Daily Cardiology Research Analysis

BACKGROUND: Atrial fibrillation, the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 (T-box 5) is essential for normal atrial rhythm. Its inactivation causes loss of atrial cardiomyocyte (aCM) enhancer accessibility, looping, transcriptional identity, and spontaneous atrial fibrillation. TBX5 interacts with CHD4 (chromodomain helicase DNA-binding protein 4), a chromatin remodeling ATPase canonically associated with the NuRD (nucleosome remodeling and deacetylase) repressor complex. METHODS: We investigated mechanisms by which TBX5 regulates chromatin organization by studying mice with aCM-selective inactivation of TBX5 or CHD4. We integrated multiple genomics approaches including concurrent single-nucleus transcriptome and open chromatin profiling and genome-wide TBX5 and CHD4 chromatin occupancy assays. RESULTS: We found that TBX5 recruits CHD4 to 33 170 genomic regions (TBX5-enhanced CHD4 sites). In addition to the canonical repressive activity of CHD4, we uncovered a CHD4 activator function predominantly at sites to which it was recruited by TBX5. TBX5-enhanced CHD4 recruitment increased local chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of CHD4 recruitment by TBX5 was crucial for sinus rhythm; mice with CHD4 inactivation in aCMs had increased atrial fibrillation vulnerability. Assaying TBX5 binding in CONCLUSIONS: Our findings reveal that normal atrial rhythm requires CHD4, which activates and represses atrial genes in a context-dependent manner to maintain aCM gene expression, aCM identity, and atrial rhythm homeostasis.

BACKGROUND AND AIMS: Invasive coronary function testing (CFT) identifies coronary vasomotor disorders in up to 90% of patients with angina with non-obstructive coronary arteries (ANOCA). The ILIAS ANOCA trial hypothesized that routine ad hoc CFT would be feasible, safe, and effective in providing an early, comprehensive diagnosis. Additionally, it was anticipated that combining CFT with a disease-specific treatment protocol would significantly improve quality of life in ANOCA patients compared with standard care. METHODS: After excluding patients with obstructive coronary artery disease (CAD) during clinically indicated invasive coronary angiography (ICA), eligible patients underwent CFT and were randomized to either the standard care group, where CFT results remained blinded, or the intervention group, where CFT results were disclosed along with a tailored medical therapy protocol. The primary outcome was the mean difference in the within-subject change in Seattle Angina Questionnaire summary score (SAQSS) between groups from baseline to a follow-up of 6 months. The trial is registered with the International Clinical Trials Registry Platform (NL-OMON20739). RESULTS: A total of 255 patients consented, of whom 153 patients (60%) without CAD underwent CFT and were randomized 1:1 to the standard care (n = 76) or intervention group (n = 77). All CFT procedures were successful without adverse events. A vasomotor disorder was identified in 120 patients (78%). At 6-month follow-up, the SAQSS improved significantly in the intervention group compared with the control group, with an intervention effect of 9.4 units (95% confidence interval 3.9-14.9, P = .001). There were no major adverse cardiac events at the 6-month follow-up. CONCLUSIONS: Routine CFT during the initial ICA was feasible, safe, and had high diagnostic yield. Implementing a pragmatic CFT protocol combined with a disease-specific treatment protocol significantly improved disease-related quality of life in patients with ANOCA compared with standard care.

BACKGROUND AND AIMS: Guidelines recommend against routine initiation of low-dose aspirin in older adults for primary prevention of atherosclerotic cardiovascular disease events. This study aimed to estimate long-term and post-trial effects of aspirin on major adverse cardiovascular events (MACE) and major haemorrhage using extended follow-up of participants from the ASPREE trial. METHODS: In-trial (2010-17) and post-trial (2017-22) data were analysed. At enrolment, participants were aged ≥70 years (≥65 years for US minorities) without prior cardiovascular events, dementia, or independence-limiting physical disability. Randomization was to daily low-dose aspirin or matching placebo for the 4.7 years of the trial. RESULTS: Of the 19 114 participants randomized (9525 aspirin, 9589 placebo), 15 668 without in-trial MACE consented to post-trial follow-up. No long-term benefit of randomization to aspirin was observed for MACE for the entire in-trial and post-trial period [hazard ratio (HR) 1.04, 95% confidence interval (CI) .94, 1.15]. However, during the post-trial period (median 4.3 years), there was a higher rate of MACE (HR 1.17, 95% CI 1.01, 1.36) in those randomized to aspirin compared with placebo. Over the entire period, a higher rate of major haemorrhage was observed in the randomized aspirin group compared with placebo (HR 1.24, 95% CI 1.10, 1.39). CONCLUSIONS: The present study provides novel evidence concerning long-term MACE and haemorrhage following aspirin use in initially healthy older adults. The finding of no long-term MACE benefit needs to be considered in clinical decision-making if aspirin is being considered for use in this context.