Mechanisms of human atrial fibrillation initiation: clinical and computational studies of repolarization restitution and activation latency

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) was then initiated to determine impact on these parameters. Compared with baseline in AF patients, isoproterenol and rapid pacing decreased activation latency (64±14 versus 31±13 versus 24±14 ms; P<0.05), steepened maximum APD restitution slope (0.8±0.7 versus 1.7±0.5 versus 1.1±0.5; P<0.05), and increased AF incidence (12% versus 64% versus 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 L-type calcium current and decreased activation latency via enhanced rapid delayed potassium reactifier current inactivation, whereas rapid pacing steepened APD restitution via increased cardiac inward potassium rectifier current.

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 that AF initiation from each intervention uses distinct ionic mechanisms. This insight may help design interventions to prevent AF.

Figure 1

(A) Premature extrastimuli initiate AF at CL 500/210 in a paroxysmal AF patient, with an activation latency of 19 msec. (B) Patient with Persistent AF with activation latency of 62 msec at 500/250, and AF is not initiated. Maximum activation latency (C) is greater in persistent (blue) versus paroxysmal (red) AF, illustrated by these representative patients. Baseline action potential duration (APD) restitution slope (D) was <1 in persistent AF (blue) but >1 in paroxysmal (red), as shown for these individuals. Key: ABL-D=distal electrode of MAP catheter.

Figure 2

(A) Extrastimulus pacing at baseline (left) and during isoproterenol infusion (right) in a patient with persistent AF. (B) Activation latency curves in the same patient, showing isoproterenol infusion (red) decreases maximum activation latency versus baseline (blue) and permits shorter extrastimuli to conduct. (C) APD restitution, for this patient, illustrate how isoproterenol (red) extends the curve to shorter diastolic intervals (leftward) versus baseline (blue), permitting shorter APDs and steepening APD restitution. (D) Premature extrastimulus induces AF in the same patient during isoproterenol, in whom no AF was observed at baseline.

Figure 3

(A) Baseline single extrastimulus pacing (left) and rapid pacing (right) in a persistent AF patient. Maximum activation latency is less during rapid pacing (14 msec) than baseline (82 msec). Activation latency restitution for the same patient (B) show rapid pacing suppresses maximum activation latency (red) versus baseline S1S2 pacing (blue). Rapid pacing steepens action potential duration (APD) restitution versus S1S2 pacing, as illustrated in the APD restitution plot (C) from this patient. Atrial fibrillation was inducible with rapid pacing in this patient (D), but not at baseline.

Figure 4

(A) Adenosine allows more premature extrastimuli to conduct, but with greater activation latency in a persistent AF patient. (B) In the same patient, action potential duration (APD) restitution slope is <1 at baseline (blue) and during adenosine infusion (red). In a separate persistent AF patient, an extrastimulus (210 msec) fails to induce AF during adenosine infusion. Note substantial activation latency (97 msec).

Figure 5

(A) Activation latency curves in a representative control patient at baseline (blue) and during isoproterenol (red) show a similar reduction in minimum conducted S2 and maximum activation latency to AF patients. However, action potential duration restitution slope (B) remains <1 during isoproterenol, as shown in this representative patient. (C) shows failure of shortest conducted extrastimulus to induce AF in a control patient during isoproterenol.

Figure 6

Action potential duration (APD) and activation latency restitution in a computer model of human atrial tissue. (A) Atrial tissue dimensions. (B) Action potentials for pacing cycle length of 500 ms. (C) APD restitution and (D) activation latency restitution for control (black) and persistent atrial fibrillation (blue) models during extrastimulus pacing.

Figure 7

Action potential duration (APD) and activation latency (AL) restitution for rapid pacing, isoproterenol and adenosine in the atrial fibrillation tissue model. (A) Isoproterenol and rapid pacing (S1) increased APD restitution slope >1, while adenosine did not. (B) Isoproterenol and rapid pacing (S1) decreased maximum activation latency, while adenosine increased maximum activation latency (C). Differences in APD restitution slope (top), activation latency magnitude (middle) and activation latency onset (bottom) between the isoproterenol and adenosine AF models (see online supplement for details, note that differences are the inverse of the contribution of each ionic current modification shown in panels A and B).