{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:26:41Z","timestamp":1780403201861,"version":"3.54.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T00:00:00Z","timestamp":1703030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> An electrical storm of Torsade de Pointes arrhythmias (TdP) can be reproducibly induced in the anesthetized chronic AV-block (CAVB) dog by infusion of the I<jats:sub>Kr<\/jats:sub>-blocker dofetilide. Earlier studies showed that these arrhythmias 1) arise from locations with high spatial dispersion in repolarization (SDR) and 2) can be suppressed by high-rate pacing. We examined whether suppression of TdP by high-rate pacing is established through a decrease in SDR in the CAVB dog.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Dofetilide (25\u00a0\u03bcg\/kg in 5\u00a0min) was administered to 5 anesthetized CAVB dogs to induce TdP arrhythmias. During the experiments, animals were continuously paced from the right ventricular apex at 50 beats\/minute (RVA50). Upon TdP occurrence and conversion, RVA pacing was consecutively set to 100, 80 and 60 beats\/minute for 2\u00a0min, referred to as pacing blocks. To determine the additional anti-arrhythmic effects of HRP over defibrillation alone, the number of arrhythmic events and SDR at RVA100 were compared to data from three previously conducted experiments, in which dogs underwent the same experimental protocol but were paced at RVA60 upon TdP occurrence (RVA60<jats:sub>retro<\/jats:sub>). In all experiments, recordings included surface electrocardiogram and mapping by 56 intramural needles, each recording four electrograms, evenly inserted into the ventricular walls and septum. For each pacing block, the number of ectopic beats (EB), and TdP severity were scored. SDR was quantified as the average difference in repolarization time within four squared needles (SDR<jats:sub>cubic<\/jats:sub>).<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> In 4 out of 5 animals, pacing at RVA100 suppressed TdP occurrence. One dog could not be converted by defibrillation after the initial TdP. Compared to RVA50, pacing at RVA100, but not RVA80 and RVA60, significantly reduced the TdP score (78 \u00b1 33 vs<jats:italic>.<\/jats:italic> 0 \u00b1 0, <jats:italic>p<\/jats:italic> &amp;lt; 0.05 and vs<jats:italic>.<\/jats:italic> 12.5 \u00b1 25 and 25 \u00b1 50, both <jats:italic>p<\/jats:italic> &amp;gt; 0.05). The reduction in TdP score was reflected by a significant decrease in SDR<jats:sub>cubic<\/jats:sub> (125 \u00b1 46\u00a0ms before TdP vs<jats:italic>.<\/jats:italic> 49 \u00b1 18\u00a0ms during RVA100, <jats:italic>p<\/jats:italic> &amp;lt; 0.05), and SDR was smaller than in the RVA60<jats:sub>retro<\/jats:sub> animals (101 \u00b1 52\u00a0ms, <jats:italic>p<\/jats:italic> &amp;lt; 0.05 vs<jats:italic>.<\/jats:italic> RVA100).<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> In CAVB dogs, high-rate pacing effectively suppresses TdP, which, at least in part, results from a spatial homogenization of cardiac repolarization, as reflected by a decrease in SDR.<\/jats:p>","DOI":"10.3389\/fphys.2023.1330230","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T08:46:49Z","timestamp":1703062009000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["High-rate pacing suppresses Torsade de Pointes arrhythmias and reduces spatial dispersion of repolarization in the chronic AV-block dog model"],"prefix":"10.3389","volume":"14","author":[{"given":"Vera","family":"Loen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie Y. H.","family":"Van Weperen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri\u00ebtte D. M.","family":"Beekman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne J. A.","family":"Van Bavel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique M. F.","family":"Meijborg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne G.","family":"Van der Waal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Coronel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel A. G.","family":"van der Heyden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc A.","family":"Vos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e73","DOI":"10.1016\/j.hrthm.2017.10.036","article-title":"2017 AHA\/ACC\/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American college of cardiology\/American heart association task force on clinical practice guidelines and the heart rhythm society","volume":"15","author":"Al-Khatib","year":"2018","journal-title":"Heart rhythm."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e024294","DOI":"10.1161\/JAHA.121.024294","article-title":"Temporal changes in beat-to-beat variability of repolarization predict imminent nonsustained ventricular tachycardia in patients with ischemic and nonischemic dilated cardiomyopathy","volume":"11","author":"Amoni","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2470","DOI":"10.1111\/bph.14217","article-title":"Selective late sodium current inhibitor GS-458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia","volume":"175","author":"Bossu","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1161\/01.cir.73.5.1022","article-title":"Comparison of the defibrillation threshold and the upper limit of ventricular vulnerability","volume":"73","author":"Chen","year":"1986","journal-title":"Circulation"},{"key":"B5","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/s41569-019-0179-0","article-title":"Animal models of arrhythmia: classic electrophysiology to genetically modified large animals","volume":"16","author":"Clauss","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1161\/01.cir.69.5.1013","article-title":"Effects of pacing on triggered activity induced by early afterdepolarizations","volume":"69","author":"Damiano","year":"1984","journal-title":"Circulation"},{"key":"B7","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1161\/CIRCULATIONAHA.111.023838","article-title":"Epidemiology and genetics of sudden cardiac death","volume":"125","author":"Deo","year":"2012","journal-title":"Circulation"},{"key":"B8","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1093\/europace\/euw087","article-title":"Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog","volume":"19","author":"Dunnink","year":"2017","journal-title":"Europace"},{"key":"B9","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1093\/europace\/eur311","article-title":"Ventricular remodelling is a prerequisite for the induction of dofetilide-induced torsade de pointes arrhythmias in the anaesthetized, complete atrio-ventricular-block dog","volume":"14","author":"Dunnink","year":"2012","journal-title":"Europace"},{"key":"B10","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/s0735-1097(87)80203-6","article-title":"Permanent cardiac pacing in patients with the long QT syndrome","volume":"10","author":"Eldar","year":"1987","journal-title":"J. Am. Coll. Cardiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1111\/j.1540-8159.1987.tb06039.x","article-title":"Antiarrhythmic effects of VVI pacing at physiologic rates: a crossover controlled evaluation","volume":"10","author":"Fisher","year":"1987","journal-title":"Pacing Clin. Electrophysiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1161\/CIRCRESAHA.116.304679","article-title":"Cardiac innervation and sudden cardiac death","volume":"116","author":"Fukuda","year":"2015","journal-title":"Circ. Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1046\/j.1460-9592.2002.01708.x","article-title":"Ventricular rate stabilization for the prevention of pause dependent ventricular tachyarrhythmias: results from a prospective study in 309 ICD recipients","volume":"25","author":"Gronefeld","year":"2002","journal-title":"Pacing Clin. Electrophysiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"4189","DOI":"10.1113\/jphysiol.2013.261198","article-title":"Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs","volume":"591","author":"Jost","year":"2013","journal-title":"J. Physiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"H848","DOI":"10.1152\/ajpheart.00787.2012","article-title":"Bradycardia alters Ca(2+) dynamics enhancing dispersion of repolarization and arrhythmia risk","volume":"304","author":"Kim","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"147","DOI":"10.31083\/j.rcm.2021.01.207","article-title":"Sudden cardiac death: epidemiology, pathogenesis and management","volume":"22","author":"Kumar","year":"2021","journal-title":"Rev. Cardiovasc Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1111\/bph.15436","article-title":"The canine chronic atrioventricular block model in cardiovascular preclinical drug research","volume":"179","author":"Loen","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1111\/j.1540-8167.2010.01824.x","article-title":"High-rate pacing reduces variability of repolarization and prevents repolarization-dependent arrhythmias in dogs with chronic AV block","volume":"21","author":"Oosterhoff","year":"2010","journal-title":"J. Cardiovasc Electrophysiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.pharmthera.2008.03.006","article-title":"The canine model with chronic, complete atrio-ventricular block","volume":"119","author":"Oros","year":"2008","journal-title":"Pharmacol. Ther."},{"key":"B20","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/s0169-2607(02)00014-7","article-title":"Software design for analysis of multichannel intracardial and body surface electrocardiograms","volume":"69","author":"Potse","year":"2002","journal-title":"Comput. Methods Programs Biomed."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2793","DOI":"10.1093\/eurheartj\/ehv316","article-title":"2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European society of cardiology (ESC). Endorsed by: association for European paediatric and congenital cardiology (AEPC)","volume":"36","author":"Priori","year":"2015","journal-title":"Eur. Heart J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1046\/j.1540-8167.2004.03493.x","article-title":"Spatial dispersion of repolarization is a key factor in the arrhythmogenicity of long QT syndrome","volume":"15","author":"Restivo","year":"2004","journal-title":"J. Cardiovasc Electrophysiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.hrthm.2020.09.020","article-title":"Critical repolarization gradients determine the induction of reentry-based torsades de pointes arrhythmia in models of long QT syndrome","volume":"18","author":"Rivaud","year":"2021","journal-title":"Heart rhythm."},{"key":"B24","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1111\/j.1469-7793.2001.00721.x","article-title":"Rate dependency of delayed rectifier currents during the Guinea-pig ventricular action potential","volume":"534","author":"Rocchetti","year":"2001","journal-title":"J. Physiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"H569","DOI":"10.1152\/ajpheart.00945.2020","article-title":"Interplay between temporal and spatial dispersion of repolarization in the initiation and perpetuation of torsades de pointes in the chronic atrioventricular block dog","volume":"321","author":"Smoczynska","year":"2021","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1016\/j.hrthm.2020.07.023","article-title":"High-rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias automatically by an implantable cardioverter-defibrillator in the chronic atrioventricular block dog model","volume":"17","author":"Smoczynska","year":"","journal-title":"Heart rhythm."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e018133","DOI":"10.1161\/JAHA.120.018133","article-title":"Short-term variability of the QT interval can be used for the prediction of imminent ventricular arrhythmias in patients with primary prophylactic implantable cardioverter defibrillators","volume":"9","author":"Smoczynska","year":"","journal-title":"J. Am. Heart Assoc."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1007\/s00424-014-1581-4","article-title":"Contribution of ion currents to beat-to-beat variability of action potential duration in canine ventricular myocytes","volume":"467","author":"Szentandrassy","year":"2015","journal-title":"Pflugers Arch."},{"key":"B31","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.cardiores.2006.11.025","article-title":"Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation","volume":"73","author":"Thomsen","year":"2007","journal-title":"Cardiovasc Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2453","DOI":"10.1161\/01.CIR.0000145162.64183.C8","article-title":"Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs","volume":"110","author":"Thomsen","year":"2004","journal-title":"Circulation"},{"key":"B33","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1016\/j.jacc.2009.06.006","article-title":"The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy","volume":"54","author":"Tops","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1016\/j.jacep.2017.06.016","article-title":"Short-lasting episodes of torsade de Pointes in the chronic atrioventricular block dog model have a focal mechanism, while longer-lasting episodes are maintained by Re-entry","volume":"3","author":"Vandersickel","year":"2017","journal-title":"JACC Clin. Electrophysiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/0160-5402(89)90015-6","article-title":"An improved method to correct the QT interval of the electrocardiogram for changes in heart rate","volume":"22","author":"Van de Water","year":"1989","journal-title":"J. Pharmacol. Methods"},{"key":"B37","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1097\/FJC.0000000000000748","article-title":"Point of view: electrophysiological endpoints differ when comparing the mode of action of highly successful anti-arrhythmic drugs in the CAVB dog model with TdP","volume":"74","author":"van Weperen","year":"2019","journal-title":"J. Cardiovasc Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"642083","DOI":"10.3389\/fphys.2021.642083","article-title":"Severe bradycardia increases the incidence and severity of torsade de Pointes arrhythmias by augmenting preexistent spatial dispersion of repolarization in the CAVB dog model","volume":"12","author":"van Weperen","year":"2021","journal-title":"Front. Physiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1093\/europace\/euac164","article-title":"Chronically altered ventricular activation causes pro-arrhythmic cardiac electrical remodelling in the chronic AV block dog model","volume":"25","author":"van Weperen","year":"2023","journal-title":"Europace"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1016\/j.hrthm.2012.05.016","article-title":"Beat-to-beat variability of repolarization as a new biomarker for proarrhythmia in vivo","volume":"9","author":"Varkevisser","year":"2012","journal-title":"Heart rhythm."},{"key":"B41","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1111\/j.1476-5381.2011.01367.x","article-title":"Cardiac ventricular repolarization reserve: a principle for understanding drug-related proarrhythmic risk","volume":"164","author":"Varro","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1136\/heart.83.6.661","article-title":"Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent?","volume":"83","author":"Viskin","year":"2000","journal-title":"Heart"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1161\/01.cir.98.11.1125","article-title":"Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling","volume":"98","author":"Vos","year":"1998","journal-title":"Circulation"},{"key":"B45","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.hrthm.2017.02.007","article-title":"Electrophysiological measurements that can explain and guide temporary accelerated pacing to avert (re)occurrence of torsade de pointes arrhythmias in the canine chronic atrioventricular block model","volume":"14","author":"Wijers","year":"2017","journal-title":"Heart rhythm."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1330230\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T08:46:53Z","timestamp":1703062013000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1330230\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,20]]},"references-count":41,"alternative-id":["10.3389\/fphys.2023.1330230"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2023.1330230","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,20]]},"article-number":"1330230"}}