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Epicardial fat drives macrophage response in atrial cardiomyopathy

ABSTRACT: Inflammation contributes to atrial fibrillation (AF) and atrial cardiomyopathy (ACM). Spatial transcriptomic profiling of human right atrial appendage FFPE sections identified macrophage-associated fibro-fatty remodeling and inflammatory gene expression patterns associated with atrial adiposity during ACM progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE331446 | GEO | 2026/05/20

REPOSITORIES: GEO

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Project description:Aims Targeted therapies for atrial fibrillation (AF), the most common arrhythmia provoking heart failure and stroke, are urgently needed. However, the development of such therapies requires understanding of the cellular mechanisms that culminate in atrial cardiomyopathy (ACM) as a substrate for AF. Like in humans, increased persistent Na+ current leads to the development of ACM and spontaneous episodes of AF in mice. Here, we aim to identify and target the proteomic and metabolomic consequences of intracellular Na+-overload resulting in mitochondrial redox imbalance and contractile dysfunction of atrial myocytes (AMs). Methods and Results Transgenic mice expressing human gain-of-function mutant NaV1.5-F1759A channels in the fully redox-competent C57BL/6N background presented intracellular Na+-overload leading to AM hypertrophy, left atrial (LA) enlargement, contractile dysfunction and episodes of AF at early ages. Hence, we employed mass spectrometry of NaV1.5-F1759A LA myocardium to reveal the proteomic and metabolomic nature of ACM. In total we quantified 3,294 proteins across individual LA samples, of which 440 were differentially regulated in transgenic mice, including functionally relevant enzymes of key metabolic pathways. Metabolomic analyses confirmed changes in glycolytic and anaplerotic substrates, and identified a significant decrease in the cardioprotective antioxidant glutathione. Transgenic expression of the redox biosensor Grx1-roGFP in NaV1.5-F1759A AMs showed an oxidized glutathione redox potential indicative of mitochondrial ROS production upon catecholaminergic stimulation and field-pacing, which was not observed in control cells. Finally, we targeted the decreased expression of the sarcoplasmic reticulum protein junctophilin-2 by transgenic overexpression in NaV1.5-F1759A animals, which recued AM hypertrophy, LA contractility and AF burden in intracellular Na+-overload. Conclusions Atrial cardiomyopathy induced by intracellular Na+-overload in mice is characterized by profound cellular, proteomic and metabolomic changes culminating in mitochondrial redox imbalance and contractile dysfunction, which can be attenuated by restoring atrial junctophilin-2 expression.

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Epicardial fat drives macrophage response in atrial cardiomyopathy

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