Accumulating evidence suggests that epitranscriptomic regulation, particularly the m6A modification, contributes to heart failure progression. However, modification dynamics are not yet mapped and studied at base resolution and transcript isoform level. Here we use Nanopore direct RNA sequencing to profile m6A remodeling at transcriptome-wide and site-specific resolution in a mouse heart failure model. We identify thousands of differentially methylated sites with distinct sequence motifs and associations with RNA regulatory and cardiac function processes. Cross-species comparison reveals conserved m6A regulatory features in mouse and human heart failure. Isoform-resolved analysis further uncovers co/posttranscriptional regulation events involving isoform switching and m6A regulation in the SYNPO2L transcript. Mechanistically, m6A modification, alternative promoter usage and associated regulatory elements collectively explain this observation. Overall, our study provides a comprehensive, high-resolution characterization of m6A landscape and its remodeling in heart failure. Isoform-level regulation exemplifies an underappreciated shaping of RNA expression and modification. Xu et al. use nanopore direct RNA sequencing to map heart failure-associated m6A RNA modifications at transcriptome-wide and single-site resolution. Their findings reveal conserved m6A remodeling patterns and isoform-specific regulation of SYNPO2L, highlighting complex epitranscriptomic mechanisms that influence cardiac gene expression and contribute to heart failure progression.
Invasive coronary angiography remains central to the management of coronary artery disease, but it is interpreted visually, one projection at a time. Now, in a non-randomized two-center study, a video-text foundation model generates reports that predicts clinical outcomes and aligns more closely with expert assessments than routine single-reader reports.
Base-resolution, long-read RNA sequencing reveals that an apparent loss of m6A on transcripts from a heart-failure-associated gene reflects a switch to an inherently less methylated isoform, rather than a loss of methylation per se.
Clonal hematopoiesis (CH), the expansion of blood cell clones carrying acquired mutations, is an independent risk factor for cardiovascular disease. Although mutations in DNMT3A and TET2 are well studied, the cardiovascular consequences of KDM6A mutations remain unclear. KDM6A is an X-linked histone demethylase that is commonly mutated in patients with heart failure (HF). Here we performed multiomics profiling and functional characterization of mouse models and patient-derived data to show that hematopoietic KDM6A loss impairs cardiac recovery after myocardial infarction (MI). KDM6A deficiency increases myeloid cell recruitment to the injured heart and reprograms monocytes, macrophages and neutrophils toward inflammatory, migratory and glycolytic states. Patients with HF and KDM6A-driven CH show similar pro-inflammatory monocyte signatures. KDM6A-silenced macrophages promote cardiomyocyte hypertrophy and cardiac fibroblast activation. Notably, IL-1β blockade after MI rescued the adverse cardiac phenotype of hematopoietic KDM6A loss. These findings identify KDM6A-driven CH as a driver of immune dysregulation and IL-1β signaling as a potential therapeutic target in CH-associated HF. Solomonidis et al. reveal that hematopoietic KDM6A-driven clonal hematopoiesis worsens post-MI cardiac recovery by promoting inflammatory myeloid reprogramming. IL-1β blockade reverses these adverse effects, highlighting a potential therapeutic strategy.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is promoted by atrial fibrosis, a form of structural remodelling for which effective therapies are lacking. MicroRNA-31-5p (miR-31-5p), an aging-associated, atrial-enriched microRNA, has been linked to AF, but its role in atrial fibrosis is unknown. Here we show that atrial fibroblasts from patients with persistent AF exhibit increased miR-31-5p expression and reduced expression of the calcitonin receptor (CTR, encoded by CALCR). MiR-31-5p directly represses CTR and promotes pro-fibrotic fibroblast responses, whereas its inhibition restores CTR expression. Fibroblast-specific overexpression of miR-31 in mice reduces atrial CTR expression, increases atrial fibrosis and enhances arrhythmia susceptibility. Selective disruption of miR-31-5p−CALCR binding using a locked nucleic acid target site blocker restores atrial CTR expression, prevents fibrosis progression and reduces arrhythmia burden. In mice with established atrial remodeling, this strategy promotes fibrosis regression, identifying the miR-31-5p−CTR axis as a potential therapeutic target in AF. Trompf, Cox, Hulsurkar et al. show that the selective disruption of the miR-31-5p−CTR interaction in atrial fibrillation reverses established atrial fibrosis and reduces atrial fibrillation susceptibility, highlighting a promising RNA-based therapeutic strategy.
