Bos, Martijn

Abstract Aims SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

Abstract Background The extravascular implantable cardioverter defibrillator (EV-ICD) was designed to avoid lead-related complications associated with transvenous systems and deliver features such as anti-tachycardia pacing (ATP) and reduced generator size that provide an advantage over a subcutaneous ICD (S-ICD). As such, the EV-ICD is an attractive alternative for younger patients with genetic heart diseases (GHDs) who are not in need of permanent pacing. Objective To examine the indications, complications, and the clinical outcomes of patients with GHDs who received an EV-ICD. Methods A retrospective review of the electronic record was done for all GHD patients evaluated in genetic heart rhythm and/or cardiomyopathy clinics who had an EV-ICD implanted between 1/2021 and 2/2025. Basic demographic, ICD indications, complications, and therapy data were then extracted for all study patients. Results Overall, 23 patients (35% female; mean age 39 ± 16 years; 61% with a disease-causative genetic variant; mean LVEF 57%) with an underlying GHD (hypertrophic cardiomyopathy in 9, arrhythmogenic cardiomyopathy in 8, idiopathic ventricular fibrillation in 3, dilated cardiomyopathy in 2, and long QT syndrome in 1) had an EV-ICD implanted. For the majority, an EV-ICD was implanted for primary prevention (15/23; 65%) and represented their first ICD system (21/23; 91%). The success rate of the procedure was 96% with only one abandoned procedure because of poor R-wave sensing. Inadvertent intraprocedural lead placement in the pericardial space occurred in 1 patient with previous thoracotomy and surgically placed epicardial lead without sequelae or need for revision. Over a mean follow-up of 8±9 months, the rate of complications was low (1/23; 4%) with one electrode displacement and this patient underwent defibrillation threshold testing (DFT), the device properly detected VF and emitted a successful shock 30 J. Thus far, 2 patients have received appropriate VT/VF-terminating therapies (3 ICD shocks, 0 ATP) with successful conversion to sinus rhythm. One patient died following an electrical storm. One patient had 3 inappropriate ICD shock for sinus tachycardia while exercising followed by 1 successful shock for VF. Conclusion In this early experience, EV-ICDs appear to be safe and effective in younger patients with genetic arrhythmogenic and hypertrophic cardiomyopathies. Future studies are needed to better understand the utility of EV-ICDs in patients with cardiac channelopathies and advantages of EV-ICDs over transvenous and S-ICD systems in patients with an array of sudden death-predisposing GHDs.

Introduction: Long QT syndrome (LQTS) is an autosomal dominant disorder characterized by a prolonged QT interval on a 12-lead electrocardiogram (ECG). Cascade genetic testing for LQTS is standard of care, including in infants, but takes 2-4 weeks for return of results. For newborns of parent with confirmed LQTS, the ECG is obtained after birth as an initial assessment, but QTc values during the immediate newborn period may be misleading. Thus, our objective was to determine the ECG’s diagnostic accuracy in the first 48 hours of life for neonates born to a parent with LQTS. Methods: We performed a retrospective review of the electronic medical records of neonates born to a parent with ≥ 1 pathogenic variant in a LQTS-causative gene for which at least 1 ECG in the first 48 hours of life was obtained. Clinical data was collected on all neonates with focus on the 12-lead ECG, family history, and genetic testing results. The sensitivity and specificity of the diagnostic ECG were calculated using QTc thresholds of 440, 460, and 470 ms. Results: Overall, 70 infants (35 [50%] females) met inclusion criteria and the mean QTc on the first ECG was 484 ± 61 ms. Following genetic testing, a LQTS-causing variant was identified in 46 infants (66%), including 22 (48%) with LQT1 ( KCNQ1 ), 12 (26%) with LQT2 ( KCNH2 ), and 8 (17%) with LQT3 ( SCN5A ). Mean QTc in the first 48 hours of life for neonates that ultimately were genotype-positive was 502 ± 59 ms compared to 451 ± 50 ms (p < 0.001) for genotype-negative neonates. When using a recommended threshold QTc of ≥ 440 ms, 6/46 genotype-positive neonates (13%) were missed (underdiagnosed) and 13/24 genotype-negative neonates (54%) were overdiagnosed (sensitivity: 87%, specificity: 45%). At a QTc threshold ≥ 460 ms, 15 (21%) were classified erroneously (sensitivity: 85%, specificity: 67%) while at a threshold of ≥ 470 ms, 18 (26%) were misclassified (sensitivity: 76%, specificity: 71%). Conclusions: Although a baseline ECG should still be obtained before a newborn’s dismissal, reliance solely on the QTc for diagnosing LQTS and initiating therapy will result in an unacceptable number of misclassifications. Thus, genetic testing must be initiated prior to the baby’s discharge and proper anticipatory guidance is vital while awaiting genetic test results.

Abstract Hypertrophic Cardiomyopathy (HCM) is an inheritable heart disease with the highest rate of sudden cardiac death (SCD) in young adults. Implantable Cardioverter Defibrillator (ICD) therapy is recommended for HCM patients at high risk for SCD. Reviewing the recent clinical literature revealed the potential to improve the selection of candidates for ICD implantation. The current study uses information extracted from echocardiography reports to evaluate HCM patients with ICD and aims to provide a comparative insight into patients who benefited the most from the device therapy, including shock and anti-tachycardia pacing (ATP). The proposed interpretable machine learning approach has used the XGboost algorithm. The model’s performance was considered satisfactory, as evidenced by an accuracy score of 81% and an area under the receiver operating characteristic curve (AUC) value of 69% and SHapley Additive exPlanations (SHAP) identified common properties of HCM patients in each category and provided high-level reasoning and foundation for a clinical decision support tool.

Importance Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. Objective To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity. Design, Setting, and Participants This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled. Exposures Amount and intensity of physical activity. Main Outcomes and Measures The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient’s exercise category. Results Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority. Conclusions and Relevance Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

Introduction: Safety of vigorous exercise for individuals with appropriately-treated HCM remains debated. Physical activity practices in this population have not been described. The objective of this report is to describe physical activity pattern in HCM patients. Long term follow up which is ongoing will determine safety of vigorous exercise. Methods: The NIH-funded LIVE-HCM study prospectively enrolled individuals age 8-60 years with clinically overt HCM or patients with a positive genetic test for sarcomeric HCM. Participants (or parents, for children) answered surveys describing activity patterns. Vigorous exercise was defined as > 6 METS for > 60 hours per year. Clinical and demographic data were derived from medical record review. Results: Among 1798 participants, 745 (41%) reported exercising vigorously, including 296 competitive athletes, with 59 at high-school or college varsity level, 770 (43%) were exercising at moderate, and 283 (16%) at low levels. Of those working, 6% described jobs more active than walking, including 16 in protective services, and 11 in sports/coaching. Clinical/demographic data including imaging characteristics and treatments, are shown in Table, and were mostly similar amongst the exercise-groups. Conclusions: Many patients with HCM are engaged in vigorous exercise including competitive athletics. Prospective follow-up of this cohort is ongoing. Comparison of arrhythmic outcomes outcomes in vigorous exercisers vs moderate/low level exercisers will help determine the safety of exercise in HCM patients.