Abstract 14949: Mechanisms for Human Atrial Fibrillation Initiation: Clinical and Computational Studies Implicating Repolarization Restitution
Background: Isoproterenol, rapid pacing and adenosine are known to induce atrial fibrillation (AF). We studied whether effects on atrial action potential duration (APD) restitution and activation latency (AL) explain AF initiation from these interventions using clinical measurements and computer models.
Methods: In 50 patients (20 persistent AF, 7 controls), we delivered single extrastimuli and used monophasic action potential catheters to determine baseline restitution of left atrial APD and AL. We infused isoproterenol (n=14), adenosine (n=10), or performed rapid pacing (n=33) to evaluate the impact on electrophysiologic properties and AF initiation. Ionic mechanisms were explored using computational modeling.
Results: AF patients were aged 62±9 years. Notably, interventions that promoted AF steepened APD restitution, but by distinct mechanisms. Compared with baseline, isoproterenol (Fig A) and rapid pacing (Fig B) steepened APD restitution (0.70±0.20 vs 1.79±0.59 vs 1.10±0.50 respectively, p<0.05), decreased AL (61±17 vs 33±15 vs 17±11 ms, p<0.05) and increased AF incidence (12% vs 71% vs 80%, p<0.05, Fig C and D). While adenosine shortened APD (p<0.05), it increased AL (86±12 ms, p=0.002 vs baseline), did not steepen APD restitution (1.0±0.5, p=NS) and did not increase AF incidence (12.5%, p=NS). In controls, no intervention steepened APD restitution or initiated AF. Modeling showed that isoproterenol steepened APD restitution and decreased AL occurred via decreased IKr inactivation, increased IKs and enhanced INa, while rapid pacing increased INaK.
Conclusions: Adrenergic stimulation and tachycardia facilitate AF via distinct mechanisms, ultimately resulting in steepened APD restitution. Future work should examine whether therapies targeting these mechanisms may prevent AF.
- © 2011 by American Heart Association, Inc.