Introduction: Atrial fibrillation (AFib) is frequently associated with heart failure (HF), but its specific contribution to left ventricular (LV) dysfunction remains incompletely understood. While hemodynamic irregularity contributes to HF pathogenesis, emerging data suggest that AFib induces systemic metabolic and inflammatory alterations, which may directly impair myocardial function. This study aimed to clarify the pathophysiology of AFib by examining the link between enhanced inflammation, oxidative stress-induced protein oxidation, and impaired protein quality control (PQC) in LV cardiomyocyte dysfunction.
Methods and Results: We studied LV myocardium from patients with aortic stenosis and preserved LV function, comparing those with sinus rhythm (SR) to those with rate-controlled AFib. We evaluated apoptotic biomarkers, inflammatory signaling pathways, and the redox state of cardiac proteins using the OxICAT method coupled with mass spectrometry (MS) to detect and quantify oxidized peptides. Our analysis revealed a significant increase in protein oxidation in AFib patients compared to SR patients, with many peptides from sarcomeric and mitochondrial proteins showing high oxidation levels.
In AFib patients, inflammation markers such as ICAM, VCAM, IL-6, and TNFα were significantly elevated, along with markers of oxidative stress including H₂O₂, lipid peroxidation (LPO), and 3-nitrotyrosine. These stressors promoted widespread protein oxidation and impaired PQC. Proteases such as cathepsin, calcineurin A, calpain, and caspases (3, 9, and 12) were upregulated, suggesting caspase-dependent apoptosis and proteolytic activation. Ubiquitin levels were reduced, indicating UPS dysfunction and accumulation of damaged proteins.
To better define upstream drivers of this remodeling, we integrated multi-omics, which included transcriptomic, proteomic, metabolomic, and phosphoproteomic analyses of AFib patients. These data revealed altered mitochondrial metabolism, impaired TCA cycle flux, redox imbalance, and activation of fibrotic and inflammatory signaling cascades. In peripheral blood samples, elevated levels of mitochondrial overload markers (e.g., xanthine, hypoxanthine), tryptophan breakdown products (e.g., kynurenine), and liver-derived metabolites supported a systemic inflammatory and metabolic phenotype. The cumulative effect of these changes led to an increase in passive stiffness of LV cardiomyocytes in AFib patients. Notably, the phenotype was reversible with the antioxidant N-acetylcysteine and an anti-inflammatory inhibitor targeting IL-6. Additional analysis showed that exosomal markers (CD63, CD81) were significantly elevated, suggesting a role for extracellular vesicle-mediated signaling in the AFib-associated cardiac response. Inflammatory molecules including NFAT and Alix were modestly increased, while markers such as PECAM-1 and TSG101 were decreased.
Conclusion: Enhanced inflammation, mitochondrial redox imbalance, and protein oxidation in AFib patients impair PQC and contribute to LV stiffness and cardiomyocyte dysfunction. Integrated multi-omics profiling corroborates these mechanisms, revealing key metabolic and inflammatory pathways involved in the AFib-to-HF transition. Targeting these mechanisms with antioxidant and anti-inflammatory therapies offers a promising strategy to mitigate AFib-induced LV remodeling and progression toward HF.
