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Objectives: This first-in-human feasibility study was undertaken to translate the novel low-voltage MultiPulse Therapy (MPT) (Cardialen, Inc., Minneapolis, Minnesota), which was previously been shown to be effective in preclinical studies in terminating atrial fibrillation (AF), into clinical use., Background: Current treatment options for AF, the most common arrhythmia in clinical practice, have limited success. Previous attempts at treating AF by using implantable devices have been limited by the painful nature of high-voltage shocks., Methods: Forty-two patients undergoing AF ablation were recruited at 6 investigational centers worldwide. Before ablation, electrode catheters were placed in the coronary sinus, right and/or left atrium, for recording and stimulation. After the induction of AF, MPT, which consists of up to a 3-stage sequence of far- and near-field stimulation pulses of varied amplitude, duration, and interpulse timing, was delivered via temporary intracardiac leads. MPT parameters and delivery methods were iteratively optimized., Results: In the 14 patients from the efficacy phase, MPT terminated 37 of 52 (71%) of AF episodes, with the lowest median energy of 0.36 J (interquartile range [IQR]: 0.14 to 1.21 J) and voltage of 42.5 V (IQR: 25 to 75 V). Overall, 38% of AF terminations occurred within 2 seconds of MPT delivery (p < 0.0001). Shorter time between AF induction and MPT predicted success of MPT in terminating AF (p < 0.001)., Conclusions: MPT effectively terminated AF at voltages and energies known to be well tolerated or painless in some patients. Our results support further studies of the concept of implanted devices for early AF conversion to reduce AF burden, symptoms, and progression., Competing Interests: Funding Support and Author Disclosures This study was supported by Cardialen Inc., Minneapolis, Minnesota; Medtronic Plc., Dublin, Ireland; and the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number 1 R43 HL107055-01. Dr. Ng was supported by the National Institute of Health Research (NIHR) (Clinical Lectureship 1716) and British Heart Foundation (RG/16/3/32175). Drs. Ng, Qureshi, and Peters were supported the Imperial College Centre for Cardiac Engineering and the NIHR Imperial Biomedical Research Centre. Drs. Ng, Mead, Peters and Efimov have or had consulting agreements with Cardialen. Mr. Shelton and Drs. Bourn and Sharma are current or former employees of Cardialen. Drs. Efimov and Peters are shareholders of Cardialen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The goal of this study is to investigate the mechanisms responsible for the increase in the upper limit of vulnerability (ULV; highest shock strength that induces arrhythmia) following the increase in pacing rate. To accomplish this goal, the study employs a three-dimensional bidomain finite element model of a slice through the canine ventricles. The preparation was paced eight times at a basic cycle length (BCL) of either 80 or 150ms followed by delivery of shocks of various strengths and timings. Our results demonstrate that the shock strength, which induced an arrhythmia 50% of the time, increased 20% for the faster pacing compared to the slower pacing. Analysis of the mechanisms underlying the increased vulnerability revealed that delayed post-shock activations originating in the tissue depths appear as breakthrough activations on the surfaces of the preparation following an isoelectric window (IW). However, the IW duration was consistently shorter in the faster-paced preparation. Consequently, breakthrough activations appeared on the surfaces of this preparation earlier, when the tissue was less recovered, resulting in higher probability of unidirectional block and reentry. This explains why shocks of the same strength were more likely to result in arrhythmia induction when delivered to a preparation that was rapidly paced.

Background: Studies have demonstrated that failed defibrillation shocks often are followed by an electrically quiescent period (isoelectric window); however, the underlying mechanisms remain incompletely understood. We recently suggested a new mechanism termed "virtual electrode polarization-induced propagated graded responses" (VEPiPGRs) that might play a role in the origin of the global postshock activation following the isoelectric window., Objectives: The purpose of this study to elucidate the circumstances under which VEPiPGR activations originate for shocks given to paced right ventricular preparations. Specifically, we examined the dependence of VEPiPGRs on coupling interval (CI) and shock polarity and whether VEPiPGRs emerge preferentially on the epicardium or the endocardium., Methods: Simultaneous endocardial and epicardial activity in isolated right ventricular preparations (n = 4) was imaged optically following shocks of strength +/-5A. All VEPiPGRs were analyzed, and the time T from shock end to activation onset was recorded (isoelectric window is the smallest T among activations that propagated globally)., Results: VEPiPGR activations occurred for CIs in the range from 80 to 150 ms. Average duration of T was 64.5 +/- 18.15 ms, with T decreasing as CI increased (Tmax = 82 ms, Tmin = 46 ms, linear-fit slope = -0.675). The average earliest CI at which cathodal (+5A) shocks resulted in VEPiPGRs was 87 ms compared with 116 ms for anodal (-5A) shocks. All VEPiPGR activations emerged first on the epicardium in a focal pattern, and all induced ventricular fibrillation., Conclusion: The global activation that terminates the isoelectric window could result from VEPiPGRs that find an exit pathway. VEPiPGRs originate at the sites of maximum action potential abbreviation by the shock, always on the epicardium for the preparation used here.