| By the year 2050, it is estimated that 10 million Americans will be living with atrial fibrillation, a fast and chaotically irregular heart rhythm. For years, case reports and clinical studies have shown that patients paradoxically die suddenly from new ventricular arrhythmias occurring soon after the termination of atrial fibrillation, a condition called proarrhythmia. In contrast, patients have a low risk of these arrhythmias while they experience atrial fibrillation. This dichotomy of risk is not seen in patients with regular tachycardias. This dissertation includes the hypothesis that the irregularity of the ventricular response observed during atrial fibrillation alters repolarization in a way that could confer protection from developing repolarization-related arrhythmias. Because many patients with atrial fibrillation are treated with drugs that block IKr, such as dofetilide, and nearly all forms of proarrhythmic death are associated with abnormal repolarization caused by blocking IKr, an additional hypothesis is that repolarization may be further altered with dofetilide treatment. To test these hypotheses, domestic pigs were anesthetized and paced in the right atrium of the heart with a random sequence to mimic the irregular tachycardia of atrial fibrillation. Controls were designed to account for the heart rate variation of atrial fibrillation. Since QT intervals vary with heart rate, formulas have been developed to correct the QT interval for changing rates. These correction formulas were tested and found to be unreliable for group QT correction, therefore in the dofetilide arm of these studies, constant rate pacing at 150 beats/min was used for baseline comparisons. After fixed, sinusoidal, and random tachypacing treatments, these studies found that the QT interval and TpTe segment did not change, while the beat-to-beat variability index and QT interval recovery varied extensively across individual pigs. Each pig had a unique response, but no pattern could be attributed to the type of tachypacing. Dofetilide, when administered to pigs, has an unusual dual-effect elimination that has not been previously described. The serum concentration of dofetilide, was lower during random tachypacing compared to sinusoidal tachypacing, suggesting that the clinical theory of protection may be due to a pharmacokinetic protective effect during atrial fibrillation. Random and sinusoidal tachypacing in dofetilide treated pigs is associated with an increase in the RT interval just after the termination of tachypacing. This suggests that tachycardia of any type may confer a post-tachycardia vulnerability though irregularity per se did not alter repolarization differently than the control forms of tachypacing. |
