Mechanisms of Human Atrial Fibrillation Initiation

Abstract

Background Mechanisms of atrial fibrillation (AF) initiation are incompletely understood. We hypothesized that rate-dependent changes (restitution) in action potential duration (APD) and activation latency are central targets for clinical interventions that induce AF. We tested this hypothesis using clinical experiments and computer models. Methods and Results In 50 patients (20 persistent, 23 paroxysmal AF, 7 controls), we used monophasic action potential catheters to define left atrial APD restitution, activation latency and AF incidence from premature extrastimuli. Isoproterenol (n=14), adenosine (n=10), or rapid pacing (n=36) were then initiated to determine impact on these parameters. Compared with baseline in AF patients, isoproterenol and rapid pacing decreased activation latency (64±14vs 31±13 vs 24±14 ms, p<0.05), steepened maximum APD restitution slope (0.8±0.7 vs 1.7±0.5 vs 1.1±0.5, p<0.05), and increased AF incidence (12% vs 64% vs 84%, p<0.05). Conversely, adenosine shortened APD (p<0.05), yet increased activation latency (86±27 ms, p=0.002) so that maximum APD restitution slope did not steepen (1.0±0.5, p=NS) and AF incidence was unchanged (10%, p=NS). In controls, no intervention steepened APD restitution or initiated AF. Computational modeling revealed that isoproterenol steepened APD restitution by increased ICaL and decreased activation latency via enhanced IKr inactivation, while rapid pacing steepened APD restitution via increased IK1. Conclusions Steep APD restitution is a common pathway for AF initiation by isoproterenol and tachycardia, via reduced activation latency that enables engagement of steep APD restitution at rapid rates. Modeling suggests AF initiation from each intervention uses distinct ionic mechanisms. This insight may help design interventions to prevent AF.

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation

“…Koivumaäki et al 29 further extended the Nygren and Maleckar models by accounting for atria-specific characteristics of sarcoplasmic reticulum (SR) Ca uptake and release, and specifically, the delay between peripheral and central SR Ca release, characteristic of cells lacking t-tubules. Krummen et al 30 modified the Courtemanche model to account for extracellular K accumulation during rapid pacing and to fit AP duration (APD) and its restitution to newly available clinical recordings.…”

“…A combined clinical-simulation study by Krummen et al 30 examined the mechanisms behind the clinical interventions that induce AF, namely the administration of isoproterenol or adenosine, as well as rapid pacing. Isoproterenol and rapid pacing both steepened maximum APD restitution slope promoting AF initiation, although via distinct mechanisms, as demonstrated by the simulations.…”

Three-Dimensional Impulse Propagation in Myocardium

“…75 APD alternans precedes episodes of AF and occurs at lower rates and with higher magnitudes in persistent than in paroxysmal AF. 75 Atrial APD alternans is thought to reveal dynamic substrates for AF, and it has been linked with altered ion channel expression that occurs in AF 76 and with altered intracellular calcium handling. 75 However, it is likely that fibrosis amplifies regional rhythm instability because of its effects on local propagation and electrotonic current flow.…”

Blind analysis of atrial fibrillation electrograms: A sparsity-aware formulation

“…One of the most prominent hypothesis considers multiple uncoordinated activation foci placed at different locations inside the atrium. These fast and asynchronous activations cause a disordered global electrical activity that contributes to AF maintenance [13]. In contrast, during normal heart operation conditions (sinus rhythm) we observe a single activation focus, placed at the sinus node, acting as a pacemaker for the whole heart and leading to a regular global electrical activity.…”