NOD1 is a key mediator of atrial myopathy in heart failure.

UNLABELLED: Heart failure (HF)-associated atrial myopathy is driven by complex and poorly understood mechanisms. Emerging evidence suggests that innate immune components contribute to atrial remodeling, yet the role of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) receptors remains unclear.

METHODS: NOD1 expression was characterized in atrial myocardium of HF patients (n = 36) and non-failing controls (n = 45) undergoing valve surgery, and in two porcine models of atrial myopathy with divergent ventricular phenotypes: aortic banding (AoB; preserved LVEF) and left atrial infarction (LAI; reduced LVEF). The causal role of NOD1 in atrial remodeling was assessed using genetic (Nod1⁻/⁻) and pharmacological (ML-130) loss-of-function approaches in a murine transverse aortic constriction (TAC) model, and through selective NOD1 activation with C12-iE-DAP in wild-type, Nod1⁻/⁻ , and RyR2-S2814A mice. Proteomic, phosphoproteomic, transcriptomic, and Ca²⁺ imaging analyses were performed across experimental systems.

RESULTS: NOD1 was markedly upregulated in atrial myocardium of HF patients and in both porcine models, across divergent ventricular phenotypes and irrespective of documented rhythm status, correlating with structural and functional indices of atrial disease severity. Genetic NOD1 deficiency in TAC mice prevented atrial dysfunction, structural remodeling, activation of profibrotic molecular pathways and Ca²⁺ mishandling. Pharmacological NOD1 inhibition with ML-130 reproduced the protective effects on atrial structural and Ca²⁺ handling. Selective NOD1 activation with C12-iE-DAP induced atrial Ca²⁺ dysregulation through CaMKII-dependent RyR2-Ser2814 hyperphosphorylation, effects that were abrogated by CaMKII inhibition, and absent in RyR2-S2814A mice. Human atrial transcriptomic analysis confirmed enrichment of inflammatory, Ca²⁺-signaling, and extracellular matrix remodeling pathways in HF. Increased CaMKII phosphorylation in human atrial myocardium further corroborated the translational relevance of the NOD1-CaMKII-RyR2 axis.

CONCLUSIONS: These findings identify the NOD1-CaMKII-RyR2 axis as a cardiomyocyte-centered mechanism linking innate immune activation to atrial Ca²⁺ dysregulation and structural remodeling in HF, establishing NOD1 as a molecular indicator of atrial myopathy burden and a mechanism-based therapeutic target.