Inducibility of Short-Coupled Purkinje Ectopy by Pharmacological Tests in Patients With Spontaneous Short-Coupled Idiopathic Ventricular Fibrillation.

HomeCirculationVol. 148, No. 1Inducibility of Short-Coupled Purkinje Ectopy by Pharmacological Tests in Patients With Spontaneous Short-Coupled Idiopathic Ventricular Fibrillation Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBInducibility of Short-Coupled Purkinje Ectopy by Pharmacological Tests in Patients With Spontaneous Short-Coupled Idiopathic Ventricular Fibrillation Michel Haissaguerre, Josselin Duchateau, Mikael Laredo, Thomas Lavergne, Pierre F. Winum, Ghassen Cheniti, Xavier Waintraub, Sophie Samson, Elodie Surget, Romain Tixier, Frederic Sacher, Eloi Marijon, Olivier Bernus and Estelle Gandjbakhch Michel HaissaguerreMichel Haissaguerre Correspondence to: Michel Haissaguerre, MD, Hopital Cardiologique Haut-Leveque, Avenue de Magellan, Bordeaux, 33604, France. Email E-mail Address: [email protected] https://orcid.org/0000-0001-7644-6146 Université de Bordeaux, CRCTB U1045, Inserm, France (M.H., J.D., G.C., E.S., F.S., O.B.). IHU LIRYC, Electrophysiology and Heart Modeling Institute, Bordeaux, France (M.H., F.S., O.B.). Cardiac Electrophysiology and Stimulation Department, Bordeaux University Hospital, France (M.H., R.T., F.S., O.B.). Search for more papers by this author , Josselin DuchateauJosselin Duchateau https://orcid.org/0000-0002-4367-1117 Université de Bordeaux, CRCTB U1045, Inserm, France (M.H., J.D., G.C., E.S., F.S., O.B.). Search for more papers by this author , Mikael LaredoMikael Laredo Cardiology Institute, Pitié-Salpetriere, AP-HP, Sorbonne Université, Paris, France (M.L., X.W., E.G.). Search for more papers by this author , Thomas LavergneThomas Lavergne Cardiology Department, European Hospital Georges Pompidou, AP-HP, Paris University, France (T.L., E.M.). Search for more papers by this author , Pierre F. WinumPierre F. Winum Cardiology Department, University Hospital, CHU Nimes, France (P.F.W.). Search for more papers by this author , Ghassen ChenitiGhassen Cheniti https://orcid.org/0000-0001-7305-311X Université de Bordeaux, CRCTB U1045, Inserm, France (M.H., J.D., G.C., E.S., F.S., O.B.). Search for more papers by this author , Xavier WaintraubXavier Waintraub Cardiology Institute, Pitié-Salpetriere, AP-HP, Sorbonne Université, Paris, France (M.L., X.W., E.G.). Search for more papers by this author , Sophie SamsonSophie Samson Search for more papers by this author , Elodie SurgetElodie Surget https://orcid.org/0000-0003-0362-6351 Université de Bordeaux, CRCTB U1045, Inserm, France (M.H., J.D., G.C., E.S., F.S., O.B.). Search for more papers by this author , Romain TixierRomain Tixier https://orcid.org/0000-0003-4093-0483 Cardiac Electrophysiology and Stimulation Department, Bordeaux University Hospital, France (M.H., R.T., F.S., O.B.). Search for more papers by this author , Frederic SacherFrederic Sacher https://orcid.org/0000-0001-8348-9320 Université de Bordeaux, CRCTB U1045, Inserm, France (M.H., J.D., G.C., E.S., F.S., O.B.). IHU LIRYC, Electrophysiology and Heart Modeling Institute, Bordeaux, France (M.H., F.S., O.B.). Cardiac Electrophysiology and Stimulation Department, Bordeaux University Hospital, France (M.H., R.T., F.S., O.B.). Inherited Arrhythmic Disease Center, Haut-Leveque Hospital, CHU Bordeaux, France (F.S.). Search for more papers by this author , Eloi MarijonEloi Marijon https://orcid.org/0000-0001-7227-3428 Cardiology Department, European Hospital Georges Pompidou, AP-HP, Paris University, France (T.L., E.M.). Search for more papers by this author , Olivier BernusOlivier Bernus https://orcid.org/0000-0003-3917-5791 Université de Bordeaux, CRCTB U1045, Inserm, France (M.H., J.D., G.C., E.S., F.S., O.B.). IHU LIRYC, Electrophysiology and Heart Modeling Institute, Bordeaux, France (M.H., F.S., O.B.). Cardiac Electrophysiology and Stimulation Department, Bordeaux University Hospital, France (M.H., R.T., F.S., O.B.). Search for more papers by this author and Estelle GandjbakhchEstelle Gandjbakhch https://orcid.org/0000-0002-4846-5021 Cardiology Institute, Pitié-Salpetriere, AP-HP, Sorbonne Université, Paris, France (M.L., X.W., E.G.). Search for more papers by this author Originally published3 Jul 2023https://doi.org/10.1161/CIRCULATIONAHA.122.063578Circulation. 2023;148:70–72In a subset of patients with idiopathic ventricular fibrillation (IVF), ventricular fibrillation (VF) is triggered by short-coupled premature ventricular complexes (ScPVCs), mostly originating from Purkinje cells, with variable prevalence (6.6% to 91%).1–4 We reported that, among patients undergoing a sodium channel blocker (SCB) challenge to unravel a Brugada ECG, 4.7% developed ScPVCs.5 However, sodium channel blocking testing in ScPVC-related IVF has not been systematically evaluated. Pharmacological inducibility could be of significant diagnostic value in the identification of at-risk patients because ScPVCs are unpredictable and recorded randomly, mainly during VF recurrences. We assessed the prevalence of ScPVCs during pharmacological tests in patients who had previously documented ScPVC-related IVF. Previously reported patients5 were not included.Of 115 patients with ScPVC-related IVF, 52 underwent pharmacological challenge with SCBs (1 mg/kg of ajmaline for 5 to 10 minutes or 2 mg/kg of flecainide for 10 minutes), adrenaline (0.03–0.3 µg·kg–1·min–1), or isoproterenol (45 µg/min for 3 minutes). The occurrence of ≥10 ScPVCs or ≥1 repetitive forms during testing, without ScPVCs during the 15 minutes preceding testing, was considered an induced arrhythmogenic response. ScPVCs were defined by an R-on-T pattern (ectopic QRS complex on the T wave) rather than by a threshold value (such as 350 ms), which would be inadequate with the rapid rates under isoproterenol. The study was approved by the institutional review committee; all subjects gave informed consent. The data that support the findings of this study are available from the corresponding author on reasonable request.Among 52 patients studied, 29 (56%) had an arrhythmic response in at least 1 test, especially using SCBs. SCBs induced an arrhythmic response in 25 of 52 patients (48%), whereas catecholamine infusion was arrhythmogenic in 7 of 32 patients (22%) using isoproterenol (among the 7 patients, 3 were SCB-inducible, and 4 were SCB-noninducible) and 2 of 16 patients (12%) using adrenaline (both were also inducible on isoprenaline). Arrhythmic responses (Figure) included isolated ScPVCs in 11 patients (21±6 PVCs; coupling interval 321±33 ms on SCBs; 228±9 ms on isoprenaline) and repetitive forms in 18 patients (couplet/triplets in 12; polymorphic ventricular tachycardia runs in 6), leading to premature discontinuation of the drug test in 9 patients. A second SCB test was performed in 5 patients during electrophysiological study and reinduced ScPVCs in all 5.Download figureDownload PowerPointFigure. Pharmacological testing in patients with idiopathic VF and spontaneous documented ScPVCs. Examples of induced ScPVCs during sodium channel blocker infusion in 2 patients (A and B) and during isoproterenol infusion in another patient (C). The left traces show the spontaneous ScPVCs on previously recorded ECG (A and B) and a rarely occurring ScPVC captured on single-lead monitoring and on recorded VF initiation on the implanted defibrillator (C). The right traces show the pharmacologically induced ScPVCs (asterisks) using ajmaline (A and B) or isoprenaline (C). The appearance of ScPVCs usually occurs in a cluster over a few minutes. Note that the QRS morphology of the induced ectopic is similar to the morphology of spontaneous arrhythmias, originating from the right ventricle (A) or left ventricle (B). Other morphologies were also inducible in patients B and C (not shown). ICD indicates implantable defibrillator; ScPVC, short-coupled premature ventricular complex; and VF, ventricular fibrillation.Patients with SCB-induced ScPVCs were more often male (72% versus 44%; Pearson χ2 [df=1] test, P=0.044) than patients without SCB-induced ScPVCs. Other clinical characteristics, such as age at first VF (32±9 versus 33±13 years), family history of VF (24% versus 7%), median number of VF episodes (3 [interquartile range, 2–18] versus 3 [interquartile range, 1–13]), and history of VF storm (32% versus 44%) were similar between the 2 groups. Also, patients with SCB-induced ScPVCs had a wider baseline QRS complex (96±12 versus 88±8 ms; t test, P=0.01) but a similar QTc and similar coupling interval of spontaneous ScPVCs (299±36 versus 287±31 ms) than patients without SCB-induced ScPVCs. An arrhythmic response was seen more often after ajmaline than after flecainide (22/39 versus 3/13; χ2P=0.03). No patient developed Brugada pattern or J-point elevation during the tests. No SCN5A mutation was evidenced for the 31 analyzed patients.An arrhythmic response to SCB testing correlated with an incomplete therapeutic effect of quinidine. Specifically, among 19 patients treated with hydroquinidine, only 2 of 11 patients (18%) with arrhythmogenic SCBs versus 7 of 8 patients (87%) with nonarrhythmogenic SCBs remained completely VF-free (Fisher exact test, P=0.002). The hydroquinidine dose (750±175 versus 667±103 mg/d) and the follow-up duration (3.0±0.8 versus 7.4±3.9 years) were similar in arrhythmogenic and nonarrhythmogenic test groups, respectively. A Purkinje fiber origin of the ScPVCs was confirmed for 31 of the 33 patients who underwent catheter ablation of VF triggers.We show that pharmacological tests can induce ScPVCs in 56% of patients with ScPVC-related IVF. This incidence is higher than in a previous study,5 as the present group consists of patients with documented spontaneous ScPVCs. The SCB test had the highest yield (48%), whereas catecholamines could be arrhythmogenic in some individual patients. This proarrhythmic effect of SCBs on Purkinje excitability is likely mediated by reported effects on potassium and calcium channel function and on calcium handling.5 Functional and genetic studies are needed to elucidate the specific pathophysiological mechanism at work in this phenotype. Regardless of its exact mechanism, the arrhythmogenic response described here could become a pharmacological test for the subset of patients at risk in a malignant pathology critically lacking a diagnostic test. If confirmed by additional studies, these findings could allow detection of a susceptibility to ScPVCs in patients with unexplained syncope or cardiac arrest, or those with family sudden death.Finally, the lower therapeutic efficacy of quinidine among patients with arrhythmogenic SCBs is intriguing because quinidine is currently the most effective drug in IVF. This negative correlation may be mechanistically related to the fact that quinidine not only blocks the transient outward potassium channels but is also an SCB. Alternatively, this observation could reflect patient-selection bias because patients with quinidine-resistant IVF were more likely to be referred to the centers participating in this study.In conclusion, this study demonstrates that ScPVCs can be replicated by pharmacological testing, notably with SCBs, in a significant subset of ScPVC-related IVF.Article InformationSources of FundingThis work was supported by the French National Research Agency (ANR-10-IAHU04-LIRYC) and the Leducq Foundation (RHYTHM network, 16CVD02).Nonstandard Abbreviations and AcronymsIVFidiopathic ventricular fibrillationSCBsodium channel blockerScPVCsshort-coupled premature ventricular complexesVFventricular fibrillationDisclosures None.FootnotesFor Sources of Funding and Disclosures, see page 72.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Michel Haissaguerre, MD, Hopital Cardiologique Haut-Leveque, Avenue de Magellan, Bordeaux, 33604, France. Email michel.[email protected]frReferences1. Viskin S, Belhassen B. Idiopathic ventricular fibrillation.Am Heart J. 1990; 120:661–671. doi: 10.1016/0002-8703(90)90025-sCrossrefMedlineGoogle Scholar2. Steinberg C, Davies B, Mellor G, Tadros R, Laksman ZW, Roberts JD, Green M, Alqarawi W, Angaran P, Healey J, et al. Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry.Eur Heart J. 2021; 42:2827–2838. doi: 10.1093/eurheartj/ehab275CrossrefMedlineGoogle Scholar3. Groeneveld SA, Van der Ree MH, Mulder BA, Balt J, Wilde AAM, Postema PG, Hassink RJ. Prevalence of short-coupled ventricular fibrillation in a large cohort of Dutch patients with idiopathic ventricular fibrillation.Circulation. 2022; 145:1437–1439. doi: 10.1161/CIRCULATIONAHA.121.057878LinkGoogle Scholar4. Haïssaguerre M, Duchateau J, Dubois R, Hocini M, Cheniti G, Sacher F, Lavergne T, Probst V, Surget E, Vigmond E, et al. Idiopathic ventricular fibrillation: role of Purkinje system and microstructural myocardial abnormalities.JACC Clin Electrophysiol. 2020; 6:591–608. doi: 10.1016/j.jacep.2020.03.010CrossrefMedlineGoogle Scholar5. Escande W, Gourraud JB, Haissaguerre M, Gandjbakhch E, Lavergne T, Martins R, Cheniti G, Krisai P, Hermida JS, Maury P, et al. Malignant Purkinje ectopy induced by sodium channel blockers.Heart Rhythm J. 2022; 19:1595–1603. doi: 10.1016/j.hrthm.2022.06.034CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc.This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.https://doi.org/10.1161/CIRCULATIONAHA.122.063578PMID: 37399260 Originally publishedJuly 3, 2023 KeywordsPurkinje fiberssodium channel blockersventricular premature complexesventricular fibrillationPDF download Advertisement SubjectsArrhythmiasElectrophysiologySudden Cardiac DeathVentricular Fibrillation