NOD1 as a key mediator of atrial remodelling in heart failure

Abstract Introduction Heart failure (HF) is a multifactorial syndrome and a leading cause of cardiovascular mortality worldwide, with atrial remodelling playing a pivotal role in disease progression and adverse outcomes. While the inflammatory response is increasingly recognized as a key driver of myocardial dysfunction, the molecular mechanisms linking innate immune activation to atrial pathology remain poorly understood. Our previous research identified nucleotide-binding oligomerization domain 1 (NOD1), an innate immune receptor, as a key contributor to left ventricular dysfunction in HF. However, its potential role in HF-atrial myopathy remains unexplored. Purpose To investigate the contribution of NOD1 to atrial remodelling and dysfunction in human and experimental HF models and to evaluate its potential as a therapeutic target. Methods Atrial tissue samples were obtained from 81 individuals undergoing heart valve surgery, including 45 non-failing (NF) patients with left ventricular ejection fraction (LVEF) 50% and N-terminal pro-brain natriuretic peptide (NT-proBNP) 200 pg/mL, and 36 HF patients with LVEF ≤50% and NT-proBNP ≥200 pg/mL. Experimental models included swine subjected to ascending aortic constriction (AoB) or left circumflex artery occlusion (LAI), and mice undergoing transverse aortic constriction (TAC). Echocardiographic assessment was performed to evaluate cardiac function in patients, while cardiac magnetic resonance (CMR) imaging was used for experimental models. Immunohistochemistry and Western blot analysis were performed to determine NOD1 expression in atrial myocardium. Additionally, the effects of genetic deletion and pharmacological activation of NOD1 were evaluated in mice. Intracellular calcium handling was assessed using confocal microscopy in isolated murine atrial cardiomyocytes. Results HF patients exhibited significant atrial enlargement and impaired atrial reservoir function compared to NF controls. NOD1 axis was significantly upregulated in the atria of HF patients, independently of atrial fibrillation (AF) status. Similar upregulation was observed across all preclinical HF models, whereas genetic deletion of NOD1 in mice prevented structural and functional atrial remodelling, primarily by mitigating intracellular calcium mishandling. Conversely, pharmacological activation of NOD1 in mice induced atrial dilation and calcium dysregulation, further supporting its detrimental role in atrial pathology. Conclusions This study identifies NOD1 as a novel mediator of atrial remodelling in HF, contributing to structural and functional alterations through calcium dysregulation. The consistent upregulation of NOD1 across human and preclinical models underscores its translational significance, highlighting its potential as a therapeutic strategy for HF-associated atrial dysfunction.