Daily Cardiology Research Analysis

BACKGROUND: Catheter ablation for atrial fibrillation (AF) is one of the most common cardiovascular procedures being performed worldwide. Despite the large body of evidence of its effectiveness, with a single exception, prior ablation studies were largely unblinded trials. Accordingly, residual concerns remained about placebo effects, both for AF recurrence and, in particular, on subjective outcomes such as quality of life or anxiety. Here, we compared pulsed field ablation (PFA) with a sham procedure to treat patients with symptomatic AF. METHODS: This prospective, sham-controlled, single-blind, randomized clinical trial with blinded end-point assessment enrolled patients with AF that was highly symptomatic (Atrial Fibrillation Effect on Quality-of-Life score <50). Patients were assigned 1:1 to PFA or a sham procedure. All participants received implantable cardiac monitors for continuous rhythm monitoring during follow-up. The 6-month co-primary outcomes were (1) time to first recurrence of atrial tachyarrhythmia and (2) changes from baseline in Atrial Fibrillation Effect on Quality-of-Life scores compared between groups. Secondary outcomes were AF burden and psychological distress (assessed by the Hospital Anxiety and Depression Scale [HADS]). RESULTS: Patients (n=60) were randomized to PFA or sham. At 6 months, the first co-primary end point of AF recurrence was met in 2 patients (6.7%) who underwent PFA and 25 patients (83.3%) who underwent sham (posterior hazard ratio, 19.6 [95% bayesian credible intervals, 6.7-76.9]; posterior probability of superiority >0.99). For the second co-primary end point, Atrial Fibrillation Effect on Quality-of-Life scores showed greater improvement from baseline with PFA than sham (improved by 43.9+18.1 points versus 11.3+27.9 points; posterior median difference, 32.6 [95% bayesian credible interval, 20.2-44.9]; posterior probability of superiority >0.99). AF burden at 6 months was significantly lower in the PFA than the sham group (0 [0-0] versus 0.43 [0.04-3.47]; between group median difference, -0.39 [95% credible interval, -2.5 to -0.1], posterior probability of superiority >0.99). The Hospital Anxiety and Depression Scale score changed by -4 points (-7.8 to -2.0) with PFA and by -0.5 (-4.5 to 1.0) with sham (group median difference, -3.5 [95% credible interval, -6.0 to -1.0]; posterior probability of superiority >0.99). CONCLUSIONS: In patients with AF, PFA was superior to sham in reducing arrhythmia recurrences and burden and improving quality of life and AF-associated psychological distress.

Rare coding alleles have crucial roles in the molecular diagnosis of genetic diseases. However, the systematic identification of these alleles has been challenging due to their scarcity in the general population. Here we discovered and characterized rare coding alleles contributing to genetic dyslipidemia, a principal risk for coronary artery disease (CAD), among 1,158,017 multi-ancestral individuals. Testing 2,997,401 rare coding variants, we identified 800 exome-wide significant associations (176 predicted loss of function (pLoF) and 624 missense variants). Associated alleles are enriched in functional variant classes, show significant additive and recessive associations, exhibit similar effects across populations and resolve pathogenicity for variants of unknown significance. Furthermore, we identified five lipid-associated genes associated with CAD. Among them, silencing RORC represents a potential therapeutic target for lowering low-density lipoprotein cholesterol. This study provides resources and insights for understanding causal mechanisms, quantifying the expressivity of rare coding alleles and identifying new drug targets for dyslipidemia across diverse populations.

BACKGROUND: Prior analyses of trials comparing direct oral anticoagulants (DOACs) to warfarin in atrial fibrillation (AF) have not routinely incorporated patient preferences, despite substantial variation in how patients value the trade-off between outcomes such as stroke and bleeding. By applying patient-centered approaches, we aimed to provide intuitive metrics to inform shared decision-making, particularly for frail older adults for whom DOAC benefit remains controversial. METHODS: Individual-level data from 58,634 participants in four randomized controlled trials (RCTs) comparing DOACs to warfarin (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation; COMBINE-AF) were analyzed using two patient-centered methods. Seven clinical outcomes (death, disabling stroke, major bleeding, moderate-severity stroke, systemic embolism, clinically relevant non-major bleeding, and minor stroke) were weighted based on a prior 1028-patient preference study with all values scaled relative to death. For the weighted composite endpoint (WCE), a survival-based approach incorporated weights of initial and recurrent events to estimate event-free survival. For win statistics, outcomes were hierarchically ranked for pairwise comparisons. The primary estimand was the 2-year difference in weighted death-equivalent events per 100 patients for the WCE. The win ratio was a secondary estimand. A prespecified subgroup analysis was conducted in frail, older patients. RESULTS: In the overall cohort, compared to warfarin, DOACs were associated with a more favorable outcome (WCE: 11.74 vs. 12.85 events per 100 patients; difference, -1.11 [95% confidence interval (CI): -1.61 to -0.61]; P<0.001; win ratio 1.11 [95% CI: 1.07 to 1.15]). In the prespecified subgroup of 5913 frail participants, the difference in the WCE was +0.50 events [95% CI: -1.39 to 2.40]) with a win ratio of 0.99 [95% CI: 0.90 to 1.08]) in individuals treated with DOAC versus warfarin. CONCLUSIONS: In individuals with atrial fibrillation pooled from four RCTs, DOACs were associated with a favorable net clinical benefit compared to warfarin when evaluated using a patient-weighted composite clinical outcome. (Funded by a Fellows Supplemental Funding grant from the Duke Clinical Research Institute's Executive Director Pathway Committee.).