Noninvasive electrocardiographic risk factors for sudden cardiac death in dilated ca rdiomyopathy: is ambulatory electrocardiography still relevant?

Risk stratification for sudden cardiac death in dilated cardiomyopathy is a field of constant debate, and the currently proposed criteria have been widely questioned due to their low positive and negative predictive value. In this study, we conducted a systematic review of the literature utilizing the PubMed and Cochrane library platforms, in order to gain insight about dilated cardiomyopathy and its arrhythmic risk stratification utilizing noninvasive risk markers derived mainly from 24 h electrocardiographic monitoring. The obtained articles were reviewed in order to register the various electrocardiographic noninvasive risk factors used, their prevalence, and their prognostic significance in dilated cardiomyopathy. Premature ventricular complexes, nonsustained ventricular tachycardia, late potentials on Signal averaged electrocardiography, T wave alternans, heart rate variability and deceleration capacity of the heart rate, all have both some positive and negative predictive value to identify patients in higher likelihood for ventricular arrhythmias and sudden cardiac death. Corrected QT, QT dispersion, and turbulence slope-turbulence onset of heart rate have yet to establish a predictive correlation in the literature. Although ambulatory electrocardiographic monitoring is frequently used in clinical practice in DCM patients, no single risk marker can be used for the selection of patients at high-risk for malignant ventricular arrhythmic events and sudden cardiac death who could benefit from the implantation of a defibrillator. More studies are needed in order to establish a risk score or a combination of risk factors with the purpose of selecting high-risk patients for ICD implantation in the context of primary prevention.

Risk assessment of post-myocardial infarction patients with preserved ejection fraction using 45-min short resting Holter electrocardiographic recordings.

BACKGROUND: Risk stratification for sudden cardiac death in post-myocardial infarction (post-MI) patients remains a challenging task. Several electrocardiographic noninvasive risk factors (NIRFs) have been associated with adverse outcomes and were used to refine risk assessment. This study aimed to evaluate the performance of NIRFs extracted from 45-min short resting Holter ECG recordings (SHR), in predicting ventricular tachycardia inducibility with programmed ventricular stimulation (PVS) in post-MI patients with preserved left ventricular ejection fraction (LVEF). METHODS: We studied 99 post-MI ischemia-free patients (mean age: 60.5 ± 9.5 years, 86.9% men) with LVEF ≥40%, at least 40 days after revascularization. All the patients underwent PVS and a high-resolution SHR. The following parameters were evaluated: mean heart rate, ventricular arrhythmias (premature ventricular complexes, couplets, tachycardias), QTc duration, heart rate variability (HRV), deceleration capacity, heart rate turbulence, late potentials, and T-wave alternans. RESULTS: PVS was positive in 24 patients (24.2%). HRV, assessed by the standard deviation of normal-to-normal R-R intervals (SDNN), was significantly decreased in the positive PVS group (42 ms vs. 51 ms, p = .039). SDNN values <50 ms were also associated with PVS inducibility (OR 3.081, p = .032 in univariate analysis, and 4.588, p = .013 in multivariate analysis). No significant differences were identified for the other NIRFs. The presence of diabetes, history of ST-elevation MI (STEMI) and LVEF <50% were also important predictors of positive PVS. CONCLUSIONS: HRV assessed from SHR, combined with other noninvasive clinical and echocardiographic variables (diabetes, STEMI history, LVEF), can provide an initial, practical, and rapid screening tool for arrhythmic risk assessment in post-MI patients with preserved LVEF.

Association of non-invasive electrocardiographic risk factors with left ventricular systolic function in post-myocardial infarction patients with mildly reduced or preserved ejection fraction: Insights from the PRESERVE-EF study.

BACKGROUND: Electrocardiographic non-invasive risk factors (NIRFs) have an important role in the arrhythmic risk stratification of post-myocardial infarction (post-MI) patients with preserved or mildly reduced left ventricular ejection fraction (LVEF). However, their specific relation to left ventricular systolic function remains unclear. We aimed to evaluate the association between NIRFs and LVEF in the patients included in the PRESERVE-EF trial. METHODS: We studied 575 post-MI ischemia-free patients with LVEF≥40% (mean age: 57.0 ± 10.4 years, 86.2% men). The following NIRFs were evaluated: premature ventricular complexes, non-sustained ventricular tachycardia (NSVT), late potentials (LPs), prolonged QTc, increased T-wave alternans, reduced heart rate variability, and abnormal deceleration capacity with abnormal turbulence. RESULTS: There was a statistically significant relationship between LPs (Chi-squared = 4.975; p < .05), nsVT (Chi-squared = 5.749, p < .05), PVCs (r= -.136; p < .01), and the LVEF. The multivariate linear regression analysis showed that LPs (p = .001) and NSVT (p < .001) were significant predictors of the LVEF. The results of the multivariate logistic regression analysis indicated that LPs (OR: 1.76; 95% CI: 1.02-3.05; p = .004) and NSVT (OR: 2.44; 95% CI: 1.18-5.04; p = .001) were independent predictors of the mildly reduced LVEF: 40%-49% versus the preserved LVEF: ≥50%. CONCLUSION: Late potentials and NSVT are independently related to reduced LVEF while they are independent predictors of mildly reduced LVEF versus the preserved LVEF. These findings may have important implications for the arrhythmic risk stratification of post-MI patients with mildly reduced or preserved LVEF.

Noninvasive risk factors for the prediction of inducibility on programmed ventricular stimulation in post-myocardial infarction patients with an ejection fraction ≥40% at risk for sudden cardiac arrest: Insights from the PRESERVE-EF study.

BACKGROUND: In the PRESERVE-EF study, a two-step sudden cardiac death (SCD) risk stratification approach to detect post-myocardial infarction (MI) patients with left ventricle ejection fraction (LVEF) ≥40% at risk for major arrhythmic events (MAEs) was used. Seven noninvasive risk factors (NIRFs) were extracted from a 24-h ambulatory electrocardiography (AECG) and a 45-min resting recording. Patients with at least one NIRF present were referred for invasive programmed ventricular stimulation (PVS) and inducible patients received an Implantable Cardioverter - Defibrillator (ICD). METHODS: In the present study, we evaluated the performance of the NIRFs, as they were described in the PRESERVE-EF study protocol, in predicting a positive PVS. In the PRESERVE-EF study, 152 out of 575 patients underwent PVS and 41 of them were inducible. For the present analysis, data from these 152 patients were analyzed. RESULTS: Among the NIRFs examined, the presence of signal averaged ECG-late potentials (SAECG-LPs) ≥ 2/3 and non-sustained ventricular tachycardia (NSVT) ≥1 eposode/24 h cutoff points were important predictors of a positive PVS study, demonstrating in the logistic regression analysis odds ratios 2.285 (p = .027) and 2.867 (p = .006), respectively. A simple risk score based on the above cutoff points in combination with LVEF < 50% presented high sensitivity but low specificity for a positive PVS. CONCLUSION: Cutoff points of NSVT ≥ 1 episode/24 h and SAECG-LPs ≥ 2/3 in combination with a LVEF < 50% were important predictors of inducibility. However, the final decision for an ICD implantation should be based on a positive PVS, which is irreplaceable in risk stratification.

Syncope associated with supraventricular tachycardia: Diagnostic role of implantable loop recorders.

Syncope represents a relatively uncommon symptom of supraventricular tachycardia (SVT). It is likely that an impaired autonomic vasomotor response to the hemodynamic stress of tachycardia is the determinant of hemodynamic changes leading to cerebral hypoperfusion and syncope. In this regard, tilt-table test may detect abnormalities in the autonomic nervous function and predict the occurrence of syncope during SVT. Electrophysiology studies may reproduce the SVT, distinguish it from other life-threatening ventricular tachyarrhythmias, and exclude other causes of syncope. Not infrequently mixed syncope mechanisms are revealed during the above diagnostic workup raising doubts about the operating mechanism in the clinical setting. In such cases of uncertainty, an implantable loop recorder, providing long-term cardiac monitoring, may play a pivotal role in the establishment of the diagnosis, confirming the association of an arrhythmic event with the symptom. Herein, we present four such cases with recurrent unexplained syncope finally attributed to paroxysmal SVT guiding them to a potentially radical treatment through radiofrequency catheter ablation.

Beneficial Effect of Flecainide Controlled Release on the Quality of Life of Patients with Atrial Fibrillation-the REFLEC-CR Study.

PURPOSE: Atrial fibrillation (AF) is the most common cardiac arrhythmia with a considerable impact on patients' quality of life (QoL). METHODS: This prospective, multicenter, observational study aimed to evaluate the effect of oral treatment with controlled-release (CR) flecainide on AF patients' QoL and treatment compliance during a 12-week period. A total of 70 sites enrolled consecutive patients with paroxysmal (PAF) or persistent AF (PerAF), treated with flecainide CR in the context of a rhythm control strategy. The effect on QoL was assessed by the Canadian Cardiovascular Society Severity of Atrial Fibrillation scale (CCS-SAF). RESULTS: In total, 679 patients (53.2% females, 66 ± 11.7 years, 86.9% PAF) were included. Prior antiarrhythmic medication had been administered in 43.8% of patients. A daily dose of 200 mg was administered to 66.4% of patients by the end of study. Flecainide CR resulted in a significant reduction in the CCS-SAF score (mean (SD)) at the end of the study as compared with baseline (1.32 (0.57) vs 1.64 (0.73), p < 0.0001). Flecainide CR significantly reduced the CCS-SAF score both in PAF (1.27 (0.52) vs 1.61 (0.72), p < 0.0001) as well as in PerAF (1.63(0.77) vs 1.84(0.81), p = 0.017). Overall, 4 (0.6%) patients experienced a total of 6 adverse events during the study period. The compliance to flecainide CR treatment was very high with 93.6% of patients responding that they had not missed any dose during the study period. CONCLUSION: Treatment with flecainide CR significantly improves QoL in both paroxysmal as well as persistent AF patients, with an excellent safety profile and associated patient compliance.

Temporal changes of noninvasive electrocardiographic risk factors for sudden cardiac death in post-myocardial infarction patients with preserved ejection fraction: Insights from the PRESERVE-EF study.

BACKGROUND: Several noninvasive risk factors (NIRFs) have been proposed for sudden cardiac death risk stratification in post-myocardial infarction (post-MI) patients with preserved ejection fraction (EF). However, it remains unclear if these factors change over time. METHODS: We evaluated seven electrocardiographic NIRFs as they were described in the PRESERVE-EF trial in 80 post-MI patients with EF ≥ 40%, at least 40 days after revascularization and 1 year later. RESULTS: Mean patient age was 56 ± 10 years, and 88% were men. Mean EF was 50 ± 5%. The prevalence of (a) positive late potentials (27.5% vs. 28.8%, p = .860), (b) >30 premature ventricular complexes/hour (8.8% vs. 11.3%, p = .598), (c) nonsustained ventricular tachycardia (8.8% vs. 5%, p = .349), (d) standard deviation of normal RR intervals <75 ms (3.8% vs. 3.8%, p = 1.000), (e) QTc derived from 24-hr electrocardiography >440 ms (men) or >450 ms (women) (17.5% vs. 17.5%, p = 1.000), (f) deceleration capacity ≤4.5 ms and heart rate turbulence onset ≥0% and slope ≤2.5 ms (2.5% vs. 3.8%. p = 1.000), and (g) ambulatory T-wave alternans ≥65 µV in two Holter channels (6.3% vs. 6.3%, p = 1.000) were similar between the two measurements. However, five patients (6.3%) without any NIRFs during the first assessment had at least one positive NIRF at the second assessment and six patients (7.5%) with at least one NIRF at baseline had no positive NIRFs at 1 year. CONCLUSIONS: While the prevalence of the examined electrocardiographic NIRFs between the two examinations was similar on a population basis, some patients without NIRFs at baseline developed NIRFs at 1 year and vice versa, highlighting the need for risk factor reassessment during follow-up.

Arrhythmic risk stratification in post-myocardial infarction patients with preserved ejection fraction: the PRESERVE EF study.

AIMS: Sudden cardiac death (SCD) annual incidence is 0.6-1% in post-myocardial infarction (MI) patients with left ventricular ejection fraction (LVEF)≥40%. No recommendations for implantable cardioverter-defibrillator (ICD) use exist in this population. METHODS AND RESULTS: We introduced a combined non-invasive/invasive risk stratification approach in post-MI ischaemia-free patients, with LVEF ≥ 40%, in a multicentre, prospective, observational cohort study. Patients with at least one positive electrocardiographic non-invasive risk factor (NIRF): premature ventricular complexes, non-sustained ventricular tachycardia, late potentials, prolonged QTc, increased T-wave alternans, reduced heart rate variability, abnormal deceleration capacity with abnormal turbulence, were referred for programmed ventricular stimulation (PVS), with ICDs offered to those inducible. The primary endpoint was the occurrence of a major arrhythmic event (MAE), namely sustained ventricular tachycardia/fibrillation, appropriate ICD activation or SCD. We screened and included 575 consecutive patients (mean age 57 years, LVEF 50.8%). Of them, 204 (35.5%) had at least one positive NIRF. Forty-one of 152 patients undergoing PVS (27-7.1% of total sample) were inducible. Thirty-seven (90.2%) of them received an ICD. Mean follow-up was 32 months and no SCDs were observed, while 9 ICDs (1.57% of total screened population) were appropriately activated. None patient without NIRFs or with NIRFs but negative PVS met the primary endpoint. The algorithm yielded the following: sensitivity 100%, specificity 93.8%, positive predictive value 22%, and negative predictive value 100%. CONCLUSION: The two-step approach of the PRESERVE EF study detects a subpopulation of post-MI patients with preserved LVEF at risk for MAEs that can be effectively addressed with an ICD. CLINICALTRIALS.GOV IDENTIFIER: NCT02124018.

Effect of cryoballoon and radiofrequency ablation for pulmonary vein isolation on left atrial function in patients with nonvalvular paroxysmal atrial fibrillation: A prospective randomized study (Cryo-LAEF study).

BACKGROUND: Isolation of the pulmonary veins (PVI) has become a mainstay in atrial fibrillation (AFib) therapy. Lesions in left atrial tissue lead to scar formation and this may affect left atrial function. METHODS: Patients with paroxysmal AFib were randomly assigned in a 1:2 allocation scheme to radiofrequency (RF) ablation or cryoballoon. Real-time three-dimensional echocardiography was performed (under sinus rhythm in all cases) before ablation and at 1 and 3 months to evaluate the left atrial functional indices. The primary outcome measure was change in left atrial ejection fraction (LAEF) at 1 month. RESULTS: 120 patients were randomized (80 to cryoballoon, 40 to RF). The absolute change in LAEF at 1 month was 4.0 (Q1-Q3, -0.1to 7.6)% in the cryoballoon group and -0.8 (Q1-Q3, -1.9 to 0.9)% in the RF group (P < 0.001 for the comparison between groups). At 3 months, the corresponding changes were 6.7 (Q1-Q3, 3.4-11.2)% and 0.7 (Q1-Q3, -0.7 to 3.5)%, respectively (P < 0.001). Overall, the rate of patients with lower LAEF at 3 months compared to baseline was 2.5% in the cryoballoon group and 32.5% in the RF group (P < 0.001). AFib recurrence rate at 6 months was higher in patients with decreased LAEF (odds ratio, 6.2; 95% confidence interval, 2.0-19.5; P = 0.002). CONCLUSION: The Cryo-LAEF study prospectively compared the effects of RF and cryoballoon ablation on left atrial function. Both at 1 and 3 months postablation, LAEF was either improved or stable in both ablation groups.

Coincidental ganglionated plexus modification during radiofrequency pulmonary vein isolation and post-ablation arrhythmia recurrence.

AIMS: Vagal responses (VR) during left atrial ablation for atrial fibrillation (AF) treatment have been reported to be associated with less recurrences, presumably because they are a sign of ganglionated plexi modification. Our objective was to evaluate whether coincidentally elicited VR during left atrial ablation are associated with lower AF recurrence rates. METHODS AND RESULTS: This is a post hoc analysis of a prospective study of 291 patients with paroxysmal AF undergoing radiofrequency pulmonary vein isolation (PVI). Vagal responses were defined as episodes of heart rate <40 bpm or asystole lasting >5 s elicited during energy application. Sixty-eight patients (23.4%) had a VR during ablation. In Kaplan-Meier analysis, mean recurrence-free survival was 449 days (95% confidence interval 411-488) in patients with VR when compared with 435 days (95% confidence interval 415-455) in those without (P = 0.310). The 12-month recurrence rate estimates were 25 and 27%, respectively. In an unadjusted Cox model, VR was associated with an odds ratio for recurrence of 0.77 (95% confidence interval 0.46-1.28). CONCLUSION: Coincidentally elicited VR during radiofrequency PVI in patients with paroxysmal AF do not appear to be related to lower risk of arrhythmia recurrence. This may mean that, even if a VR is truly a sign of coincidental ablation of a ganglionated plexus, this does not necessarily mean that a therapeutic modification has been effected, at least to a degree associated with clinical benefit.

The natural history of multifocal atrial rhythms in elderly outpatients: insights from the "Ikaria study".

BACKGROUND: Multifocal atrial tachycardias confer an adverse prognosis in hospitalized patients. We assessed the prognostic impact of multifocal atrial rhythms (MARs-either chaotic atrial rhythm or multifocal atrial tachycardia/bradycardia) in very elderly outpatients. METHODS: One hundred ten subjects aged 60-74 years, 112 aged 75-89 years, and 61 over 90 years old, were enrolled and prospectively evaluated. Several demographic and clinical characteristic were recorded in all individuals. RESULTS: A high prevalence of MARs was detected in the study population (namely, 6%), which in subjects >90 years was even higher (15%). Individuals with MARs were older, more often female and less active. In multivariate analysis, independent predictors of MARs were age (OR = 1.07, 95% CI: 1.02-1.13, P = 0.01) and female sex (OR = 4.77, 95% CI: 1.23-18.48, P = 0.02). The mortality rate during the follow-up period was 8.4% without differences between age groups (P = 0.209). In particular, mortality rate was 6% in individuals with MARs and 9% in those without (P = 0.72). Mortality was associated with age (OR 1.07, 95% CI: 1.02-1.12, P = 0.005) and history of cardiovascular disease at baseline (OR 4.57, 95% CI: 1.87-11.2 P = 0.001). CONCLUSIONS: Contrary to hospitalized individuals with multifocal atrial tachycardias, MARs were not associated with increased mortality in elderly outpatients in this study.

Aggressive Rhythm Control Strategy in Atrial Fibrillation Patients Presenting at the Emergency Department: The HEROMEDICUS Study Design and Initial Results.

Atrial fibrillation has progressively become a more common reason for emergency department visits, representing 0.5% of presenting reasons. Registry data have indicated that about 60% of atrial fibrillation patients who present to the emergency department are admitted, emphasizing the need for more efficient management of atrial fibrillation in the acute phase. Management of atrial fibrillation in the setting of the emergency department varies between countries and healthcare systems. The most plausible reason to justify a conservative rather than an aggressive strategy in the management of atrial fibrillation is the absence of specific guidelines from diverse societies. Several trials of atrial fibrillation treatment strategies, including cardioversion, have demonstrated that atrial fibrillation in the emergency department can be treated safely and effectively, avoiding admission. In the present study, we present the epidemiology and characteristics of atrial fibrillation patients presenting to the emergency department, as well as the impact of diverse management strategies on atrial-fibrillation-related hospital admissions. Lastly, the design and initial data of the HEROMEDICUS protocol will be presented, which constitutes an electrophysiology-based aggressive rhythm control strategy in patients with atrial fibrillation in the emergency department setting.

Management of dyslipidemia in coronary artery disease: the present and the future.

Coronary artery disease (CAD) remains a leading cause of global morbidity and mortality, necessitating continuous refinement in the management of dyslipidemia, one of its major risk factors, to mitigate cardiovascular risks. Previous studies have proven the critical role of immediate and robust low-density lipoprotein cholesterol (LDL-C) reduction in the aftermath of acute coronary syndrome (ACS). Emphasizing the evidence supporting this approach, we delve into the impact of early intervention on cardiovascular outcomes and propose optimal strategies for achieving rapid LDL-C lowering, while also providing the rationale for early proprotein convertase subtilisin/kexin 9 inhibitor use after an ACS. Given the importance of the residual lipidemic risk, we present an overview of emerging therapeutic avenues poised to reshape dyslipidemia management, such as bempedoic acid, lipoprotein(a) inhibition, ApoC3 modulation, and angiopoietin-like protein 3 targeting. This comprehensive review amalgamates current evidence with future prospects, offering a holistic perspective on the management of dyslipidemia in CAD. By exploring both the urgency for immediate post-ACS LDL-C reduction and the exciting advancements on the horizon, this article provides a roadmap for clinicians navigating the intricate landscape of lipid-lowering therapies in CAD.

Unravelling the effect of renal denervation on glucose homeostasis: more questions than answers?

Renal Denervation (RDN) is an interventional, endovascular procedure used for the management of hypertension. The procedure itself aims to ablate the renal sympathetic nerves and to interrupt the renal sympathetic nervous system overactivation, thus decreasing blood pressure (BP) levels and total sympathetic drive in the body. Recent favorable evidence for RDN resulted in the procedure being included in the recent European Guidelines for the management of Hypertension, while RDN is considered the third pillar, along with pharmacotherapy, for managing hypertension. Sympathetic overactivation, however, is associated with numerous other pathologies, including diabetes, metabolic syndrome and glycemic control, which are linked to adverse cardiovascular health and outcomes. Therefore, RDN, via ameliorating sympathetic response, could be also proven beneficial for maintaining an euglycemic status in patients with cardiovascular disease, alongside its BP-lowering effects. Several studies have aimed, over the years, to provide evidence regarding the pathophysiological effects of RDN in glucose homeostasis as well as investigate the potential clinical benefits of the procedure in glucose and insulin homeostasis. The purpose of this review is, thus, to analyze the pathophysiological links between the autonomous nervous system and glycemic control, as well as provide an overview of the available preclinical and clinical data regarding the effect of RDN in glycemic control.

Ischemia testing and revascularization in patients with monomorphic ventricular tachycardia: A relic of the past?

Testing for myocardial ischemia in patients presenting with sustained monomorphic Ventricular Tachycardia(VT) even without evidence of acute myocardial infarction is a tempting strategy that is frequently utilized in clinical practice. Monomorphic VT is mainly caused by re-entry around chronic myocardial scar and active ischemia has no role in its pathogenesis, thus making testing for ischemia futile, at least in theory. This systematic literature review sought to address the usefulness of ischemia testing (mainly coronary angiography) in patients presenting with monomorphic VT through 8 selected studies after evaluating a total of 130 published manuscripts. Particularly, we sought to unveil whether coronary angiography and possibly concomitant revascularization leads to lesser tachycardia recurrence. Our conclusion can be summarized as follows: this approach whether combined with revascularization or not, does not seem to reduce VT recurrence nor does it affect mortality in such patients. Even though most of the published literature points at this direction, validation from randomized controlled trials is imperative.

Atrial Fibrillation After Patent Foramen Ovale Closure: Incidence, Pathophysiology, and Management.

This comprehensive review explores the incidence, pathophysiology, and management of atrial fibrillation (AF) following percutaneous closure of patent foramen ovale (PFO). Although AF is considered a common adverse event post PFO closure, its incidence, estimated at <5%, varies based on monitoring methods. The review delves into the challenging task of precisely estimating AF incidence, given subclinical AF and diverse diagnostic approaches. Notably, a temporal pattern emerges, with peak incidence around the 14th day after closure and a subsequent decline after the 45th day, mimicking general population AF trends. The pathophysiological mechanisms behind post PFO closure AF remain elusive, with proposed factors including local irritation, device-related interference, tissue stretch, and nickel hypersensitivity. Management considerations encompass rhythm control, with flecainide showing promise, and anticoagulation tailored to individual risk profiles. The authors advocate for a personalized approach, weighing factors like age, comorbidities, and device characteristics. Notably, postclosure AF is generally considered benign, often resolving spontaneously within 45 days, minimizing thromboembolic risks. Further studies are required to refine understanding and provide evidence-based guidelines.

SCN5A gene variants and arrhythmic risk in Brugada syndrome: An updated systematic review and meta-analysis.

BACKGROUND: A rare gene variant in SCN5A can be found in approximately 20%-25% of patients with Brugada syndrome (BrS). OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the differences in clinical characteristics of BrS patients with and without SCN5A rare variants and the prognostic role of SCN5A for ventricular arrhythmias in BrS. METHODS: PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched from inception to January 2024 to identify all relevant studies. Studies were analyzed if they included patients diagnosed with BrS in whom genetic testing for SCN5A variants was performed and arrhythmic outcomes were reported. RESULTS: A total of 17 studies with 3568 BrS patients, of whom 3030 underwent genetic testing for SCN5A variants, fulfilled the eligibility criteria and were included. Compared with SCN5A- patients, SCN5A+ BrS patients more frequently had spontaneous type 1 electrocardiogram, history of syncope, and documented arrhythmias. Furthermore, higher PQ and QRS intervals in SCN5A+ BrS patients compared with SCN5A- have been found. The pooled analysis demonstrated a significant association between the presence of SCN5A rare variants in BrS patients and the risk of major arrhythmic events, with a pooled odds ratio of 2.14 (95% confidence interval, 1.53-2.99; I2 = 29%). CONCLUSION: SCN5A+ BrS patients showed a worse clinical phenotype compared with SCN5A-. The pooled analysis demonstrated a significant association between SCN5A+ mutation status and the risk of major arrhythmic events in BrS patients.