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      Role of the Purkinje-Muscle Junction on the Ventricular Repolarization Heterogeneity in the Healthy and Ischemic Ovine Ventricular Myocardium

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          Abstract

          Alteration of action potential duration (APD) heterogeneity contributes to arrhythmogenesis. Purkinje-muscle junctions (PMJs) present differential electrophysiological properties including longer APD. The goal of this study was to determine if Purkinje-related or myocardial focal activation modulates ventricular repolarization differentially in healthy and ischemic myocardium. Simultaneous epicardial (EPI) and endocardial (ENDO) optical mapping was performed on sheep left ventricular (LV) wedges with intact free-running Purkinje network ( N = 7). Preparations were paced on either ENDO or EPI surfaces, or the free-running Purkinje fibers (PFs), mimicking normal activation. EPI and ENDO APDs were assessed for each pacing configuration, before and after (7 min) of the onset of no-flow ischemia. Experiments were supported by simulations. In control conditions, maximal APD was found at endocardial PMJ sites. We observed a significant transmural APD gradient for PF pacing with PMJ APD = 347 ± 41 ms and EPI APD = 273 ± 36 ms ( p < 0.001). A similar transmural gradient was observed when pacing ENDO (49 ± 31 ms; p = 0.005). However, the gradient was reduced when pacing EPI (37 ± 20 ms; p = 0.005). Global dispersion of repolarization was the most pronounced for EPI pacing. In ischemia, both ENDO and EPI APD were reduced ( p = 0.005) and the transmural APD gradient (109 ± 55 ms) was increased when pacing ENDO compared to control condition or when pacing EPI ( p < 0.05). APD maxima remained localized at functional PMJs during ischemia. Local repolarization dispersion was significantly higher at the PMJ than at other sites. The results were consistent with simulations. We found that the activation sequence modulates repolarization heterogeneity in the ischemic sheep LV. PMJs remain active following ischemia and exert significant influence on local repolarization patterns.

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          Mapping and ablation of idiopathic ventricular fibrillation.

          Ventricular fibrillation is the main mechanism of sudden cardiac death. The feasibility of eliminating recurrent episodes by catheter ablation has not been reported. Twenty-seven patients without known heart disease (13 men, 14 women, 41+/-14 years of age) were studied after being resuscitated from recurrent (10+/-12) episodes of primary idiopathic ventricular fibrillation; 23 had received a defibrillator. The first initiating beat of ventricular fibrillation had an identical electrocardiographic morphology and coupling interval (297+/-41 ms) to preceding isolated premature beats typically noted in the aftermath of resuscitation. These triggers were localized by mapping the earliest electrical activity and ablated by local radiofrequency delivery. Outcome was assessed by Holter and defibrillator memory interrogation. Premature beats were elicited from the Purkinje conducting system in 23 patients: from the left ventricular septum in 10, from the anterior right ventricle in 9, and from both in 4. The interval from the Purkinje potential to the following myocardial activation varied from 10 to 150 ms during premature beat but was 11+/-5 ms during sinus rhythm, indicating location at peripheral Purkinje arborization. The premature beats originated from the right ventricular outflow tract muscle in 4 patients. The accuracy of mapping was confirmed by acute elimination of premature beats during local radiofrequency delivery. During a follow-up of 24+/-28 months, 24 patients (89%) had no recurrence of ventricular fibrillation without drug. Primary idiopathic ventricular fibrillation is a syndrome characterized by dominant triggers from the distal Purkinje system. These sources can be eliminated by focal energy delivery.
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            Role of Purkinje conducting system in triggering of idiopathic ventricular fibrillation.

            Ventricular fibrillation is the main mechanism of sudden cardiac death, but the source of its spontaneous initiation has not been mapped. 16 patients were investigated by electrography and radiofrequency ablation after resuscitation from recurrent idiopathic ventricular fibrillation. Triggers of ventricular fibrillation originated from various locations within the Purkinje system in 12 patients and from the ordinary myocardial muscle in four. The accuracy of mapping was confirmed by acute elimination of triggers by radiofrequency delivery, and there was no recurrence of ventricular fibrillation in 14 patients. Long-term follow-up is necessary to establish that ablation is curative and avoids use of a defibrillator.
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              Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes.

              Congenital long-QT syndrome (LQTS) is caused by mutations of genes encoding the slow component of the delayed rectifier current (LQT1, LQT5), the rapid component of the delayed rectifier current (LQT2, LQT6), or the Na(+) current (LQT3), resulting in ST-T-wave abnormalities on the ECG. This study evaluated the spectrum of ST-T-wave patterns and repolarization parameters by genotype and determined whether genotype could be identified by ECG. ECGs of 284 gene carriers were studied to determine ST-T-wave patterns, and repolarization parameters were quantified. Genotypes were identified by individual ECG versus family-grouped ECG analysis in separate studies using ECGs of 146 gene carriers from 29 families and 233 members of 127 families undergoing molecular genotyping, respectively. Ten typical ST-T patterns (4 LQT1, 4 LQT2, and 2 LQT3) were present in 88% of LQT1 and LQT2 carriers and in 65% of LQT3 carriers. Repolarization parameters also differed by genotype. A combination of quantified repolarization parameters identified genotype with sensitivity/specificity of 85%/70% for LQT1, 83%/94% for LQT2, and 47%/63% for LQT3. Typical patterns in family-grouped ECGs best identified the genotype, being correct in 56 of 56 (21 LQT1, 33 LQT2, and 2 LQT3) families with mutation results. Typical ST-T-wave patterns are present in the majority of genotyped LQTS patients and can be used to identify LQT1, LQT2, and possibly LQT3 genotypes. Family-grouped ECG analysis improves genotype identification accuracy. This approach can simplify genetic screening by targeting the gene for initial study. The multiple ST-T patterns in each genotype raise questions regarding the pathophysiology and regulation of repolarization in LQTS.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                14 June 2018
                2018
                : 9
                : 718
                Affiliations
                [1] 1Centre de Recherche Cardio-Thoracique de Bordeaux, Université de Bordeaux , Bordeaux, France
                [2] 2INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux , Bordeaux, France
                [3] 3IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université , Bordeaux, France
                [4] 4UMR5251, Centre National De La Recherche Scientifique, Institut de Mathématiques de Bordeaux , Bordeaux, France
                [5] 5Centre Hospitalier Universitaire, Bordeaux University Hospital, Hopital Cardiologique du Haut Lévèque , Bordeaux, France
                Author notes

                Edited by: T. Alexander Quinn, Dalhousie University, Canada

                Reviewed by: Rachel C. Myles, University of Glasgow, United Kingdom; David Sedmera, Charles University, Czechia

                *Correspondence: Marine E. Martinez, marine.martinez@ 123456ihu-liryc.fr Olivier Bernus, olivier.bernus@ 123456u-bordeaux.fr

                This article was submitted to Cardiac Electrophysiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2018.00718
                6010581
                29410630
                db03a703-1e5e-4eb6-835b-55a023822822
                Copyright © 2018 Martinez, Walton, Bayer, Haïssaguerre, Vigmond, Hocini and Bernus.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 March 2018
                : 24 May 2018
                Page count
                Figures: 9, Tables: 1, Equations: 0, References: 42, Pages: 15, Words: 0
                Funding
                Funded by: European Research Council 10.13039/501100000781
                Award ID: Advanced Grant SYMPHONY
                Funded by: Agence Nationale de la Recherche 10.13039/501100001665
                Award ID: ANR-10-IAHU04-LIRYC
                Funded by: Fondation Leducq 10.13039/501100001674
                Award ID: Transatlantic Network of Excellence RHYTHM
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                transmural heterogeneity,activation sequence,purkinje-muscle junction,repolarization,optical mapping

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