Performance of a Protein Language Model for Variant Annotation in Cardiac Disease.

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: All genetic variants from an inherited arrhythmia program were examined using AlphaMissense via VarCard.io and compared with the ClinVar variant classification system, as well as another variant classification platform (Franklin by Genoox). The mutation reclassification rate and genotype-phenotype concordance were examined for all variants in the study. We included 266 patients with heritable cardiac diseases, harboring 339 missense variants. Of those, 230 (67.8%) were classified by ClinVar as either variants of unknown significance or nonclassified. Using VarCard.io, 198 variants of unknown significance (86.1%, 95% CI, 80.9-90.3) were reclassified to either likely pathogenic or likely benign. The reclassification rate was significantly higher for VarCard.io than for Franklin (86.1% versus 34.8%, P<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.

Catheter ablation alone versus catheter ablation with combined percutaneous left atrial appendage closure for atrial fibrillation: a systematic review and meta-analysis.

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: 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.

Catheter ablation compared to medical therapy for ventricular tachycardia in sarcoidosis: nationwide outcomes and hospital readmissions.

Background: Catheter ablation (CA) for ventricular tachycardia (VT) can be a useful treatment strategy, however, few studies have compared CA to medical therapy (MT) in the sarcoidosis population. Objective: To assess in-hospital outcomes and unplanned readmissions following CA for VT compared to MT in patients with sarcoidosis. Methods: Data was obtained from the Nationwide Readmissions Database between 2010 and 2019 to identify patients with sarcoidosis admitted for VT either undergoing CA or MT during elective and non-elective admission. Primary endpoints were a composite endpoint of inpatient mortality, cardiogenic shock, cardiac arrest and 30-day hospital readmissions. Procedural complications at index admission and causes of readmission were also identified. Results: Among 1581 patients, 1217 with sarcoidosis and VT underwent MT compared to 168 with CA during non-elective admission. 63 patients admitted electively underwent CA compared with 129 managed medically. There was no difference in the composite outcome for patients undergoing catheter ablation or medical therapy during both non-elective (9.0 % vs 12.0 %, p = 0.312) and elective admission (3.2 % vs. 7.8 %, p = 0.343). The most common cause of readmission were ventricular arrhythmias (VA) in both groups, however, those undergoing elective CA were less likely to be readmitted for VA compared to non-elective CA. The most common complication in the CA group was cardiac tamponade (4.8 %). Conclusion: VT ablation is associated with similar rates of 30-day readmission compared to MT and does not confer increased risk of harm with respect to inpatient mortality, cardiogenic shock or cardiac arrest. Further research is warranted to determine if a subgroup of sarcoidosis patients admitted with VT are better served with an initial conservative management strategy followed by VT ablation.

Pulsed Field vs Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation: Recurrent Atrial Arrhythmia Burden.

BACKGROUND: The ADVENT randomized trial revealed no significant difference in 1-year freedom from atrial arrhythmias (AA) between thermal (radiofrequency/cryoballoon) and pulsed field ablation (PFA). However, recent studies indicate that the postablation AA burden is a better predictor of clinical outcomes than the dichotomous endpoint of 30-second AA recurrence. OBJECTIVES: The goal of this study was to determine: 1) the impact of postablation AA burden on outcomes; and 2) the effect of ablation modality on AA burden. METHODS: In ADVENT, symptomatic drug-refractory patients with paroxysmal atrial fibrillation underwent PFA or thermal ablation. Postablation transtelephonic electrocardiogram monitor 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 transtelephonic electrocardiogram monitors. 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 antiarrhythmic drugs 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 antiarrhythmic drugs pre-ablation had no difference in AA burden between ablation groups. CONCLUSIONS: Compared with thermal ablation, PFA more often resulted in an AA burden less than the clinically significant threshold of 0.1% burden. (The FARAPULSE ADVENT PIVOTAL Trial PFA System vs SOC Ablation for Paroxysmal Atrial Fibrillation [ADVENT]; NCT04612244).

Long-Term Changes in Atrial Arrhythmia Burden After Renal Denervation Combined With Pulmonary Vein Isolation: SYMPLICITY-AF.

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: 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.

Left bundle branch area pacing using a stylet-driven, retractable-helix lead: Short-term results from a prospective multicenter IDE trial (the BIO-CONDUCT study).

BACKGROUND: Left bundle branch area pacing (LBBAP) has swiftly emerged as a safe and effective alternative to right ventricular pacing. Limited data exist on the use of retractable-helix, stylet-driven leads for LBBAP. OBJECTIVE: The objective of this study was to prospectively evaluate the performance and safety of a stylet-driven pacing lead in a rigorously controlled multicenter trial to support US market application. METHODS: A multicenter, prospective, nonrandomized trial enrolled patients with standard pacing indications. Implant procedure and lead data, including threshold, sensing, impedance, and capture type, were collected through 3 months. Primary end points were freedom from LBBAP lead-related serious complications through 3 months and LBBAP implant success according to prespecified criteria. A blinded clinical events committee adjudicated all potential end point complications. RESULTS: A total of 186 patients were included from 14 US sites. LBBAP implants were successful in 95.7% (178 of 186; 95% confidence interval 91.7%-98.1%; P < .0001 for comparison to the performance goal of 88%). Through the 3-month follow-up visit, 3 patients (1.7%) experienced a serious LBBAP complication (all lead dislodgments), resulting in a LBBAP lead-related complication-free rate of 98.3%. A total of 13 patients (7.8%) experienced any system- or procedure-related complication. The mean threshold was 0.89 V at 0.4 ms, the sensing value was 10.8 mV, and impedance was 608 Ω. CONCLUSION: The short-term results from this prospective trial demonstrate both high implant success and freedom from LBBAP lead-related complications using this stylet-driven retractable helix lead. This trial supports the safety, use, and effectiveness of stylet-driven leads for performing contemporary physiologic pacing.

QTNet: Predicting Drug-Induced QT Prolongation With Artificial Intelligence-Enabled Electrocardiograms.

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: 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.

Risk of malignant ventricular arrhythmias in patients with mildly to moderately reduced ejection fraction after permanent pacemaker implantation.

BACKGROUND: Many patients with mildly to moderately reduced left ventricular ejection fraction (LVEF) who require permanent pacemaker (PPM) implantation do not have a concurrent indication for implantable cardioverter-defibrillator (ICD) therapy. However, the risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in this population is unknown. OBJECTIVE: The aim of this study was to describe the risk of VT/VF after PPM implantation in patients with mildly to moderately reduced LVEF. METHODS: Retrospective analysis was performed of 243 patients with LVEF between 35% and 49% who underwent PPM placement and did not meet indications for an ICD. The primary end point was occurrence of sustained VT/VF. Competing risks regression was performed to calculate subhazard ratios for the primary end point. RESULTS: Median follow-up was 27 months; 73% of patients were male, average age was 79 ± 10 years, average LVEF was 42% ± 4%, and 70% were New York Heart Association class II or above. Most PPMs were implanted for sick sinus syndrome (34%) or atrioventricular block (50%). Of 243 total patients, 11 (4.5%) met the primary end point of VT/VF. Multivessel coronary artery disease (CAD) was associated with significantly higher rates of VT/VF, with a subhazard ratio of 5.4 (95% CI, 1.5-20.1; P = .01). Of patients with multivessel CAD, 8 of 82 (9.8%) patients met the primary end point for an annualized risk of 4.3% per year. CONCLUSION: Patients with mildly to moderately reduced LVEF and multivessel CAD undergoing PPM implantation are at increased risk for the development of malignant ventricular arrhythmias. Patients in this population may benefit from additional risk stratification for VT/VF and consideration for upfront ICD implantation.

Conduction velocity is reduced in the posterior wall of hypertrophic cardiomyopathy patients with normal bipolar voltage undergoing ablation for paroxysmal atrial fibrillation.

OBJECTIVES: 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: There were no differences in baseline demographics, atrial size, or valvular disease between HCM and control patients. Patients with HCM had significantly reduced atrial conduction velocity compared to controls (0.44 ± 0.17 vs 0.56 ± 0.10 m/s, p = 0.01), despite no significant differences in bipolar voltage amplitude (1.23 ± 0.38 vs 1.20 ± 0.41 mV, p = 0.76). There was a statistically significant reduction in conduction velocity in the posterior left atrium in HCM patients relative to controls (0.43 ± 0.18 vs 0.58 ± 0.10 m/s, p = 0.003), but not in the anterior left atrium (0.46 ± 0.17 vs 0.55 ± 0.10 m/s, p = 0.05). There was a significant association between conduction velocity and interventricular septal thickness (slope = -0.013, R2 = 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.

Point-of-Care Chemistry-Guided Dialysate Adjustment to Reduce Arrhythmias: A Pilot Trial.

Introduction: 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: 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: 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: 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.

Explainable SHAP-XGBoost models for in-hospital mortality after myocardial infarction.

Background: A lack of explainability in published machine learning (ML) models limits clinicians' understanding of how predictions are made, in turn undermining uptake of the models into clinical practice. Objective: The purpose of this study was to develop explainable ML models to predict in-hospital mortality in patients hospitalized for myocardial infarction (MI). Methods: Adult patients hospitalized for an MI were identified in the National Inpatient Sample between January 1, 2012, and September 30, 2015. The resulting cohort comprised 457,096 patients described by 64 predictor variables relating to demographic/comorbidity characteristics and in-hospital complications. The gradient boosting algorithm eXtreme Gradient Boosting (XGBoost) was used to develop explainable models for in-hospital mortality prediction in the overall cohort and patient subgroups based on MI type and/or sex. Results: The resulting models exhibited an area under the receiver operating characteristic curve (AUC) ranging from 0.876 to 0.942, specificity 82% to 87%, and sensitivity 75% to 87%. All models exhibited high negative predictive value ≥0.974. The SHapley Additive exPlanation (SHAP) framework was applied to explain the models. The top predictor variables of increasing and decreasing mortality were age and undergoing percutaneous coronary intervention, respectively. Other notable findings included a decreased mortality risk associated with certain patient subpopulations with hyperlipidemia and a comparatively greater risk of death among women below age 55 years. Conclusion: The literature lacks explainable ML models predicting in-hospital mortality after an MI. In a national registry, explainable ML models performed best in ruling out in-hospital death post-MI, and their explanation illustrated their potential for guiding hypothesis generation and future study design.

A Tool to Integrate Electrophysiological Mapping for Cardiac Radioablation of Ventricular Tachycardia.

Purpose: Cardiac radioablation is an emerging therapy for recurrent ventricular tachycardia. Electrophysiology (EP) data, including electroanatomic maps (EAM) and electrocardiographic imaging (ECGI), provide crucial information for defining the arrhythmogenic target volume. The absence of standardized workflows and software tools to integrate the EP maps into a radiation planning system limits their use. This study developed a comprehensive software tool to enable efficient utilization of the mapping for cardiac radioablation treatment planning. Methods and Materials: The tool, HeaRTmap, is a Python-scripted plug-in module on the open-source 3D Slicer software platform. HeaRTmap is able to import EAM and ECGI data and visualize the maps in 3D Slicer. The EAM is translated into a 3D space by registration with cardiac magnetic resonance images (MRI) or computed tomography (CT). After the scar area is outlined on the mapping surface, the tool extracts and extends the annotated patch into a closed surface and converts it into a structure set associated with the anatomic images. The tool then exports the structure set and the images as The Digital Imaging and Communications in Medicine Standard in Radiotherapy for a radiation treatment planning system to import. Overlapping the scar structure on simulation CT, a transmural target volume is delineated for treatment planning. Results: The tool has been used to transfer Ensite NavX EAM data into the Varian Eclipse treatment planning system in radioablation on 2 patients with ventricular tachycardia. The ECGI data from CardioInsight was retrospectively evaluated using the tool to derive the target volume for a patient with left ventricular assist device, showing volumetric matching with the clinically used target with a Dice coefficient of 0.71. Conclusions: HeaRTmap smoothly fuses EP information from different mapping systems with simulation CT for accurate definition of radiation target volume. The efficient integration of EP data into treatment planning potentially facilitates the study and adoption of the technique.