Cardiovascular morbidity in obstructive sleep apnea: oxidative stress, inflammation, and much more

Abstract

Sleep-disordered breathing and obstructive sleep apnea (OSA) are highly prevalent disorders throughout the lifespan, which may affect up to 2-10% of the population, and have now been firmly associated with an increased risk for cardiovascular and neurobehavioral complications. Nevertheless, the overall pathophysiologic mechanisms mediating end-organ injury in OSA remain undefined, particularly due to the very frequent coexistence of other disease states, such as obesity, that clearly complicate the potential cause-effect relationships. Two major, and to some extent overlapping, mechanisms have been proposed to explain the morbid consequences of OSA, namely increased generation and propagation of reactive oxygen species and initiation and amplification of inflammatory processes. The evidence supporting the validity of these concepts as well as that detracting from such mechanisms will be critically reviewed in the context of clinical and laboratory-based approaches. In addition, some of the contradictory issues raised by such evaluation of the literature will be interpreted in the context of putative modifications of the individual responses to OSA, as determined by genetic variants among susceptibility-related genes, and also by potential environmental modulators of the phenotypic expression of any particular end-organ morbidity associated with OSA.

Figure 1.

Schematic diagram illustrating putative alterations in the normal vessel wall with obstructive sleep apnea (OSA). OSA will induce activation of NADPH oxidase and increased formation of hydrogen peroxide (H₂O₂) as well as reactive oxygen (ROS) and nitrogen (RNS) species. OSA will also influence adipose tissue biological processes, and enhance the formation and release of cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis alpha (TNF-α), as well as promote the release of leptin and adipokines. In the liver, acute phase reactants such as serum amyloid A and C reactive protein (CRP) will be increasingly formed and released into the circulation. Circulating monocytes will be activated, express monocyte chemotactic protein 1 (MCP-1), and induce expression of adhesion molecules on the endothelial cell surface, while reducing the expression and activity of endothelial nitric oxide synthase (eNOS) and promoting endothelial cell apoptosis. Activated monocytes will migrate through disrupted endothelial cell tight junctional spaces into the vessel wall, where they will transform into activated macrophages, which in turn will internalize and accumulate fat, thereby becoming foam cells, the prototypic cell type of the initial atheromatous lesion. Furthermore, endothelial cells will also interact with platelets, and activate the initiation and propagation of thrombus formation, while signaling from all of these multiple cell populations will lead to increased proliferation of smooth muscle in the vessel wall.