Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death

Abstract

Ventricular tachyarrhythmias are the most common cause of sudden cardiac death (SCD); a healed myocardial infarction increases the risk of SCD. We determined the contribution of specific repolarization abnormalities to ventricular tachyarrhythmias in a postinfarction model of SCD. For our methods, we used a postinfarction canine model of SCD, where an exercise and ischemia test was used to stratify animals as either susceptible (VF+) or resistant (VF−) to sustained ventricular tachyarrhythmias. Our results show no changes in global left ventricular contractility or volumes occurred after infarction. At 8–10 wk postmyocardial infarction, myocytes were isolated from the left ventricular midmyocardial wall and studied. In the VF+ animals, myocyte action potential (AP) prolongation occurred at 50 and 90% repolarization ( P < 0.05) and was associated with increased variability of AP duration and afterdepolarizations. Multiple repolarizing K+ currents ( IKr, Ito) and inward IK1 were also reduced ( P < 0.05) in myocytes from VF+ animals compared with control, noninfarcted dogs. In contrast, only Ito was reduced in VF− myocytes compared with controls ( P < 0.05). While afterdepolarizations were not elicited at baseline in myocytes from VF− animals, afterdepolarizations were consistently elicited after the addition of an IKr blocker. In conclusion, the loss of repolarization reserve via reductions in multiple repolarizing currents in the VF+ myocytes leads to AP prolongation, repolarization instability, and afterdepolarizations in myocytes from animals susceptible to SCD. These abnormalities may provide a substrate for initiation of postmyocardial infarction ventricular tachyarrhythmias.