduction mediated by the Ca2+ current could occur during acute ischemia in situations in which the extracellular K+ rise was more marked relative to the degree of acidosis, as may occur at ischemic boundaries.

In open-chest, anesthetized swine, an arterial shunt from the carotid artery to the mid-left anterior descending coronary artery was created through which a solution of KCl was infused to raise extracellular K+ ([K+]e) to approximately 9.4 mmol/L before the initiation of ischemia, which we termed "K(+)-modified ischemia." Ischemia initiated at a normal [K+]e ("unmodified ischemia") resulted in a mean activation delay in the center of the ischemic zone of 55 +/- 26 milliseconds after 5 minutes of ischemia and a decrease in epicardial longitudinal conduction velocity from 53 to 21 cm/s before the onset of conduction block. K(+)-modified ischemia resulted in a mean activation delay in the center of the ischemic zone of 181 +/- 8 milliseconds and a decrease in epicardial longitudinal conduction to less than 10 cm/s. K(+)-modified ischemia was associated with ventricular fibrillation in 85% of episodes compared with 28% of episodes of unmodified ischemia (P < .01). Verapamil prevented the occurrence of marked activation delay during K(+)-modified ischemia, producing local activation block following a maximum activation delay of 74 +/- 25 milliseconds. In two experiments, responses mediated by the slow inward current were produced by regional K+ elevation to 15 to 16 mmol/L, followed by concomitant regional administration of epinephrine (10(-7) mol/L). Regional [K+]e elevation alone to this level resulted in local activation block following a maximum activity delay of 70 to 80 milliseconds, whereas administration of epinephrine in combination with high [K+]e resulted in return of local activation with an activation delay of 160 to 180 milliseconds (ie, similar to that during K(+)-modified ischemia).

Compared with unmodified ischemia, K(+)-modified ischemia resulted in marked activation delay and a high incidence of ventricular fibrillation. Based on measurements of longitudinal conduction velocity, the inhibitory effect of verapamil, and the results of experiments with high [K+]e plus epinephrine, we conclude that the marked activation delay during K(+)-modified ischemia represents conduction mediated by the slow inward current. Because the conditions produced by K(+)-modified ischemia (high [K+]e with minimal acidosis) are similar to conditions in and near ischemic border regions, we hypothesize that responses mediated by the slow inward current may occur in such regions during unmodified ischemia and may participate in the development of reentrant arrhythmias.