Search

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes—rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10−18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10−13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case–control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

BACKGROUND: Cryoballoon ablation (CBA) as a first-line rhythm control strategy is superior to antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrence; the impact of first-line CBA on quality of life (QoL) and symptoms has not been well characterized. METHOD(S): Patients aged 18 to 75 with symptomatic paroxysmal AF naive to rhythm control therapy were randomized (1:1) to CBA (Arctic Front Advance, Medtronic) or AAD (Class I or III). Symptoms and QoL were assessed at baseline, 1, 3, 6, 9, and 12 months using the EHRA classification and Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and SF-36v2 questionnaires. Symptomatic palpitations were evaluated via patient diary. RESULT(S): Overall, 107 patients were randomized to CBA and 111 to AAD; crossovers occurred in 9%. Larger improvements in the AFEQT summary, subscale and treatment satisfaction scores were observed at 12 months with CBA vs AAD (all P <0.05). At 12 months, the mean adjusted difference in the AFEQT summary score was 9.9 points higher in the CBA group (95% CI: 5.5 -14.2, P <0.001). Clinically important improvements in the SF-36 physical and mental component scores were observed at 12 months in both groups, with no significant between group differences at this timepoint. In the CBA vs AAD group, larger improvements in EHRA class were observed at 6, 9 and 12 months (P <0.05) and the incidence rate of symptomatic palpitations was lower (4.6 vs 15.2 days/year post-blanking; IRR: 0.30, P <0.001). CONCLUSION(S): In patients with symptomatic AF, first-line CBA was superior to AAD for improving AF-specific QoL and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01803438.Copyright © 2021. Published by Elsevier Inc.

Aims: Treatment guidelines for patients with atrial fibrillation (AF) suggest that patients should be managed with an antiarrhythmic drug (AAD) before undergoing catheter ablation (CA). This study evaluated whether pulmonary vein isolation employing cryoballoon CA is superior to AAD therapy for the prevention of atrial arrhythmia (AA) recurrence in rhythm control naive patients with paroxysmal AF (PAF). Methods and Results: A total of 218 treatment naive patients with symptomatic PAF were randomized (1: 1) to cryoballoon CA (Arctic Front Advance, Medtronic) or AAD (Class I or III) and followed for 12 months. The primary endpoint was >=1 episode of recurrent AA (AF, atrial flutter, or atrial tachycardia) >30 s after a prespecified 90-day blanking period. Secondary endpoints included the rate of serious adverse events (SAEs) and recurrence of symptomatic palpitations (evaluated via patient diaries). Freedom from AA was achieved in 82.2% of subjects in the cryoballoon arm and 67.6% of subjects in the AAD arm (HR = 0.48, P = 0.01). There were no group differences in the time-to-first (HR = 0.76, P = 0.28) or overall incidence [incidence rate ratio (IRR)=0.79, P = 0.28] of SAEs. The incidence rate of symptomatic palpitations was lower in the cryoballoon (7.61 days/year) compared with the AAD arm (18.96 days/year; IRR = 0.40, P < 0.001). Conclusion(s): Cryoballoon CA was superior to AAD therapy, significantly reducing AA recurrence in treatment naive patients with PAF. Additionally, cryoballoon CA was associated with lower symptom recurrence and a similar rate of SAEs compared with AAD therapy.Copyright © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Aims: Treatment guidelines for patients with atrial fibrillation (AF) suggest that patients should be managed with an antiarrhythmic drug (AAD) before undergoing catheter ablation (CA). This study evaluated whether pulmonary vein isolation employing cryoballoon CA is superior to AAD therapy for the prevention of atrial arrhythmia (AA) recurrence in rhythm control naive patients with paroxysmal AF (PAF). Methods and Results: A total of 218 treatment naive patients with symptomatic PAF were randomized (1: 1) to cryoballoon CA (Arctic Front Advance, Medtronic) or AAD (Class I or III) and followed for 12 months. The primary endpoint was >=1 episode of recurrent AA (AF, atrial flutter, or atrial tachycardia) >30 s after a prespecified 90-day blanking period. Secondary endpoints included the rate of serious adverse events (SAEs) and recurrence of symptomatic palpitations (evaluated via patient diaries). Freedom from AA was achieved in 82.2% of subjects in the cryoballoon arm and 67.6% of subjects in the AAD arm (HR = 0.48, P = 0.01). There were no group differences in the time-to-first (HR = 0.76, P = 0.28) or overall incidence [incidence rate ratio (IRR)=0.79, P = 0.28] of SAEs. The incidence rate of symptomatic palpitations was lower in the cryoballoon (7.61 days/year) compared with the AAD arm (18.96 days/year; IRR = 0.40, P < 0.001). Conclusion(s): Cryoballoon CA was superior to AAD therapy, significantly reducing AA recurrence in treatment naive patients with PAF. Additionally, cryoballoon CA was associated with lower symptom recurrence and a similar rate of SAEs compared with AAD therapy.Copyright © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

BACKGROUND: Cryoballoon ablation (CBA) as a first-line rhythm control strategy is superior to antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrence; the impact of first-line CBA on quality of life (QoL) and symptoms has not been well characterized. METHOD(S): Patients aged 18 to 75 with symptomatic paroxysmal AF naive to rhythm control therapy were randomized (1:1) to CBA (Arctic Front Advance, Medtronic) or AAD (Class I or III). Symptoms and QoL were assessed at baseline, 1, 3, 6, 9, and 12 months using the EHRA classification and Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and SF-36v2 questionnaires. Symptomatic palpitations were evaluated via patient diary. RESULT(S): Overall, 107 patients were randomized to CBA and 111 to AAD; crossovers occurred in 9%. Larger improvements in the AFEQT summary, subscale and treatment satisfaction scores were observed at 12 months with CBA vs. AAD (all P<0.05). At 12 months, the mean adjusted difference in the AFEQT summary score was 9.9 points higher in the CBA group (95% CI: 5.5-14.2, P<0.001). Clinically important improvements in the SF-36 physical and mental component scores were observed at 12 months in both groups, with no significant between group differences at this timepoint. In the CBA vs. AAD group, larger improvements in EHRA class were observed at 6, 9 and 12 months (P<0.05) and the incidence rate of symptomatic palpitations was lower (4.6 vs. 15.2 days/year post-blanking; IRR: 0.30, P<0.001). CONCLUSION(S): In patients with symptomatic AF, first-line CBA was superior to AAD for improving AF-specific QoL and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01803438.Copyright © 2021. Published by Elsevier Inc.

Background: By consensus statements, catheter ablation is a recommended treatment for patients with symptomatic drug-refractory paroxysmal atrial fibrillation (AF), as patients try to alleviate the burdensome AF symptoms that reduce the Quality of Life (QoL). Yet, first-line treatment of symptomatic patients via catheter ablation prior to initiation of antiarrhythmic drugs (AADs) is only a reasonable alternative (Class IIa). Clearly, more clinical data is necessary that compares catheter ablation to AAD therapy in treatment naive patients. Purpose(s): The Cryo-FIRST trial was designed to compare AAD treatment against pulmonary vein isolation (PVI) while using a cryoballoon catheter (Arctic Front Advance; Medtronic, Inc.). This current data analysis examines the QoL endpoints when comparing AADs to cryoballoon ablation in patients with symptomatic treatment naive paroxysmal AF. Method(s): This randomized multicenter trial enrolled 220 patients from 18 sites in 9 countries (Europe, Australia, and Latin America) in a prospective open-blinded endpoint study design. Patients had not been administered a class I or III AAD for longer than 48 hours for inclusion into the study. Subjects were randomized (1:1) into a cohort that was administered AAD therapy or a cohort that received PVI via cryoablation. The prespecified QoL endpoint at 12 months was measured using the Atrial Fibrillation Effect on Quality of Life (AFEQT) scores, and QoL recordings were taken at baseline, 1, 3, 6, 9, and 12 months following the index treatment. Result(s): Of the 218 patients randomized (age 52+/-13 years, 68% male) 86% completed the 12-month follow-up. Crossovers occurred in 9% of subjects (N=20), including: 1 subject in the cryoablation arm and 19 subjects in the AAD arm. At 12 months, 86.5% of the patients in the cryoablation arm and 70.4% of the patients in the AAD arm where without symptoms (EHRA score 1). The mean AFEQT summary score was more favorable in the catheter ablation group comp