Cardiometabolic stress induces atrial myopathy in mice, characterized by structural remodelling, metabolic dysfunction, and incomplete transcriptional recovery

Background The mechanisms underlying atrial remodelling and recovery following the withdrawal of cardiometabolic stress remain incompletely understood. We investigated the functional, metabolic, and transcriptional consequences of metabolic-hypertensive stress (MHS), a murine model of cardiometabolic HFpEF, in the left atrium (LA) and assessed the reversibility of these alterations following myocardial recovery. Methods and Results Male and female mice underwent a two-hit HFpEF-inducing protocol consisting of angiotensin II infusion and a high-fat diet combined with physical inactivity (metabolic-hypertensive stress, MHS). Following 4 weeks of MHS, mice underwent a 4-week myocardial recovery (MR) phase involving stress withdrawal, dietary normalization, and voluntary exercise. We assessed LA function by speckle-tracking echocardiography, mitochondrial respiration by high-resolution respirometry, and transcriptomic remodelling by bulk RNA sequencing. MHS markedly reduced LA reservoir, conduit, and contractile strain, consistent with atrial myopathy. Transcriptomic analyses revealed substantially greater remodelling in the LA than previously observed in the left ventricle under comparable experimental conditions. Hallmark pathway analysis showed activation of extracellular matrix remodelling and profibrotic signalling pathways, along with suppression of oxidative phosphorylation and fatty acid metabolism. Weighted gene co-expression network analysis identified a structural remodelling module enriched for extracellular matrix organization and angiogenesis pathways, as well as a bioenergetic module enriched for mitochondrial respiratory functions. Although inflammatory and structural remodelling pathways largely normalized following myocardial recovery, mitochondrial and metabolic programs exhibited incomplete restoration. Persistent transcriptional alterations were concentrated within a stress-responsive gene network enriched for adaptive cellular response pathways. In parallel, a discrete regulatory module displayed significant sex-dependent expression patterns. Conclusions Metabolic-hypertensive stress induces profound atrial functional, metabolic, and transcriptomic remodelling, consistent with the development of cardiometabolic atrial myopathy. While many stress-induced changes resolve following myocardial recovery, key bioenergetic and stress-responsive transcriptional programs persist, suggesting that cardiometabolic stress leaves a lasting molecular imprint within the atrium.