Wearable electrocardiogram devices in patients with congenital long QT syndrome: The SMART-QT study.

BACKGROUND: In patients with congenital long QT syndrome (LQTS), the risk of ventricular arrhythmia is correlated with the duration of the corrected QT interval and the changes in the ST-T wave pattern on the 12-lead surface electrocardiogram (12L-ECG). Remote monitoring of these variables could be useful. AIM: To evaluate the abilities of two wearable electrocardiogram devices (Apple Watch and KardiaMobile 6L) to provide reliable electrocardiograms in terms of corrected QT interval and ST-T wave patterns in patients with LQTS. METHODS: In a prospective multicentre study (ClinicalTrials.gov identifier: NCT04728100), a 12L-ECG, a 6-lead KardiaMobile 6L electrocardiogram and two single-lead Apple Watch electrocardiograms were recorded in patients with LQTS. The corrected QT interval and ST-T wave patterns were evaluated manually. RESULTS: Overall, 98 patients with LQTS were included; 12.2% were children and 92.8% had a pathogenic variant in an LQTS gene. The main genotypes were LQTS type 1 (40.8%), LQTS type 2 (36.7%) and LQTS type 3 (7.1%); rarer genotypes were also represented. When comparing the ST-T wave patterns obtained with the 12L-ECG, the level of agreement was moderate with the Apple Watch (k=0.593) and substantial with the KardiaMobile 6L (k=0.651). Regarding the corrected QT interval, the correlation with 12L-ECG was strong for the Apple Watch (r=0.703 in lead II) and moderate for the KardiaMobile 6L (r=0.593). There was a slight overestimation of corrected QT interval with the Apple Watch and a subtle underestimation with the KardiaMobile 6L. CONCLUSIONS: In patients with LQTS, the corrected QT interval and ST-T wave patterns obtained with the Apple Watch and the KardiaMobile 6L correlated with the 12L-ECG. Although wearable electrocardiogram devices cannot replace the 12L-ECG for the follow-up of these patients, they could be interesting additional monitoring tools.

Position paper on sustainability in cardiac pacing and electrophysiology from the Working Group of Cardiac Pacing and Electrophysiology of the French Society of Cardiology.

Sustainability in healthcare, particularly within the domain of cardiac electrophysiology, assumes paramount importance for the near future. The escalating environmental constraints encountered necessitate a proactive approach. This position paper aims to raise awareness among physicians, spark critical inquiry and identify potential solutions to enhance the sustainability of our practice. Reprocessing of single-use medical devices has emerged as a potential solution to mitigate the environmental impact of electrophysiology procedures, while also offering economic advantages. However, reprocessing remains unauthorized in certain countries. In regions where it is possible, stringent regulatory standards must be adhered to, to ensure patient safety. It is essential that healthcare professionals, policymakers and manufacturers collaborate to drive innovation, explore sustainable practices and ensure that patient care remains uncompromised in the face of environmental challenges. Ambitious national/international programmes of disease prevention should be the cornerstone of the strategy. It is equally vital to implement immediate actions, as delineated in this position paper, to bring about tangible change quickly.

Ventricular Arrhythmias in Adults With Congenital Heart Disease, Part I: JACC State-of-the-Art Review.

Patients with congenital heart disease associated with a higher risk for ventricular arrhythmias (VA) and sudden cardiac death (SCD) can be divided conceptually into those with discrete mechanisms for reentrant monomorphic ventricular tachycardia (VT) (Group A) and those with more diffuse substrates (Group B). Part I of this review addresses Group A lesions, which predominantly consist of tetralogy of Fallot and related variants. Well-defined anatomic isthmuses for reentrant monomorphic VT are interposed between surgical scars and the pulmonary or tricuspid annulus. The most commonly implicated critical isthmus for VT is the conal septum that divides subpulmonary from subaortic outlets. Programmed ventricular stimulation can be helpful in risk stratification. Although catheter ablation is not generally considered an alternative to the implantable cardioverter-defibrillator (ICD) for prevention of SCD, emerging data suggest that there is a subset of carefully selected patients who may not require ICDs after successful monomorphic VT ablation.

Ventricular Arrhythmias in Adults With Congenital Heart Disease, Part II: JACC State-of-the-Art Review.

There are marked variations in the incidence of sudden cardiac death (SCD) and in the substrates for ventricular arrhythmias (VAs) across the gamut of congenital heart defects. In this 2-part review, patients with higher-risk forms of congenital heart disease (CHD) were conceptually categorized into those with discrete anatomic isthmuses for macro-reentrant ventricular tachycardia (VT) (Group A) and those with more diffuse or less well-defined substrates (Group B) that include patchy or extensive myocardial fibrosis. The latter category encompasses CHD lesions such as Ebstein anomaly, transposition of the great arteries with a systemic right ventricle (RV), and congenital aortic stenosis. For Group B patients, polymorphic VT and ventricular fibrillation account for a higher proportion of VA. The prognostic value of programmed ventricular stimulation is less well established, and catheter ablation plays a less prominent role. As cardiomyopathies evolve over time, pathophysiological mechanisms for VA among Groups A and B become increasingly blurred.

Catheter ablation of atrial tachyarrhythmias in patients with atrioventricular septal defect.

AIMS: The incidence of atrial tachyarrhythmias is high in patients with atrioventricular septal defect (AVSD). No specific data on catheter ablation have been reported so far in this population. We aimed to describe the main mechanisms of atrial tachyarrhythmias in patients with AVSD and to analyse outcomes after catheter ablation. METHODS AND RESULTS: This observational multi-centric cohort study enrolled all patients with AVSD referred for catheter ablation of an atrial tachyarrhythmia at six tertiary centres from 2004 to 2022. The mechanisms of the different tachyarrhythmias targeted were described and outcomes were analysed. Overall, 56 patients (38.1 ± 17.4 years, 55.4% females) were included. A total of 87 atrial tachyarrhythmias were targeted (mean number of 1.6 per patient). Regarding main circuits involved, a cavo-annular isthmus-dependent intra-atrial re-entrant tachycardia (IART) was observed in 41 (73.2%) patients and an IART involving the right lateral atriotomy in 10 (17.9%) patients. Other tachyarrhythmias with heterogeneous circuits were observed in 13 (23.2%) patients including 11 left-sided and 4 right-sided tachyarrhythmias. Overall, an acute success was achieved in 54 (96.4%) patients, and no complication was reported. During a mean follow-up of 2.8 ± 3.8 years, 22 (39.3%) patients had at least one recurrence. Freedom from atrial tachyarrhythmia recurrences was 77.5% at 1 year. Among 15 (26.8%) patients who underwent repeated ablation procedures, heterogeneous circuits including bi-atrial and left-sided tachyarrhythmias were more frequent. CONCLUSION: In patients with AVSD, most circuits involve the cavo-annular isthmus, but complex mechanisms are frequently encountered in patients with repeated procedures. The acute success rate is excellent, although recurrences remain common during follow-up.

Sinus rhythm QRS morphology reflects right ventricular activation and anatomical ventricular tachycardia isthmus conduction in repaired tetralogy of Fallot.

BACKGROUND: Patients with repaired tetralogy of Fallot (TOF) are at risk for ventricular tachycardia (VT) related to well-described anatomical isthmuses. OBJECTIVE: The purpose of this study was to explore QRS morphology as an indicator of anatomical isthmus conduction. METHODS: Patients with repaired TOF and complete right bundle branch block referred for transcatheter pulmonary valve replacement (PVR) or presenting with sustained VT underwent comprehensive 3-dimensional mapping in sinus rhythm. Electrocardiographic characteristics were compared to right ventricular (RV) activation and anatomical isthmus conduction properties. RESULTS: Twenty-two patients (19 pre-pulmonary valve replacement and 3 clinical VT) underwent comprehensive 3-dimensional mapping (median 39 years; interquartile range [IQR] 27-48 years; 12 [55%] male). Septal RV activation (median 40 ms; IQR 34-46 ms) corresponded to the nadir in lead V1 and free wall activation (median 71 ms; IQR 64-81 ms) to the transition point in the upstroke of the R' wave. Patients with isthmus block between the pulmonary annulus and the ventricular septal defect patch and between the ventricular septal defect patch and the tricuspid annulus (when present), were more likely to demonstrate lower amplitude R' waves in lead V1 (5.8 mV vs 9.4 mV; P = .005), QRS fragmentation in lead V1 (15 [94%] vs 2 [13%]; P < .001), and terminal S waves in lead aVF (15 [94%] vs 6 [40%]; P < .001) than those with intact conduction. During catheter ablation, these QRS changes developed during isthmus block. CONCLUSION: For patients with repaired TOF, the status of septal isthmus conduction was evident from sinus rhythm QRS morphology. Low-amplitude, fragmented R' waves in lead V1 and terminal S waves in the inferior leads were related to septal isthmus conduction abnormalities, providing a mechanistic link between RV activation and common electrocardiographic findings.

Rationale and Design of the Multicenter Catheter Ablation of Ventricular Tachycardia Before Transcatheter Pulmonary Valve Replacement in Repaired Tetralogy of Fallot Study.

Patients with repaired tetralogy of Fallot are at elevated risk for ventricular arrhythmia and sudden cardiac death. Over the past decade, the pathogenesis and natural history of ventricular tachycardia has become increasingly understood, and catheter ablation has emerged as an effective treatment modality. Concurrently, there has been great progress in the development of a versatile array of transcatheter valves that can be placed in the native right ventricular outflow tract for the treatment of long-standing pulmonary regurgitation. Although such valve platforms may eliminate the need for repeat cardiac operations, they may also impede catheter access to the myocardial substrates responsible for sustained macro-reentrant ventricular tachycardia. This manuscript provides the rationale and design of a recently devised multicenter study that will examine the clinical outcomes of a uniform, preemptive strategy to eliminate ventricular tachycardia substrates before transcatheter pulmonary valve implantation in patients with tetralogy of Fallot.

Subcutaneous Implantable Cardioverter-Defibrillators in Patients With Congenital Heart Disease.

BACKGROUND: Very few data have been published on the use of subcutaneous implantable cardioverter-defibrillators (S-ICDs) in patients with congenital heart disease (CHD). OBJECTIVES: The aim of this study was to analyze outcomes associated with S-ICDs in patients with CHD. METHODS: This nationwide French cohort including all patients with an S-ICD was initiated in 2020 by the French Institute of Health and Medical Research. Characteristics at implantation and outcomes were analyzed in patients with CHD. RESULTS: From October 12, 2012, to December 31, 2019, among 4,924 patients receiving an S-ICD implant in 150 centers, 101 (2.1%) had CHD. Tetralogy of Fallot, univentricular heart, and dextro-transposition of the great arteries represented almost one-half of the population. Patients with CHD were significantly younger (age 37.1 ± 15.4 years vs 50.1 ± 14.9 years; P < 0.001), more frequently female (37.6% vs 23.0%; P < 0.001), more likely to receive an S-ICD for secondary prevention (72.3% vs 35.9%; P < 0.001), and less likely to have severe systolic dysfunction of the systemic ventricle (28.1% vs 53.1%; P < 0.001). Over a mean follow-up period of 1.9 years, 16 (15.8%) patients with CHD received at least 1 appropriate shock, with all shocks successfully terminating the ventricular arrhythmia. The crude risk of appropriate S-ICD shock was twice as high in patients with CHD compared with non-CHD patients (annual incidences of 9.0% vs 4.4%; HR: 2.1; 95% CI: 1.3-3.4); however, this association was no longer significant after propensity matching (especially considering S-ICD indication, P = 0.12). The burden of all complications (HR: 1.2; 95% CI: 0.7-2.1; P = 0.4) and inappropriate shocks (HR: 0.9; 95% CI: 0.4-2.0; P = 0.9) was comparable in both groups. CONCLUSIONS: In this nationwide study, patients with CHD represented 2% of all S-ICD implantations. Our findings emphasize the effectiveness and safety of S-ICD in this particularly high-risk population. (S-ICD French Cohort Study [HONEST]; NCT05302115).

Heart transplantation as a rescue strategy for patients with refractory electrical storm.

AIMS: Heart transplantation (HT) can be proposed as a therapeutic strategy for patients with severe refractory electrical storm (ES). Data in the literature are scarce and based on case reports. We aimed at determining the characteristics and survival of patients transplanted for refractory ES. METHODS AND RESULTS: Patients registered on HT waiting list during the following days after ES and eventually transplanted, from 2010 to 2021, were retrospectively included in 11 French centres. The primary endpoint was in-hospital mortality. Forty-five patients were included [82% men; 55.0 (47.8-59.3) years old; 42.2% and 26.7% non-ischaemic dilated or ischaemic cardiomyopathies, respectively]. Among them, 42 (93.3%) received amiodarone, 29 received (64.4%) beta blockers, 19 (42.2%) required deep sedation, 22 had (48.9%) mechanical circulatory support, and 9 (20.0%) had radiofrequency catheter ablation. Twenty-two patients (62%) were in cardiogenic shock. Inscription on wait list and transplantation occurred 3.0 (1.0-5.0) days and 9.0 (4.0-14.0) days after ES onset, respectively. After transplantation, 20 patients (44.4%) needed immediate haemodynamic support by extracorporeal membrane oxygenation (ECMO). In-hospital mortality rate was 28.9%. Predictors of in-hospital mortality were serum creatinine/urea levels, need for immediate post-operative ECMO support, post-operative complications, and surgical re-interventions. One-year survival was 68.9%. CONCLUSION: Electrical storm is a rare indication of HT but may be lifesaving in those patients presenting intractable arrhythmias despite usual care. Most patients can be safely discharged from hospital, although post-operative mortality remains substantial in this context of emergency transplantation. Larger studies are warranted to precisely determine those patients at higher risk of in-hospital mortality.

Management for atrial arrhythmias in adults with complex congenital heart disease.

INTRODUCTION: The prevalence of congenital heart disease (CHD) is steadily increasing among adults. Atrial arrhythmias are frequent late complications and are associated with substantial morbidity. AREAS COVERED: We discuss key considerations regarding management strategies for atrial arrhythmias in common forms of CHD and offer future perspectives. EXPERT OPINION: An appreciation of the types of atrial arrhythmias encountered in patients with diverse forms of CHD, combined with the growing clinical and research experience, appears to be yielding favorable results, whereas little progress has been made on the antiarrhythmic drug front, indications for anticoagulation have considerably evolved. Advances in interventional techniques have propelled catheter ablation to the forefront to treat a variety of atrial arrhythmias in patients with complex CHD. Nevertheless, much work remains to be done to elucidate underlying pathophysiology, triggers, and critical substrates that predispose patients with specific CHD malformations to develop atrial arrhythmias. Future advances could allow for the implementation of individualized, possibly preemptive, approaches to arrhythmia management. With the prevalence of atrial fibrillation on the rise in the aging population with CHD, concerted efforts must be directed toward optimizing patient selection for catheter ablation as well as refining procedural aspects to safely and more effectively improve long-term outcomes.

Systematic Electrophysiological Study Prior to Pulmonary Valve Replacement in Tetralogy of Fallot: A Prospective Multicenter Study.

BACKGROUND: Ventricular arrhythmias and sudden death are recognized complications in tetralogy of Fallot. Electrophysiological studies (EPS) before pulmonary valve replacement (PVR), the most common reintervention in tetralogy of Fallot, could potentially inform therapy to improve arrhythmic outcomes. METHODS: A prospective multicenter study was conducted to systematically assess EPS with programmed ventricular stimulation in patients with tetralogy of Fallot referred for PVR from January 2020 to December 2021. A standardized stimulation protocol was used across all centers. RESULTS: A total of 120 patients were enrolled, mean age 39.2±14.5 years, 53.3% males. Sustained ventricular tachycardia was induced in 27 (22.5%) patients. When identifiable, the critical isthmus most commonly implicated (ie, in 90.0%) was between the ventricular septal defect patch and pulmonary annulus. Factors independently associated with inducible ventricular tachycardia were history of atrial arrhythmia (odds ratio, 8.56 [95% CI, 2.43-34.73]) and pulmonary annulus diameter >26 mm (odds ratio, 5.05 [95% CI, 1.47-21.69]). The EPS led to a substantial change in management in 23 (19.2%) cases: 18 (15.0%) had catheter ablation, 3 (2.5%) surgical cryoablation during PVR, and 9 (7.5%) defibrillator implantation. Repeat EPS 5.1 (4.8-6.2) months after PVR was negative in 8 of 9 (88.9%) patients. No patient experienced a sustained ventricular arrhythmia during 13 (6.1-20.1) months of follow-up. CONCLUSIONS: Systematically performing programmed ventricular stimulation in patients with tetralogy of Fallot referred for PVR yields a high rate of inducible ventricular tachycardia and carries the potential to alter management. It remains to be determined whether a standardized treatment approach based on the results of EPS will translate into improved outcomes. REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT04205461; Unique identifier: NCT04205461.

Impact of Neuroeffector Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia.

Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for ADRB1 Arg389Gly and Ser49Gly, ADRB2 Gln27Glu and Gly16Arg, and ADRA2C Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes. Of 156 investigated genetic constructs, 19 (12.2%) exhibited significantly (P<0.05) reduced association with incident VF, and none was associated with increased VF risk except for ADRB1 Gly389 homozygotes in the subset of patients not receiving ß-blockers. ADRB1 Gly49 carriers (prevalence 23.0%) had an OR (95% CI) of 0.70 (0.49-0.98), and the ADRA2C 322-325 deletion (Del) carriers (prevalence 13.5%) had an OR of 0.61 (0.39-0.94). When present in genotype combinations (8 each), both ADRB1 Gly49 carriers (OR, 0.67 [0.56-0.80]) and ADRA2C Del carriers (OR, 0.57 [0.45- 0.71]) were associated with reduced VF risk. Conclusions In ST-segment-elevation myocardial infarction, the adrenergic receptor minor alleles ADRB1 Gly49, whose encoded receptor undergoes enhanced agonist-mediated internalization and ß-arrestin interactions leading to cardioprotective biased signaling, and ADRA2C Del322-325, whose receptor causes disinhibition of norepinephrine release, are associated with a lower incidence of VF. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT00859300.

Spironolactone as a Potential New Treatment to Prevent Arrhythmias in Arrhythmogenic Cardiomyopathy Cell Model.

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic disease associated with ventricular arrhythmias in patients. The occurrence of these arrhythmias is due to direct electrophysiological remodeling of the cardiomyocytes, namely a reduction in the action potential duration (APD) and a disturbance of Ca2+ homeostasis. Interestingly, spironolactone (SP), a mineralocorticoid receptor antagonist, is known to block K+ channels and may reduce arrhythmias. Here, we assess the direct effect of SP and its metabolite canrenoic acid (CA) in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) of a patient bearing a missense mutation (c.394C>T) in the DSC2 gene coding for desmocollin 2 and for the amino acid replacement of arginine by cysteine at position 132 (R132C). SP and CA corrected the APD in the muted cells (vs. the control) in linking to a normalization of the hERG and KCNQ1 K+ channel currents. In addition, SP and CA had a direct cellular effect on Ca2+ homeostasis. They reduced the amplitude and aberrant Ca2+ events. In conclusion, we show the direct beneficial effects of SP on the AP and Ca2+ homeostasis of DSC2-specific hiPSC-CMs. These results provide a rationale for a new therapeutical approach to tackle mechanical and electrical burdens in patients suffering from ACM.

Collaborative work in a complex case of Fontan for treating intra-atrial reentrant tachycardia and severe aortic stenosis: a case report.

Background: Intra-atrial reentrant tachycardia (IART) is a frequent arrhythmia in patients with Fontan circulation. Although its supraventricular origin, such arrhythmia can be poorly tolerated as it leads to haemodynamic impairment. Concomitant assessment of pressure/volume overload of cardiac chambers due to valvular disease or residual shunts is necessary. Case summary: We report the case of a 33-year-old male with Fontan extracardiac conduit, suffering from IART with initial poor haemodynamic tolerance. He had a medical history of pulmonary atresia with intact ventricular septum and Type 0 bicuspid aortic valve, with a total of four cardiac surgeries. Echocardiography demonstrated a severe impairment of the univentricular ejection fraction and a critical aortic stenosis. Given the limited medical treatment options of the arrhythmia and the risks of another heart surgery, both IART ablation and transcatheter aortic valve replacement (TAVR) were performed during the same procedure. The IART critical isthmus located in the antero-lateral region of the extracardiac conduit was effectively treated with radiofrequency. Rapid pacing during TAVR was provided by a catheter placed in the unique ventricle via a transconduit puncture. The aortic valve was deployed with minimal para-valvular regurgitation and a satisfactory transvalvular gradient. At follow-up, the univentricular ejection fraction normalized and no arrhythmic episode was recorded in absence of anti-arrhythmic drugs. Discussion: This case highlights the need of a collaborative approach for treating complex cases of adult congenital heart disease, suffering from both electrophysiological and haemodynamic disorders. This combination offered an elegant and safest solution for treating concomitantly a life-threatening arrhythmia and an aortic stenosis.

Carbon footprint of atrial fibrillation catheter ablation.

AIMS: Climate change represents the biggest global health threat of the 21st century. Health care system is itself a large contributor to greenhouse gas (GHG) emissions. In cardiology, atrial fibrillation (AF) catheter ablation is an increasing activity using numerous non-reusable materials that could contribute to GHG emission. Determining a detailed carbon footprint analysis of an AF catheter ablation procedure allows the identification of the main polluting sources that give opportunities for reduction of environmental impact. To assess the carbon footprint of AF catheter ablation procedure. To determine priority actions to decrease pollution. METHODS AND RESULTS: An eco-audit method used to predict the GHG emission of an AF catheter ablation procedure was investigated. Two workstations were considered including surgery and anaesthesia. In the operating room, every waste produced by single-use medical devices, pharmaceutical drugs, and energy consumption during intervention were evaluated. All analyses were limited to the operating room. Thirty procedures were analysed over a period of 8 weeks: 18 pulmonary veins isolation RF ablations, 7 complex RF procedures including PVI, roof and mitral isthmus lines, ethanol infusion of the Marshall vein and cavo tricuspid isthmus line, and 5 pulmonary vein isolation with cryoballoon. The mean emission during AF catheter ablation procedures was 76.9 kg of carbon dioxide equivalent (CO2-e). The operating field accounted for 75.4% of the carbon footprint, while only 24.6% for the anaesthesia workstation. On one hand, material production and manufacturing were the most polluting phases of product life cycle which, respectively, represented 71.3% (54.8 kg of CO2-e) and 17.0% (13.1 kg of CO2-e) of total pollution. On the other hand, transport contributed in 10.6% (8.1 kg of CO2-e), while product use resulted in 1.1% (0.9 kg of CO2-e) of GHG production. Electrophysiology catheters were demonstrated to be the main contributors of environmental impact with 29.9 kg of CO2-e (i.e. 38.8%). Three dimensional mapping system and electrocardiogram patches were accounting for 6.8 kg of CO2-e (i.e. 8.8% of total). CONCLUSION: AF catheter ablation involves a mean of 76.9 kg of CO2-e. With an estimated 600 000 annual worldwide procedures, the environmental impact of AF catheter ablation activity is estimated equal to 125 tons of CO2 emission each day. It represents an equivalent of 700 000 km of car ride every day. Electrophysiology catheters and patches are the main contributors of the carbon footprint. The focus must be on reducing, reusing, and recycling these items to limit the impact of AF ablation on the environment. A road map of steps to implement in different time frames is proposed.

Identification of Cx43 variants predisposing to ventricular fibrillation in the acute phase of ST-elevation myocardial infarction.

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://clinicaltrials.gov/ct2/show/NCT00859300.