Introduction: Atrial fibrillation (AFib) is frequently associated with heart failure (HF) but its impact on left ventricular (LV) dysfunction is poorly understood. Our study aimed to elucidate the pathophysiology of AFib by unraveling the crosstalk between impaired protein quality control system (PQC) and inflammasome activation mediated by oxidative stress and its effect on LV cardiomyocyte dysfunction.

Methods and Results: LV myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm (SR) or rate controlledAFib was studied. Apoptotic biomarkers and signaling pathways were evaluated in AFib vs. SR. We measured the in vivo redox state of cardiac proteins in AFib patients and compared them to SR patients. We used the OxICAT method coupled with mass spectrometry (MS). Using this method, we were able to detect and quantify many peptides from different cardiac proteins that were highly oxidized in AFib patients compared to SR patients. Additionally, we found significantly high levels of many markers of inflammation (eg, ICAM, VCAM, IL6, TNFα) and oxidative stress (H₂O₂, LPO, and 3-nitrotyrosine) in AFib patients. Proteases-mediated PQC such as cathepsin, calcineurin A, calpain and caspases including caspase 3, caspase 9, and caspase 12 were significantly upregulated in the AFib patients compared to the SR group. However, reduced expression of ubiquitin was observed in the AFib which may result in cytotoxicity due to the impaired ability of ubiquitin proteosome system to degrade the misfolded proteins. These results suggest a comparable caspases dependent occurrence of apoptosis and disturbances in the PQC in the AFib patients. Inflammatory biomarkers such as nuclear factor of activated T-cells (NFAT), alix, and neuropilin were slightly upregulated in the AFib hearts, whereas inflammatory signaling proteins tumor susceptibility gene 101 (TSG 101), platelet endothelial cell adhesion molecule (PECAM-1 or CD 31), neutrophil elastase exhibited a decreasing tendency, and interleukin-6 polyprotein was unchanged in the AFib patients , indicating cardiomyocyte dysfunction in AFib is not entirely dependent on inflammation. Furthermore, exosome biomarkers such as cluster of differentiation (CD) markers CD 63 and CD 81 were significantly elevated, and CD 9 marker was unchanged in the AFib group.

Conclusion: The findings of our study suggest that impaired PQC and altered inflammatory signaling pathways are the hallmarks of AF and could be a promising therapeutic approach to attenuate the severity of LV cardiomyocyte dysfunction.