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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. [ABSTRACT FROM AUTHOR]

Background: Instability in ventricular repolarization in the presence of premature activations (PA) plays an important role in arrhythmogenesis. However, such instability cannot be detected clinically. This study developed a methodology for detecting QT interval (QTI) dynamics instability from the ECG and explored the contribution of PA and QTI instability to ventricular tachycardia (VT) onset.Methods and Results: To examine the contribution of PAs and QTI instability to VT onset, ECGs of 24 patients with acute myocardial infarction, 12 of whom had sustained VT (VT) and 12 nonsustained VT (NSVT), were used. From each patient ECG, 2 10-minute-long ECG recordings were extracted, 1 right before VT onset (onset epoch) and 1 at least 1 hour before it (control epoch). To ascertain how PA affects QTI dynamics stability, pseudo-ECGs were calculated from an MRI-based human ventricular model. Clinical and pseudo-ECGs were subdivided into 1-minute recordings (minECGs). QTI dynamics stability of each minECG was assessed with a novel approach. Frequency of PAs (f(PA)) and the number of minECGs with unstable QTI dynamics (N(us)) were determined for each patient. In the VT group, f(PA) and N(us) of the onset epoch were larger than in control. Positive regression relationships between f(PA) and N(us) were identified in both groups. The simulations showed that both f(PA) and the PA degree of prematurity contribute to QTI dynamics instability.Conclusions: Increased PA frequency and QTI dynamics instability precede VT onset in patients with acute myocardial infarction, as determined by novel methodology for detecting instability in QTI dynamics from clinical ECGs. [ABSTRACT FROM AUTHOR]

Background: During phase 1B of acute regional ischemia, the subepicardial and subendocardial layers coupled to the inexcitable midmyocardium remain viable.Objective: The purpose of this study was to examine how the degree of hyperkalemia in the surviving layers, the lateral width of border zone between the normal tissue and the central ischemic zone, and the degree of cellular uncoupling between the surviving layers and the midmyocardium contribute to initiation of reentry.Methods: Simulations were conducted on the state-of-the-art model of rabbit ventricles with realistic representation of the spatial distribution of the ischemic insult.Results: Hyperkalemia in the surviving layers led to induction of reentry by increasing refractoriness and slowing conduction in the layers. Such reentries were formed solely in the subepicardium. A minimal level of hyperkalemia was required for induction of reentry. Progress increase in hyperkalemia led to a biphasic change in vulnerability to reentry. For each level of hyperkalemia, increased cellular uncoupling between subepicardium and midmyocardium increased inducibility of reentry by restoring subepicardial tissue excitability via blocking midmyocardial electrotonic effect. In addition, increased lateral width of the border zone prevented inducibility of reentry as conduction block occurred in the central ischemic zone when the wave propagated across the border zone from the normal zone.Conclusion: The degree of hyperkalemia in the surviving subepicardium, the lateral width of border zone, and cellular uncoupling between the subepicardium and midmyocardium determine dispersion of refractoriness, conduction velocity, excitability, and, therefore, inducibility of reentry during phase 1B. [ABSTRACT FROM AUTHOR]

Introduction: Our previous article examined cardiac vulnerability to reentry in the near field within the framework of the virtual electrode polarization (VEP) concept. The present study extends this examination to the far field and compares its predictions to the critical point hypothesis. Methods and Results: We simulate the electrical behavior of a sheet of myocardium using a two-dimensional bidomain model. The fiber field is extrapolated from a set of rabbit heart fiber directions obtained experimentally. An S1 stimulus is applied along the top or left border. An extracellular line electrode on the top delivers a cathodal or anodal S2 stimulus. A VEP pattern matching that seen experimentally is observed and covers the entire sheet, thus constituting a far-field effect. Reentry arises from break excitation, make excitation, or a combination of both, and subsequent propagation through deexcited and recovered areas. Reentry occurs in cross-field, parallel-field, and uniform refractoriness protocols. For long coupling intervals (CIs) above CIminmake (defined as the shortest CI at which make excitation can take place), rotors move away from the cathodal electrode and the S1 site for increases in S2 strength and CI, respectively. For cathodal S2 stimuli, findings are consistent with the critical point hypothesis. For CIs below CIminmake, reentry is initiated by break excitation only, and the resulting reentrant patterns are no longer consistent with those predicted by the critical point hypothesis. Conclusion: Shock-induced VEP can explain vulnerability in the far field. The VEP theory of vulnerability encompasses the critical point hypothesis for cathodal S2 shocks at long CIs. [ABSTRACT FROM AUTHOR]