NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and its prevalence increases with age. The irregular and rapid contraction of the atria can lead to ineffective blood pumping, local blood stasis, blood clots, ischemic stroke, and heart failure. NADPH oxidases (NOX) and mitochondria are the main sources of reactive oxygen species in the heart, and dysregulated activation of NOX and mitochondrial dysfunction are associated with AF pathogenesis. NOX- and mitochondria-derived oxidative stress contribute to the onset of paroxysmal AF by inducing electrophysiological changes in atrial myocytes and structural remodeling in the atria. Because high atrial activity causes cardiac myocytes to expend extremely high energy to maintain excitation-contraction coupling during persistent AF, mitochondria, the primary energy source, undergo metabolic stress, affecting their morphology, Ca2+ handling, and ATP generation. In this review, we discuss the role of oxidative stress in activating AF-triggered activities, regulating intracellular Ca2+ handling, and functional and anatomical reentry mechanisms, all of which are associated with AF initiation, perpetuation, and progression. Changes in the extracellular matrix, inflammation, ion channel expression and function, myofibril structure, and mitochondrial function occur during the early transitional stages of AF, opening a window of opportunity to target NOX and mitochondria-derived oxidative stress using isoform-specific NOX inhibitors and mitochondrial ROS scavengers, as well as drugs that improve mitochondrial dynamics and metabolism to treat persistent AF and its transition to permanent AF.

The Role of Oxidative Stress and Inflammatory Parameters in Heart Failure

“…It significantly contributes to tissue damage in HF by inducing oxidative damage through the formation of reactive oxidants and radicals. These pathways significantly influence the development of coronary artery disease, vascular diseases and HF, contributing to atherogenesis, plaque vulnerability and ventricular remodeling [74,75]. In HF, increased MPO activity has been linked to various diseases, including atherosclerosis.…”

“…Elevated 3-NT levels, a result of reactive nitrogen species under oxidative stress, are observed in myocardial samples from HFpEF patients compared to HFrEF. MPO derived from leukocytes contributes to vascular dysfunction and cardiovascular diseases, including HFpEF [75,76]. Several studies exploring the role of MPO in chronic HF have shown that elevated MPO levels are correlated with uric acid levels in HFpEF patients.…”

“…While MPO shows promise as a diagnostic and prognostic marker in HF, its utility in the diagnosis of acute HF varies. Reichlin et al suggest a potential role for MPO in risk management in acute HF, showing associations with 1-year mortality and long-term clinical outcomes, albeit with mixed diagnostic value compared to BNP [75][76][77]. Soluble NOX2, a significant contributor to oxidative stress, plays a crucial role in HF.…”