Identification of Cx43 variants predisposing to ventricular fibrillation in the acute phase of ST-elevation myocardial infarction
Philippe Chevalier, Adrien Moreau, Francis Bessière, Sylvain Richard, Mohamed Chahine, Gilles Millat, Elodie Morel, Franck Paganelli, Nathalie Lesavre, Leslie Placide, François Montestruc, Bénédicte Ankou, Rosa Doñate Puertas, Babken Asatryan, Antoine Delinière, MAP-IDM Investigators, Philippe Chevalier, Adrien Moreau, Francis Bessière, Sylvain Richard, Mohamed Chahine, Gilles Millat, Elodie Morel, Franck Paganelli, Nathalie Lesavre, Leslie Placide, François Montestruc, Bénédicte Ankou, Rosa Doñate Puertas, Babken Asatryan, Antoine Delinière, MAP-IDM Investigators
Abstract
Aims: Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF.
Methods and results: The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16-0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis.
Conclusion: Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI.
Clinical trial registration: Clinical Trial Registration: https://ichgcp.net/clinical-trials-registry/NCT00859300.
Keywords: Acute ventricular fibrillation; Connexin 43; GJA1 variants; ST-elevation myocardial infarction (STEMI); Sudden cardiac death.
Conflict of interest statement
Conflict of interest: None declared.
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Source: PubMed