The Influence of Arrhythmia on the Outcomes of Pediatric Patients with Idiopathic Dilated Cardiomyopathy.

Children diagnosed with dilated cardiomyopathy (DCM) are at an increased risk of developing arrhythmias, which can significantly affect their overall prognosis. However, the implantation and effectiveness of implantable cardioverter-defibrillators (ICDs) pose challenges in the pediatric population. Therefore, it is crucial to determine the prevalence of arrhythmia-related death in pediatric patients with DCM. This study investigated the correlation between arrhythmias and mortality in pediatric patients with DCM. This retrospective cohort study examined children with idiopathic DCM referred to Rajaie Cardiovascular, Medical, and Research Institute in Tehran, Iran, from 2017 to 2023. All patients underwent a standard 12-lead electrocardiogram, 24-h Holter monitoring, cardiac magnetic resonance imaging, and echocardiography. Patient outcomes, including death, heart transplantation, and survival, were evaluated within one year of Holter monitoring. A total of 178 children (79 males) with a mean age of 83.06 ± 56.41 months were included in the study. Overall, 72 deaths (40.4%) and 46 heart transplants (25.8%) were recorded and 60 patients (33.7%) survived. There was no significant association between patients' outcomes with ventricular arrhythmias, late gadolinium enhancement, corrected QT interval, and QRS interval prolongation; however, a significantly higher proportion of dead patients had abnormal heart rate variability (P = 0.034). Heart failure was the leading cause of death, with ventricular arrhythmia accounting for two out of 72 deaths. Both cases of ventricular arrhythmia were associated with severe cardiac dysfunction. Arrhythmia-related mortality is rare in children with idiopathic DCM, with severe heart failure being the primary cause of death in this population. Life-threatening arrhythmias primarily occur in DCM children with more compromised cardiac function.

Distance-dependent neuromodulation effect during thermal ablation for atrial fibrillation.

INTRODUCTION: Thermal atrial fibrillation (AF) ablation exerts an additive treatment effect on the cardiac autonomic nervous system (CANS). This effect is mainly reported during ablation of the right superior pulmonary vein (RSPV), modulating the right anterior ganglionated plexus (RAGP), which contains parasympathetic innervation to the sinoatrial node in the epicardial fat pad between RSPV and superior vena cava (SVC). However, a variable response to neuromodulation after ablation is observed, with little to no effect in some patients. Our objective was to assess clinical and anatomic predictors of thermal ablation-induced CANS changes, as assessed via variations in heart rate (HR) postablation. METHODS: Consecutive paroxysmal AF patients undergoing first-time PV isolation by the cryoballoon (CB) or radiofrequency balloon (RFB) within a 12-month time frame and with preprocedural cardiac computed tomography (CT), were evaluated. Preablation and 24-h postablation electrocardiograms in sinus rhythm were collected and analyzed to assess HR. Anatomic evaluation by CT included the measurement of the shortest distance between the SVC and RSPV ostium (RSPV-SVC distance). RESULTS: A total of 97 patients (CB, n = 50 vs. RFB, n = 47) were included, with similar baseline characteristics between both groups. A significant HR increase postablation (ΔHR ≥ 15 bpm) occurred in a total of 37 patients (38.1%), without difference in number of patients between both thermal ablation technologies (CB, 19 [51%]), RFB, 18 [49%]). Independent predictors for increased HR were RSPV-SVC distance (odds ratio [OR]: 0.49, CI: 0.34-0.71, p value < .001), and age (OR: 0.94, CI: 0.89-0.98, p value = .003). CONCLUSIONS: Thermal balloon-based PV isolation influences the CANS through its effect on the RAGP, especially in younger patients and patients with shorter RSPV-SVC distance.

Continuous Rhythm Monitoring With Implanted Loop Recorders in Children and Adolescents With Brugada Syndrome.

BACKGROUND: Young (<18 years of age) patients with Brugada syndrome (BrS) are often under-represented in BrS studies and their management, especially related to syncopal episodes, remains unclear. OBJECTIVES: This study sought to describe the arrhythmia prevalence among young patients with BrS undergoing continuous rhythm monitoring by implantable loop recorder (ILR) and to assess the etiology behind syncope of undetermined origin. METHODS: A total of 147 patients with BrS with ILR were enrolled in 12 international centers and divided into pediatric (age <12 years; n = 77, 52%) and adolescents (age 13-18 years; n = 70, 48%). RESULTS: Mean age was 11.3 years, 53 patients (36.1%) were female, and 31 (21.1%) had spontaneous type 1 electrocardiograms. Over a median follow-up of 3.6 years (Q1-Q3: 1.6-4.8 years), an arrhythmic event was recorded in 33 patients (22.4%), mainly of nonventricular origin: 15 atrial (10.2%) and 16 bradyarrhythmic events (10.9%). Ventricular arrhythmias occurred in 4 patients, all with spontaneous BrS, and were fever-related in one-half. Among all patients with recurrence of syncope during follow-up, true arrhythmic syncope was documented in 5 (17.8%), and it was due to bradyarrhythmias or atrial arrhythmias in 3 cases (60%). CONCLUSIONS: Continuous rhythm monitoring with ILRs in young patients with BrS detects a broad range of arrhythmias. Ventricular arrhythmias occur predominantly in patients with spontaneous type 1 electrocardiograms and during fever. Despite the young age, bradyarrhythmias and atrial arrhythmias are frequent and represent the cause of arrhythmic syncope in 60% of patients. Young patients with BrS with syncope of undetermined origin may benefit from ILR implant.

Catheter ablation as an adjunctive therapy to ICD implantation in Brugada syndrome.

BACKGROUND: Brugada Syndrome (BrS) is a life-threatening cardiac arrhythmia disorder associated with an increased risk ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Current management primarily relies on implantable cardioverter-defibrillators (ICDs), but patients may experience ICD shocks. Catheter ablation (CA) has emerged as a potential intervention to target the arrhythmogenic substrate. This systematic review aims to evaluate the safety and efficacy of catheter ablation in BrS patients. METHODS AND RESULTS: Studies with BrS patients undergoing catheter ablation for VAs were included. 14 studies that involved a total population of 709 BrS patients, with catheter ablation performed in 528 of them, were included. Catheter ablation resulted in non-inducibility of VAs in 91% (95% CI: 83-99, I2 = 76%) and resolution of Type 1 ECG Brugada pattern in 88% (95% CI: 81-96.2, I2 = 91%) of the patients. After a mean follow-up of 30.7 months, 87% (95% CI: 80-94, I2 = 82%) of patients remained free from VAs. The incidence of VAs during follow-up was significantly lower in the ablation cohort in comparison to the group receiving only ICD therapy (OR = 0.03, 95% CI: 0.01-0.12, I2 = 0%). CONCLUSION: Catheter ablation shows potential as a therapeutic approach to reduce VAs and improve outcomes in BrS patients. While further research with long follow-up period is required to confirm these findings, it represents a valuable tool as an add-on intervention to ICD implantation in BrS patients with high burden of VAs.Protocol registration: CRD42024506439.

Predicting and Recognizing Drug-Induced Type I Brugada Pattern Using ECG-Based Deep Learning.

BACKGROUND: Brugada syndrome (BrS) has been associated with sudden cardiac death in otherwise healthy subjects, and drug-induced BrS accounts for 55% to 70% of all patients with BrS. This study aims to develop a deep convolutional neural network and evaluate its performance in recognizing and predicting BrS diagnosis. METHODS AND RESULTS: Consecutive patients who underwent ajmaline testing for BrS following a standardized protocol were included. ECG tracings from baseline and during ajmaline were transformed using wavelet analysis and a deep convolutional neural network was separately trained to (1) recognize and (2) predict BrS type I pattern. The resultant networks are referred to as BrS-Net. A total of 1188 patients were included, of which 361 (30.3%) patients developed BrS type I pattern during ajmaline infusion. When trained and evaluated on ECG tracings during ajmaline, BrS-Net recognized a BrS type I pattern with an AUC-ROC of 0.945 (0.921-0.969) and an AUC-PR of 0.892 (0.815-0.939). When trained and evaluated on ECG tracings at baseline, BrS-Net predicted a BrS type I pattern during ajmaline with an AUC-ROC of 0.805 (0.845-0.736) and an AUC-PR of 0.605 (0.460-0.664). CONCLUSIONS: BrS-Net, a deep convolutional neural network, can identify BrS type I pattern with high performance. BrS-Net can predict from baseline ECG the development of a BrS type I pattern after ajmaline with good performance in an unselected population.

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.

Implantable loop recorders in patients with Brugada syndrome: the BruLoop study.

BACKGROUND AND AIMS: Available data on continuous rhythm monitoring by implantable loop recorders (ILRs) in patients with Brugada syndrome (BrS) are scarce. The aim of this multi-centre study was to evaluate the diagnostic yield and clinical implication of a continuous rhythm monitoring strategy by ILRs in a large cohort of BrS patients and to assess the precise arrhythmic cause of syncopal episodes. METHODS: A total of 370 patients with BrS and ILRs (mean age 43.5 ± 15.9, 33.8% female, 74.1% symptomatic) from 18 international centers were included. Patients were followed with continuous rhythm monitoring for a median follow-up of 3 years. RESULTS: During follow-up, an arrhythmic event was recorded in 30.7% of symptomatic patients [18.6% atrial arrhythmias (AAs), 10.2% bradyarrhythmias (BAs), and 7.3% ventricular arrhythmias (VAs)]. In patients with recurrent syncope, the aetiology was arrhythmic in 22.4% (59.3% BAs, 25.0% VAs, and 15.6% AAs). The ILR led to drug therapy initiation in 11.4%, ablation procedure in 10.9%, implantation of a pacemaker in 2.5%, and a cardioverter-defibrillator in 8%. At multivariate analysis, the presence of symptoms [hazard ratio (HR) 2.5, P = .001] and age >50 years (HR 1.7, P = .016) were independent predictors of arrhythmic events, while inducibility of ventricular fibrillation at the electrophysiological study (HR 9.0, P < .001) was a predictor of VAs. CONCLUSIONS: ILR detects arrhythmic events in nearly 30% of symptomatic BrS patients, leading to appropriate therapy in 70% of them. The most commonly detected arrhythmias are AAs and BAs, while VAs are detected only in 7% of cases. Symptom status can be used to guide ILR implantation.

Pericarditis prophylactic therapy after sinus node-sparing hybrid ablation for inappropriate sinus tachycardia/postural orthostatic sinus tachycardia.

Background: Pericarditis is the most common complication following hybrid sinus node-sparing ablation for inappropriate sinus tachycardia (IST)/postural orthostatic tachycardia syndrome (POTS). Objective: The study sought to evaluate the association of prophylaxis therapy on the risk of symptomatic pericarditis following hybrid IST/POTS ablation. Methods: All consecutive patients undergoing to hybrid ablation of symptomatic IST/POTS refractory or intolerant to drugs were retrospectively analyzed. Pharmacological prophylaxis therapy was based on acetylsalicylic acid and colchicine started on the day of the ablation and continued for at least 3 months. The primary endpoint was occurrence of symptomatic pericarditis. The secondary endpoint was occurrence of pericarditis-related complications, including the following: duration of pericarditis >3 months, hospitalization for pericarditis, postpericardiectomy pleuro-pericarditis, and pericardiectomy. Results: A total of 220 patients undergone to hybrid IST/POTS ablation were included and 44 (20%) underwent prophylaxis therapy. Pericarditis occurred in 101 (45.9%) patients, with 97 (96%) in the first 5 days. At survival analysis, prophylaxis was associated with higher rate of freedom from pericarditis (81.9% vs 47.2%, log-rank P < .001). Pericarditis-related complications were low, occurring in 7 (3.2%) patients. There was no difference in pericarditis-related complications between the patients who underwent prophylaxis therapy and patients who did not. At Cox multivariate analysis, predictors of pericarditis were IST (vs POTS) (hazard ratio 0.61, 95% confidence interval0.39-0.99, P = .04) and prophylaxis therapy (hazard ratio 0.27, 95% confidence interval 0.13-0.55, P < .001). Conclusion: In a large cohort of patients undergoing hybrid ablation for IST/POTS, a prophylaxis therapy with acetylsalicylic acid and colchicine was associated with a lower rate of symptomatic pericarditis.

Genetic Testing in Brugada Syndrome: A 30-Year Experience.

BACKGROUND: A pathogenic/likely pathogenic variant can be found in 20% to 25% of patients with Brugada syndrome (BrS) and a pathogenic/likely pathogenic variant in SCN5A is associated with a worse prognosis. The aim of this study is to define the diagnostic yield of a large gene panel with American College of Medical Genetics and Genomics variant classification and to assess prognosis of SCN5A and non-SCN5A variants. METHODS: All patients with BrS, were prospectively enrolled in the Universitair Ziekenhuis Brussel registry between 1992 and 2022. Inclusion criteria for the study were (1) BrS diagnosis; (2) genetic analysis performed with a large gene panel; (3) classification of variants following American College of Medical Genetics and Genomics guidelines. Patients with a pathogenic/likely pathogenic variant in SCN5A were defined as SCN5A+. Patients with a reported variant in a non-SCN5A gene or with no reported variants were defined as patients with SCN5A-. All variants were classified as missense or predicted loss of function. RESULTS: A total of 500 BrS patients were analyzed. A total of 104 patients (20.8%) were SCN5A+ and 396 patients (79.2%) were SCN5A-. A non-SCN5A gene variant was found in 75 patients (15.0%), of whom, 58 patients (77.3%) had a missense variant and 17 patients (22.7%) had a predicted loss of function variant. At a follow-up of 84.0 months, 48 patients (9.6%) experienced a ventricular arrhythmia (VA). Patients without any variant had higher VA-free survival, compared with carriers of a predicted loss of function variant in SCN5A+ or non-SCN5A genes. There was no difference in VA-free survival between patients without any variant and missense variant carriers in SCN5A+ or non-SCN5A genes. At Cox analysis, SCN5A+ or non-SCN5A predicted loss of function variant was an independent predictor of VA. CONCLUSIONS: In a large BrS cohort, the yield for SCN5A+ is 20.8%. A predicted loss of function variant carrier is an independent predictor of VA.

Posterior wall isolation via a multi-electrode radiofrequency balloon catheter: feasibility, technical considerations, endoscopic findings and comparison with cryoballoon technologies.

BACKGROUND: Posterior wall (PW) isolation is an important adjunctive ablation target in patients with non-paroxysmal atrial fibrillation (AF). Traditionally performed with point-by-point radiofrequency (RF) ablation, PW isolation has also been performed with different cryoballoon technologies. We aimed at assessing the feasibility of PW isolation with the novel RF balloon catheter Heliostar™ (Biosense Webster, CA, USA). METHODS: We prospectively enrolled 32 consecutive patients with persistent AF scheduled for first-time ablation with the Heliostar™ device. Procedural data were compared with those from 96 consecutive persistent AF patients undergoing pulmonary vein (PV) plus PW isolation with a cryoballoon device. The ratio RF balloon/cryoballoon was 1:3 for each operator involved in the study, aiming at avoiding any imbalance related to different experience. RESULTS: Single-shot PV isolation was documented in a significantly higher number of cases with the RF balloon technology compared to cryoballoon ablation (89.8% vs. 81.0%; p = 0.02, respectively). PW isolation was achieved with a similar number of balloon applications between the two groups (11 ± 4 with the RF balloon versus 11 ± 2 with the cryoballoon; p = 0.16), but in a significantly shorter time among RF balloon patients (228 ± 72 s versus 1274 ± 277 s with cryoballoon; p < 0.001). Primary safety endpoint occurred in none of the RF balloon patients versus 5 (5.2%) patients in the cryoballoon group (p = 0.33). Primary efficacy endpoint was achieved in all (100%) RF balloon patients versus 93 (96.9%) cryoballoon ones (p = 0.57). Oesophageal endoscopy did not show any signs of thermal lesions in RF balloon patients with luminal temperature rise. CONCLUSIONS: RF balloon-based PW isolation was safe and promoted shorter procedure times compared to similar cryoballoon-based ablation procedures.

Clinical Management of Brugada Syndrome: Commentary From the Experts.

Although there is consensus on the management of patients with Brugada Syndrome with high risk for sudden cardiac arrest, asymptomatic or intermediate-risk patients present clinical management challenges. This document explores the management opinions of experts throughout the world for patients with Brugada Syndrome who do not fit guideline recommendations. Four real-world clinical scenarios were presented with commentary from small expert groups for each case. All authors voted on case-specific questions to evaluate the level of consensus among the entire group in nuanced diagnostic and management decisions relevant to each case. Points of agreement, points of controversy, and gaps in knowledge are highlighted.

Coronary artery disease in atrial fibrillation ablation: impact on arrhythmic outcomes.

AIMS: Catheter ablation (CA) is an established treatment for atrial fibrillation (AF). A computed tomography (CT) may be performed before ablation to evaluate the anatomy of pulmonary veins. The aim of this study is to investigate the prevalence of patients with coronary artery disease (CAD) detected by cardiac CT scan pre-ablation and to evaluate the impact of CAD and revascularization on outcomes after AF ablation. METHODS AND RESULTS: All consecutive patients with AF diagnosis, hospitalized at Universitair Ziekenhuis Brussel, Belgium, between 2015 and 2019, were prospectively screened for enrolment in the study. Inclusion criteria were (i) AF diagnosis, (ii) first procedure of AF ablation with cryoballoon CA, and (iii) contrast CT scan performed pre-ablation. A total of 576 consecutive patients were prospectively included and analysed in this study. At CT scan, 122 patients (21.2%) were diagnosed with CAD, of whom 41 patients (7.1%) with critical CAD. At survival analysis, critical CAD at CT scan was a predictor of atrial tachyarrhythmia (AT) recurrence during the follow-up, only in Cox univariate analysis [hazard ratio (HR) = 1.79] but was not an independent predictor in Cox multivariate analysis. At Cox multivariate analysis, independent predictors of AT recurrence were as follows: persistent AF (HR = 2.93) and left atrium volume index (HR = 1.04). CONCLUSION: In patients undergoing CT scan before AF ablation, critical CAD was diagnosed in 7.1% of patients. Coronary artery disease and revascularization were not independent predictors of recurrence; thus, in this patient population, AF ablation should not be denied and can be performed together with CAD treatment.

Redo procedures after sinus node sparing hybrid ablation for inappropriate sinus tachycardia/postural orthostatic sinus tachycardia.

AIMS: A novel sinus node (SN) sparing hybrid ablation for inappropriate sinus node tachycardia (IST)/postural orthostatic tachycardia syndrome (POTS) has been demonstrated to be an effective and safe therapeutic option in patients with symptomatic drug-resistant IST/POTS. The aim of this study was to evaluate the long-term rate of redo procedures after hybrid IST ablation and procedural strategy, outcomes and safety of redo procedures. METHODS AND RESULTS: All consecutive patients from 2015 to 2023 were prospectively enrolled in the UZ Brussel monocentric IST/POTS registry. They were analysed if the following inclusion criteria were fulfilled: 1) diagnosis of IST or POTS, 2) symptomatic IST/POTS refractory or intolerant to drugs, and 3) hybrid SN sparing ablation performed. The primary endpoint was redo procedure. The primary safety endpoint was pacemaker (PM) implantation. A total of 220 patients undergone to hybrid IST ablation were included, 185 patients (84.1%) were treated for IST and 61 patients (27.7%) for POTS.After a follow-up of 73.3 ± 16.2 months, 34 patients (15.4%) underwent a redo. A total of 23 patients (67.6%) had a redo for IST recurrence and 11 patients (32.4%) for other arrhythmias. Pacemaker implantation was performed in 21 patients (9.5%). Nine patients (4.1%) had no redo procedure and experienced sick sinus syndrome requiring a PM. Twelve patients (5.4%) received a PM as a shared therapeutic choice combined with SN ablation procedure. CONCLUSION: In a large cohort of patients the long-term free survival from redo procedure after hybrid IST ablation was 84.6% with a low PM implantation rate.

Safety of the Radiofrequency Balloon for Pulmonary Vein Isolation: A Focus on Lesion Metric Analysis of Posterior Electrodes.

Previous clinical studies on pulmonary vein isolation (PVI) with radiofrequency balloons (RFB) reported safe and effective procedures for a 20 s RF delivery via posterior electrodes. Recent recommendations from the manufacturer suggest reducing the application time to 15 s on the posterior wall (PW) when facing the esophagus region. Here, we retrospectively assess whether 15 s of RF delivery time on posterior electrodes is safe while still ensuring lesion metrics of sufficient quality. This retrospective study included 133 patients with paroxysmal and persistent atrial fibrillation who underwent PVI using an RFB (Heliostar, Biosense Webster, Inc., Irvine, CA, USA) at two European centers. The ablation protocol was set for an RF duration of 20 s/60 s for the posterior/anterior electrodes. A multielectrode temperature probe was systematically used. In the case of an esophageal temperature rise (ETR) above 42 °C (ETR+), an endoscopic evaluation was performed. All posterior electrode lesion metric dynamics (temperature (T) and impedance (Z)) were collected from the RFB generator and analyzed offline. In total, 2435 posterior electrode applications were analyzed. With an RF delivery of 19.8 (19.7-19.8) s, the median impedance drop was 18.4 (12.2-25.2) Ω, while the temperature rise was 11.1 (7.1-14.9) °C. Accordingly, impedance (84.6 (79.3-90.2) Ω) and temperature plateaus (38 (35.3-41.1) °C) were reached at 13.9 (10.6-16) s and 16.4 (12.6-18.5) s, respectively. Overall, 99.6% and 95.8% of electrodes reached 90% (16.6 Ω) and 95% (17.5 Ω) of their impedance drops within 15 s of RF delivery, while 97.2% and 92.8% achieved 90% (34.2 °C) and 95% (36.1 °C) of their temperature rise to reach the plateaus within 15 s of RF delivery. An ETR >42 °C occurred in 37 (30.1%) patients after 17.7 ± 2.3 s of RF delivery. In the ETR+ group, the impedance drop and temperature rise on the posterior electrodes were higher compared to patients where ETR was <42 °C. Two asymptomatic thermal esophageal injuries were observed. In conclusion, 15 s of RF delivery on the posterior electrodes provides a good balance between safety, with no esophageal temperature rise, and efficacy with high-profile lesion metrics.

Phase 2 Re-Entry Without Ito: Role of Sodium Channel Kinetics in Brugada Syndrome Arrhythmias.

BACKGROUND: In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (Ito) is a proposed arrhythmia mechanism; yet, the most common genetic defects are loss-of-function sodium channel mutations. OBJECTIVES: The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of Ito. METHODS: Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models. RESULTS: In the presence of Ito sufficient to generate robust P2R, reducing sodium current (INa) peak amplitude alone only slightly potentiated P2R. When INa inactivation kinetics were also altered to simulate reported effects of BrS mutations and sodium channel blockers, however, P2R occurred even in the absence of Ito. These effects could be potentiated by delaying L-type calcium channel activation or increasing ATP-sensitive potassium current, consistent with experimental and clinical findings. INa-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients. CONCLUSIONS: Altered INa kinetics synergize powerfully with reduced INa amplitude to promote P2R-induced arrhythmias in BrS in the absence of Ito, establishing a robust mechanistic link between altered INa kinetics and the P2R-mediated arrhythmia mechanism.