T-wave alternans, a powerful marker of arrhythmic events, results from alternation in action potential duration (APD). The underlying cellular mechanism of APD alternans is unknown but has been attributed to either intracellular calcium (Ca ²⁺ ) cycling or membrane ionic currents, manifested by a steep slope of cellular APD restitution. To address these mechanisms, high-resolution optical mapping techniques were used to measure action potentials and Ca ²⁺ transients simultaneously from hundreds of epicardial sites in the guinea pig model of pacing-induced T-wave alternans (n=7). The pacing rates (ie, alternans threshold) at which T-wave (369±11 bpm), APD (369±21 bpm), and Ca ²⁺ (371±29 bpm) alternans first appeared were comparable. Importantly, the site of origin of APD alternans and Ca ²⁺ alternans consistently occurred together near the base of the left ventricle, not where APD restitution was steepest. In addition, APD and Ca ²⁺ alternans were remarkably similar both spatially and temporally during discordant alternans. In conclusion, the mechanism underlying T-wave alternans in the intact heart is more closely associated with intracellular Ca ²⁺ cycling rather than APD restitution.

Background: Optimal timing for catheter ablation of ventricular tachycardia is an important unresolved issue. There are no randomized trials evaluating the benefit of ablation after the first implantable cardioverter defibrillator (ICD) shock. Methods: We conducted a 2-phase, prospective, multicenter, randomized clinical trial. Patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock (phase A). After reconsenting, patients were randomly assigned 1:1 in phase B to immediate ablation (within 2 months from shock delivery) or continuation of standard therapy. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure. Amiodarone intake was not allowed except for documented atrial tachyarrhythmias. On July 23, 2021, phase B of the trial was interrupted as a result of the first interim analysis on the basis of the Bayesian adaptive design. Results: Of the 517 patients enrolled in phase A, 154 (30%) had ventricular tachycardia, 56 (11%) received an appropriate shock over a median follow-up of 2.4 years (interquartile range, 1.4–4.4), and 47 of 56 (84%) agreed to participate in phase B. After 24.2 (8.5–24.4) months, the primary end point occurred in 1 of 23 (4%) patients in the ablation group and 10 of 24 (42%) patients in the control group (hazard ratio, 0.11 [95% CI, 0.01–0.85]; P =0.034). The results met the prespecified termination criterion of >99% Bayesian posterior probability of superiority of treatment over standard therapy. No deaths were observed in the ablation group versus 8 deaths (33%) in the control group ( P =0.004); there was 1 worsening heart failure hospitalization in the ablation group (4%) versus 4 in the control group (17%; P =0.159). ICD shocks were less frequent in the ablation group (9%) than in the control group (42%; P =0.039). Conclusions: Ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined death or worsening heart failure hospitalization end point, lower mortality, and fewer ICD shocks. These findings provide support for considering ventricular tachycardia ablation after the first ICD shock. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01547208.

Background—: The substrates for human atrial fibrillation (AF) are poorly understood, but involve abnormal repolarization (action potential duration [APD]). We hypothesized that beat-to-beat oscillations in APD may explain AF substrates, and why vulnerability to AF forms a spectrum from control subjects without AF to patients with paroxysmal then persistent AF. Methods and Results—: In 33 subjects (12 with persistent AF, 13 with paroxysmal AF, and 8 controls without AF), we recorded left (n=33) and right (n=6) atrial APD on pacing from cycle lengths 600 to 500 ms (100 to 120 bpm) up to the point where AF initiated. Action potential duration alternans required progressively faster rates for patients with persistent AF, patients with paroxysmal AF, and controls (cycle length 411±94 versus 372±72 versus 218±33 ms; P 0.10). In this milieu, spontaneous ectopy initiated AF. At fast rates, APD alternans disorganized to complex oscillations en route to AF. Complex oscillations also arose at progressively faster rates for persistent AF, paroxysmal AF, and controls (cycle length: 316±99 versus 266±19 versus 177±16 ms; P =0.02). In paroxysmal AF, APD oscillations amplified before AF ( P <0.001). In controls, APD alternans arose only at very fast rates (cycle length <250 ms; P <0.001 versus AF groups) just preceding AF. In 4 AF patients in whom rapid pacing did not initiate AF, APD alternans arose transiently then extinguished. Conclusions—: Atrial APD alternans reveals dynamic substrates for AF, arising most readily (at lower rates and higher magnitudes) in persistent AF then paroxysmal AF, and least readily in controls. APD alternans preceded all AF episodes and was absent when AF did not initiate. The cellular mechanisms for APD alternans near resting heart rates require definition.

The maintenance of multiple wavelets appears to be a consistent feature of atrial fibrillation (AF). In this paper, we investigate possible mechanisms of initiation and perpetuation of multiple wavelets in a computer model of AF. We developed a simplified model of human atria that uses an ionic-based membrane model and whose geometry is derived from a segmented magnetic resonance imaging data set. The three-dimensional surface has a realistic size and includes obstacles corresponding to the location of major vessels and valves, but it does not take into account anisotropy. The main advantage of this approach is its ability to simulate long duration arrhythmias (up to 40 s). Clinically relevant initiation protocols, such as single-site burst pacing, were used. The dynamics of simulated AF were investigated in models with different action potential durations and restitution properties, controlled by the conductance of the slow inward current in a modified Luo–Rudy model. The simulation studies show that (1) single-site burst pacing protocol can be used to induce wave breaks even in tissue with uniform membrane properties, (2) the restitution-based wave breaks in an atrial model with realistic size and conduction velocities are transient, and (3) a significant reduction in action potential duration (even with apparently flat restitution) increases the duration of AF.