Oxidative Stress and Inflammation-Induced Protein Quality Control Impairment in Atrial Fibrillation: A Novel Mechanism Underlying Left Ventricular Dysfunction and Reversible Stiffness

Introduction: Atrial fibrillation (AFib) is frequently associated with heart failure (HF), but its specific impact on left ventricular (LV) dysfunction remains poorly understood. 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, 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 various cardiac proteins showing high oxidation levels. In AFib patients, inflammation markers such as ICAM, VCAM, IL-6, and TNFα were significantly elevated, alongside markers of oxidative stress, including H₂O₂, lipid peroxidation (LPO), and 3-nitrotyrosine. This increase in inflammatory and oxidative markers appears to promote protein oxidation, leading to impaired PQC. Proteases involved in PQC, such as cathepsin, calcineurin A, calpain, and caspases (caspase 3, 9, and 12), were upregulated in the AFib group, suggesting caspase-dependent apoptosis and PQC disruptions. However, a reduced expression of ubiquitin in AFib patients indicated a weakened ubiquitin-proteasome system, impairing the degradation of misfolded proteins and increasing cytotoxicity. The cumulative effect of these changes led to an increase in passive stiffness of LV cardiomyocytes in AFib patients. Notably, this passive stiffness was shown to be reversible upon treatment with the antioxidant N-acetylcysteine (NAC) and an anti-inflammatory inhibitor targeting IL-6. Inflammatory biomarkers including NFAT, alix, and neuropilin were slightly upregulated, whereas TSG101, PECAM-1, and neutrophil elastase showed a decreasing trend, and IL-6 polyprotein levels remained unchanged. These findings suggest that cardiomyocyte dysfunction in AFib is only partially driven by inflammation. Additionally, exosome biomarkers, particularly CD63 and CD81, were significantly elevated, while CD9 levels remained unchanged.

Conclusion: Our findings indicate that enhanced inflammation and oxidative stress in AFib patients lead to protein oxidation, compromising PQC and contributing to LV cardiomyocyte dysfunction and increased passive stiffness. Targeting these pathways with antioxidants like NAC and IL-6 inhibitors could offer a promising therapeutic approach to mitigate LV dysfunction and stiffness in AFib patients.