Faculty Bibliography

BACKGROUND:Genetic testing is a cornerstone in the assessment of many cardiac diseases. However, variants are frequently classified as variants of unknown significance, limiting the utility of testing. Recently, the DeepMind group (Google) developed AlphaMissense, a unique artificial intelligence-based model, based on language model principles, for the prediction of missense variant pathogenicity. We aimed to report on the performance of AlphaMissense, accessed by VarCardio, an open web-based variant annotation engine, in a real-world cardiovascular genetics center. METHODS AND RESULTS/RESULTS:<0.001). Genotype-phenotype concordance was highly aligned using VarCard.io predictions, at 95.9% (95% CI, 92.8-97.9) concordance rate. For 109 variants classified as pathogenic, likely pathogenic, benign, or likely benign by ClinVar, concordance with VarCard.io was high (90.5%). CONCLUSIONS:AlphaMissense, accessed via VarCard.io, may be a highly efficient tool for cardiac genetic variant interpretation. The engine's notable performance in assessing variants that are classified as variants of unknown significance in ClinVar demonstrates its potential to enhance cardiac genetic testing.

BACKGROUND:The autonomic nervous system plays an important role in atrial fibrillation (AF) and hypertension. Renal denervation (RDN) lowers blood pressure (BP), but its role in AF is poorly understood. OBJECTIVES/OBJECTIVE:The purpose of this study was to investigate whether RDN reduces AF recurrence after pulmonary vein isolation (PVI). METHODS:This study randomized patients from 8 centers (United States, Germany) with drug-refractory AF for treatment with PVI+RDN vs PVI alone. A multielectrode radiofrequency Spyral catheter system was used for RDN. Insertable cardiac monitors were used for continuous rhythm monitoring. The primary efficacy endpoint was ≥2 minutes of AF recurrence or repeat ablation during all follow-up. The secondary endpoints included atrial arrhythmia (AA) burden, discontinuation of class I/III antiarrhythmic drugs, and BP changes from baseline. RESULTS:A total of 70 patients with AF (52 paroxysmal, 18 persistent) and uncontrolled hypertension were randomized (RDN+PVI, n = 34; PVI, n = 36). At 3.5 years, 26.2% and 21.4% of patients in RDN+PVI and PVI groups, respectively, were free from the primary efficacy endpoint (log rank P = 0.73). Patients with mean ≥1 h/d AA had less daily AA burden after RDN+PVI vs PVI (4.1 hours vs 9.2 hours; P = 0.016). More patients discontinued class I/III antiarrhythmic drugs after RDN+PVI vs PVI (45% vs 14%; P = 0.040). At 1 year, systolic BP changed by -17.8 ± 12.8 mm Hg and -13.7 ± 18.8 mm Hg after RDN+PVI and PVI, respectively (P = 0.43). The composite safety endpoint was not significantly different between groups. CONCLUSIONS:In patients with AF and uncontrolled BP, RDN+PVI did not prevent AF recurrence more than PVI alone. However, RDN+PVI may reduce AF burden and antiarrhythmic drug usage, but this needs further prospective validation.

BACKGROUND:Combined catheter ablation (CA) with percutaneous left atrial appendage closure (LAAC) may produce comprehensive treatment for atrial fibrillation (AF) whereby rhythm control is achieved and stroke risk is reduced without the need for chronic oral anticoagulation. However, the efficacy and safety of this strategy is still controversial. METHODS:This meta-analysis was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Medline, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. The risk of bias was assessed using the Modified Newcastle-Ottawa scale and Cochrane risk of bias tool. Eligible studies reported outcomes in patients with AF who underwent combined CA and LAAC vs CA alone. Studies performing CA without pulmonary vein isolation were excluded. RESULTS:Eight studies comprising 1878 patients were included (2 RCT, 6 observational). When comparing combined CA and LAAC vs CA alone, pooled results showed no difference in arrhythmia recurrence (risk ratio (RR) 1.04; 95% confidence interval (CI) 0.82-1.33), stroke or systemic embolism (RR 0.78; 95% CI 0.27-2.22), or major periprocedural complications (RR 1.28; 95% CI 0.28-5.89). Total procedure time was shorter with CA alone (mean difference 48.45 min; 95% CI 23.06-74.62). CONCLUSION/CONCLUSIONS:Combined CA with LAAC for AF is associated with similar rates of arrhythmia-free survival, stroke, and major periprocedural complications when compared to CA alone. A combined strategy may be as safe and efficacious for patients at moderate to high risk for bleeding events to negate the need for chronic oral anticoagulation.

BACKGROUND:The ADVENT randomized trial revealed no significant difference in 1-year freedom from atrial arrhythmias (AA) between thermal (RF/Cryo) and pulsed field ablation (PFA). However, recent studies indicate that the post-ablation AA burden is a better predictor of clinical outcomes than the dichotomous endpoint of 30-second AA recurrence. OBJECTIVES/OBJECTIVE:To determine i) the impact of post-ablation AA burden on outcomes, and ii) the effect of ablation modality on AA burden. METHODS:In ADVENT, symptomatic drug-refractory paroxysmal AF (PAF) patients underwent PFA or thermal ablation. Post-ablation transtelephonic ECG monitor (TTM) recordings were collected weekly or for symptoms, and 72-hour Holters were at 6- and 12-months. AA burden was calculated from percentage AA on Holters and TTMs. Quality-of-life assessments were at baseline and 12-months. RESULTS:From 593 randomized patients (299 PFA, 294 thermal), using aggregate PFA/thermal data, an AA burden exceeding 0.1% was associated with a significantly reduced quality-of-life and an increase in clinical interventions: redo ablation, cardioversion and hospitalization. There were more patients with residual AA burden <0.1% with PFA than thermal ablation (OR 1.5, 95%CI: 1.0, 2.3; p=0.04). Evaluation of outcomes by baseline demographics revealed that patients with prior failed Class I/III AADs had less residual AA burden after PFA compared to thermal ablation (OR 2.5, 95%CI: 1.4, 4.3; p=0.002); patients receiving only Class II/IV AADs pre-ablation had no difference in AA burden between ablation groups. CONCLUSION/CONCLUSIONS:Compared to thermal ablation, PFA more often resulted in an AA burden less than the clinically-significant threshold of 0.1% burden.

BACKGROUND:Prediction of drug-induced long QT syndrome (diLQTS) is of critical importance given its association with torsades de pointes. There is no reliable method for the outpatient prediction of diLQTS. OBJECTIVES/OBJECTIVE:This study sought to evaluate the use of a convolutional neural network (CNN) applied to electrocardiograms (ECGs) to predict diLQTS in an outpatient population. METHODS:We identified all adult outpatients newly prescribed a QT-prolonging medication between January 1, 2003, and March 31, 2022, who had a 12-lead sinus ECG in the preceding 6 months. Using risk factor data and the ECG signal as inputs, the CNN QTNet was implemented in TensorFlow to predict diLQTS. RESULTS:Models were evaluated in a held-out test dataset of 44,386 patients (57% female) with a median age of 62 years. Compared with 3 other models relying on risk factors or ECG signal or baseline QTc alone, QTNet achieved the best (P < 0.001) performance with a mean area under the curve of 0.802 (95% CI: 0.786-0.818). In a survival analysis, QTNet also had the highest inverse probability of censorship-weighted area under the receiver-operating characteristic curve at day 2 (0.875; 95% CI: 0.848-0.904) and up to 6 months. In a subgroup analysis, QTNet performed best among males and patients ≤50 years or with baseline QTc <450 ms. In an external validation cohort of solely suburban outpatient practices, QTNet similarly maintained the highest predictive performance. CONCLUSIONS:An ECG-based CNN can accurately predict diLQTS in the outpatient setting while maintaining its predictive performance over time. In the outpatient setting, our model could identify higher-risk individuals who would benefit from closer monitoring.

BACKGROUND:Left bundle branch area pacing (LBBAP) has swiftly emerged as a safe and effective alternative to right ventricular (RV) pacing. Limited data exists on the use of retractable-helix, stylet-driven leads (SDL) for LBBAP. OBJECTIVE:The objective is to prospectively evaluate performance and safety of the Solia S stylet-driven pacing lead in a rigorously controlled multi-center trial to support U.S. market application. METHODS:A multi-center, prospective, non-randomized trial enrolled patients with standard pacing indications. Implant procedural and lead data, including threshold, sensing, impedance, and capture type were collected through 3-months. Primary endpoints were freedom from LBBAP lead-related serious complications through 3-months and LBBAP implant success according to pre-specified criteria. A blinded Clinical Events Committee (CEC) adjudicated all potential endpoint complications. RESULTS:A total of 186 patients were included from 14 US sites. LBBAP implants were successful in 95.7% (178/186; 95% CI: 91.7%, 98.1%; p< 0.0001 for comparison to performance goal of 88%). Through the 3-month follow-up, 3 patients experienced a serious LBBAP complication, all lead dislodgements, resulting in a LBBAP lead-related complication-free rate of 98.3%. A total of 13 patients (7.8%) experienced any system-related or procedure-related complication. Mean threshold was 0.89V at 0.4ms, sensing was 10.8mV, and impedance was 608 ohms. CONCLUSION/CONCLUSIONS:The short-term results from this prospective trial demonstrate both high implant success and freedom from LBBAP lead-related complications utilizing this stylet driven retractable helix lead. This trial supports the safety, use, and effectiveness of SDL for performing contemporary physiologic pacing.

OBJECTIVES/OBJECTIVE:We investigated characteristics of left atrial conduction in patients with HCM, paroxysmal AF and normal bipolar voltage. BACKGROUND:Patients with hypertrophic cardiomyopathy (HCM) exhibit abnormal cardiac tissue arrangement. The incidence of atrial fibrillation (AF) is increased fourfold in patients with HCM and confers a fourfold increased risk of death. Catheter ablation is less effective in HCM, with twofold increased risk of AF recurrence. The mechanisms of AF perpetuation in HCM are poorly understood. METHODS:We analyzed 20 patients with HCM and 20 controls presenting for radiofrequency ablation of paroxysmal AF normal left atrial voltage(> 0.5 mV). Intracardiac electrograms were extracted from the CARTO mapping system and analyzed using Matlab/Python code interfacing with Core OpenEP software. Conduction velocity maps were calculated using local activation time gradients. RESULTS: = 0.13, p = 0.03). CONCLUSIONS:Atrial conduction velocity is significantly reduced in patients with HCM and paroxysmal AF, possibly contributing to arrhythmia persistence after catheter ablation.

INTRODUCTION/UNASSIGNED:Excessive dialytic potassium (K) and acid removal are risk factors for arrhythmias; however, treatment-to-treatment dialysate modification is rarely performed. We conducted a multicenter, pilot randomized study to test the safety, feasibility, and efficacy of 4 point-of-care (POC) chemistry-guided protocols to adjust dialysate K and bicarbonate (HCO3) in outpatient hemodialysis (HD) clinics. METHODS/UNASSIGNED:Participants received implantable cardiac loop monitors and crossed over to four 4-week periods with adjustment of dialysate K or HCO3 at each treatment according to pre-HD POC values: (i) K-removal minimization, (ii) K-removal maximization, (iii) Acidosis avoidance, and (iv) Alkalosis avoidance. The primary end point was percentage of treatments adhering to the intervention algorithm. Secondary endpoints included pre-HD K and HCO variability, adverse events, and rates of clinically significant arrhythmias (CSAs). RESULTS/UNASSIGNED:Nineteen subjects were enrolled in the study. HD staff completed POC testing and correctly adjusted the dialysate in 604 of 708 (85%) of available HD treatments. There was 1 K ≤3, 29 HCO3 <20 and 2 HCO3 >32 mEq/l and no serious adverse events related to study interventions. Although there were no significant differences between POC results and conventional laboratory measures drawn concurrently, intertreatment K and HCO3 variability was high. There were 45 CSA events; most were transient atrial fibrillation (AF), with numerically fewer events during the alkalosis avoidance period (8) and K-removal maximization period (3) compared to other intervention periods (17). There were no significant differences in CSA duration among interventions. CONCLUSION/UNASSIGNED:Algorithm-guided K/HCO3 adjustment based on POC testing is feasible. The variability of intertreatment K and HCO3 suggests that a POC-laboratory-guided algorithm could markedly alter dialysate-serum chemistry gradients. Definitive end point-powered trials should be considered.