Laurita, Kenneth R.Piktel, Joseph S.Irish, LakenNassal, MichelleCheng, AureliaMcCauley, MatthewPawlowski, GaryDennis, Adrienne T.Suen, YiAlmahameed, SufianZiv, OhazGourdie, Robert G.Wilson, Lance D.2025-10-012025-10-012024-07-012405-500XS2405-500X(24)00262-7 (PII)https://hdl.handle.net/10919/137874Background: Ventricular tachycardia (VT)/ventricular fibrillation (VF) rearrest after successful resuscitation is common, and survival is poor. A mechanism of VT/VF, as demonstrated in ex vivo studies, is when repolarization alternans becomes spatially discordant (DIS ALT), which can be enhanced by impaired gap junctions (GJs). However, in vivo spontaneous DIS ALT–induced VT/VF has never been demonstrated, and the effects of GJ on DIS ALT and VT/VF rearrest are unknown. Objectives: This study aimed to determine whether spontaneous VT/VF rearrest induced by DIS ALT occurs in vivo, and if it can be suppressed by preserving Cx43-mediated GJ coupling and/or connectivity. Methods: We used an in vivo porcine model of resuscitation from ischemia-induced cardiac arrest combined with ex vivo optical mapping in porcine left ventricular wedge preparations. Results: In vivo, DIS ALT frequently preceded VT/VF and paralleled its incidence at normal (37°C, n = 9) and mild hypothermia (33°C, n = 8) temperatures. Maintaining GJs in vivo with rotigaptide (n = 10) reduced DIS ALT and VT/VF incidence, especially during mild hypothermia, by 90% and 60%, respectively (P < 0.001; P < 0.013). Ex vivo, both rotigaptide (n = 5) and αCT11 (n = 7), a Cx43 mimetic peptide that promotes GJ connectivity, significantly reduced DIS ALT by 60% and 100%, respectively (P < 0.05; P < 0.005), and this reduction was associated with reduced intrinsic heterogeneities of action potential duration rather than changes in conduction velocity restitution. Conclusions: These results provide the strongest in vivo evidence to date suggesting a causal relationship between spontaneous DIS ALT and VT/VF in a clinically realistic scenario. Furthermore, our results suggest that preserving GJs during resuscitation can suppress VT/VF rearrest.Pages 1271-1286application/pdfenCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalcardiac alternansconnexin 43gap junctionresuscitationsudden cardiac arrestventricular fibrillation/tachycardiaGap JunctionsAnimalsSwineTachycardia, VentricularVentricular FibrillationHeart ArrestDisease Models, AnimalOligopeptidesConnexin 43Action PotentialsFemaleMaleArticle - Refereedhttps://doi.org/10.1016/j.jacep.2024.03.027107Gourdie, Robert [0000-0001-6021-0796]387529592405-5018