Chronic intermittent hypoxia and obstructive sleep apnea: an experimental and clinical approach

Abstract

Obstructive sleep apnea (OSA) is a prevalent sleep disorder considered as an independent risk factor for cardiovascular consequences, such as systemic arterial hypertension, ischemic heart disease, cardiac arrhythmias, metabolic disorders, and cognitive dysfunction. The pathogenesis of OSA-related consequence is assumed to be chronic intermittent hypoxia (IH) inducing alterations at the molecular level, oxidative stress, persistent systemic inflammation, oxygen sensor activation, and increase of sympathetic activity. Overall, these mechanisms have an effect on vessel permeability and are considered to be important factors for explaining vascular, metabolic, and cognitive OSA-related consequences. The present review attempts to examine together the research paradigms and clinical studies on the effect of acute and chronic IH and the potential link with OSA. We firstly describe the literature data on the mechanisms activated by acute and chronic IH at the experimental level, which are very helpful and beneficial to explaining OSA consequences. Then, we describe in detail the effect of IH in patients with OSA that we can consider "the human model" of chronic IH. In this way, we can better understand the specific pathophysiological mechanisms proposed to explain the consequences of IH in OSA.

Keywords: experimental studies; hypoxia; intermittent hypoxia; obstructive sleep apnea.

Figure 1

Schematic diagram showing the mechanisms leading to clinical consequences of obstructive sleep apnea. Notes: During OSA, intermittent cycles of a fall in oxygen saturation and reoxygenation, and a rise in UA and esophageal pressure, MA, and hypercapnia occur. As a consequence, oxidative stress and systemic inflammation take place, inducing an increase in sympathetic tonus, endothelial dysfunction, and metabolic alteration, overall implicated in the majority of OSA consequences. Abbreviations: OSA, obstructive sleep apnea; UA, pharyngeal resistance; MA, microarousal; IH, intermittent hypoxia; PES, esophageal pressure.

Figure 2

Schematic presentation of the hypothesized pathways by which intermittent hypoxia leads to hypertension. Notes: Chronic intermittent hypoxia increases the HIF-1 with a rise of the HIF-1α subunit that activates pro-oxidant enzymes and a decrease of HIF-2α, inducing a fall in antioxidant enzymes. These changes induce a rise of ROS implicated in the activation of peripheral chemoreceptors, the deactivation of baroreceptors, and the activation of adrenal medullary activity, all factors promoting increase of sympathetic activation and hypertension. Abbreviations: HIF, hypoxia inducible factor; ROS, reactive oxygen species.