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Background and Aims: Long QT syndrome (LQTS) and coronary artery disease (CAD) are both associated with increased risk of ventricular tachyarrhythmia . However, there are limited data on the incremental risk conferred by CAD in adult patients with congenital LQTS. We aimed to investigate the risk associated with CAD and life threatening events (LTEs) in patients with LQTS after age 40 years., Methods: The risk of LTEs (comprising aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shock) from age 40 through 75 years was examined in 1,020 subjects from the Rochester LQTS registry, categorized to CAD ( n  = 137) or no-CAD ( n  = 883) subgroups., Results: Survival analysis showed that patients with CAD had a significantly higher cumulative event rate of LTEs from 40 to 75 years (35%) compared with those without CAD (7%; p  < 0.001 for the overall difference during follow-up). Consistently, multivariate analysis showed that the presence of CAD was associated with a 2.5-fold (HR = 2.47; p  = 0.02) increased risk of LTEs after age 40 years. Subgroup analyses showed that CAD vs. no CAD was associated with a pronounced >4-fold ( p  = 0.008) increased risk of LTEs among LQTS patients with a lower-range QTc (<500 ms). The increased risk of LTEs associated with CAD was not significantly different among the 3 main LQTS genotypes. Patient treatment was suboptimal, with only 63% on β-blockers and 44% on non-selective β-blockers., Conclusions: Our findings suggest that CAD is associated with a higher risk of LTEs in LQTS patients, with the risk being more pronounced in those with QTc <500 ms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Barsheshet, Goldenberg, Bjelic, Buturlin, Erez, Goldenberg, Chen, Polonsky, McNitt, Aktas, Zareba and Golovchiner.)

Background: Some studies have shown digoxin use to be associated with adverse outcomes, including increased mortality. There are limited data on whether digoxin use is associated with increased risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in heart failure patients with an implantable cardioverter-defibrillator (ICD)., Objectives: This study sought to assess whether digoxin use is associated with increased risk of VT/VF in patients with heart failure with reduced ejection fraction with a primary prevention ICD in landmark clinical trials., Methods: The study cohort consisted of patients with an ICD or cardiac resynchronization therapy-defibrillator who were enrolled in 4 landmark MADIT trials (Multicenter Automatic Defibrillator Implantation Trials). We employed propensity score quintile stratification for treatment with digoxin as well as additional multivariable adjustment to assess the risk of digoxin vs no-digoxin therapy for the endpoints of first and recurrent VT/VF and all-cause mortality. The proportional hazards regression models for arrhythmia-specific endpoints incorporated adjustments for the competing risk of death., Results: At baseline, 1,155 of 4,499 patients were on digoxin (26%). After propensity score quintile stratification, patients prescribed digoxin were shown to exhibit a statistically significant 48% increased risk of VT/VF (P < 0.001), 42% increased risk of the composite of VT/VF or death (P < 0.001), and a 37% increased risk of all-cause mortality (P = 0.006). Digoxin use was also associated with increased risk of appropriate ICD shocks (HR: 1.91; P < 0.001) and with increased burden of VT/VF events (HR: 1.46; P = 0.001)., Conclusions: Our findings suggests that digoxin use is associated with ventricular tachyarrhythmia and death in heart failure with reduced ejection fraction patients with an ICD., Competing Interests: Funding Support and Author Disclosures The MADIT-RISK study was supported by NIH grant HL077478. Dr Aktas has received research funding from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Data on the risk of ventricular tachycardia (VT), ventricular fibrillation (VF), and death by sex in patients with prior VT/VF are limited., Objectives: This study aimed to assess sex-related differences in implantable cardioverter-defibrillator (ICD)-treated VT/VF events and death in patients implanted for secondary prevention or primary prevention ICD indications who experienced VT/VF before enrollment in the RAID (Ranolazine Implantable Cardioverter-Defibrillator) trial., Methods: Sex-related differences in the first and recurrent VT/VF requiring antitachycardia pacing or ICD shock and death were evaluated in 714 patients., Results: There were 124 women (17%) and 590 men observed during a mean follow-up of 26.81 ± 14.52 months. Compared to men, women were at a significantly lower risk of VT/VF/death (HR: 0.67; P = 0.029), VT/VF (HR: 0.68; P = 0.049), VT/VF treated with antitachycardia pacing (HR: 0.59; P = 0.019), and VT/VF treated with ICD shock (HR: 0.54; P = 0.035). The risk of recurrent VT/VF was also significantly lower in women (HR: 0.35; P < 0.001). HR for death was similar to the other endpoints (HR: 0.61; P = 0.162). In comparison to men, women presented with faster VT rates (196 ± 32 beats/min vs 177 ± 30 beats/min, respectively; P = 0.002), and faster shock-requiring VT/VF rates (258 ± 56 beats/min vs 227 ± 57 beats/min, respectively; P = 0.30). There was a significant interaction for the risk of VT/VF by race (P = 0.013) with White women having significantly lower risk than White men (HR: 0.36; P < 0.001), whereas Black women had a similar risk to Black men (HR: 1.06; P = 0.851)., Conclusions: Women with a history of prior VT/VF experienced a lower risk recurrent VT/VF requiring ICD therapy when compared to men. Black Women had a risk similar to men, whereas the lower risk for VT/VF in women was observed primarily in White women. (Ranolazine Implantable Cardioverter-Defibrillator Trial; NCT01215253)., Competing Interests: Funding Support and Author Disclosures This study was supported by grants from the National Heart, Lung, and Blood Institute: Clinical Coordination Center (UO1 HL096607) and Data Coordination Center (UO1 HL096610. Study drug and additional financial support for drug distribution was provided by Gilead Sciences (grant IN-US-259-0125). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Both selective and nonselective beta-blockers are used to treat patients with heart failure (HF). However, the data on the association of beta-blocker type with risk of atrial arrhythmia and ventricular arrhythmia (VA) in HF patients with a primary prevention implantable cardioverter-defibrillator (ICD) are limited., Objectives: This study sought to evaluate the effect of metoprolol vs carvedilol on the risk of atrial tachyarrhythmia (ATA) and VA in HF patients with an ICD., Methods: This study pooled primary prevention ICD recipients from 5 landmark ICD trials (MADIT-II, MADIT-CRT, MADIT-RIT, MADIT-RISK, and RAID). Fine and Gray multivariate regression models, stratified by study, were used to evaluate the risk of ATA, inappropriate ICD shocks, and fast VA (defined as ventricular tachycardia ≥200 beats/min or ventricular fibrillation) by beta-blocker type., Results: Among 4,194 patients, 2,920 (70%) were prescribed carvedilol and 1,274 (30%) metoprolol. The cumulative incidence of ATA at 3.5 years was 11% in patients treated with carvedilol vs 15% in patients taking metoprolol (P = 0.003). Multivariate analysis showed that carvedilol treatment was associated with a 35% reduction in the risk of ATA (HR: 0.65; 95% CI: 0.53-0.81; P < 0.001) when compared to metoprolol, and with a corresponding 35% reduction in the risk of inappropriate ICD shocks (HR: 0.65; 95% CI: 0.47-0.89; P = 0.008). Carvedilol vs metoprolol was also associated with a 16% reduction in the risk of fast VA. However, these findings did not reach statistical significance (HR: 0.84; 95% CI: 0.70-1.02; P = 0.085)., Conclusions: These findings suggests that HF patients with ICDs on carvedilol treatment experience a significantly lower risk of ATA and inappropriate ICD shocks when compared to treatment with metoprolol., Competing Interests: Funding Support and Author Disclosures Each of the MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The MADIT-RISK study was supported by the National Heart, Lung, and Blood Institute grant HL077478. The RAID trial was supported by National Heart, Lung, and Blood Institute grants UO1 HL096607 and UO1 HL096610 and by Gilead Sciences Inc grant IN-US-259-0125. Dr Goldenberg has received research grants from Boston Scientific, ZOLL Medical Corporation, Medtronic, Biosense-Webster, and Biotronik. Dr Kutyifa has received research grants from Boston Scientific, Biotronik, and ZOLL Medical Corporation, and Spire Inc; and has consulting agreements with ZOLL Medical Corporation and Biotronik. Dr Steinberg has received research grants from the National Institutes of Health, Medtronic, AliveCor, and Atricure. Dr Zareba has received research grants from Boston Scientific. Dr Aktas has received research grants from Boston Scientific, Abbott, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact., Methods: We evaluated 2025 patients with unique mutations for LQT1-LQT3. A patient-specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen-2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life-threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C-index., Results: A total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen-2. However, none of the genetic scores correlated with the risk of CE (Harrell's C-index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen-2 = 0.52) or LTE (Harrell's C-index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen-2 = 0.52). In contrast, high-risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001)., Conclusion: In congenital LQTS patients, well-established algorithms (CADD, SIFT, REVEL, and PolyPhen-2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations., (© 2023 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)