Cardiovascular Consequences of Sleep-Disordered Breathing: Contribution of Animal Models to Understanding of the Human Disease

Abstract

Sleep-disordered breathing, and particularly the highly prevalent obstructive sleep apnea syndrome, is a multicomponent disorder combining intermittent hypoxia (IH), sleep fragmentation, and obstructed respiratory efforts. It is frequently associated with comorbidities and leads to numerous complications, including cardiovascular consequences that are conditioned by genetic predisposition and environment. The complexity of the disease and the reduced possibilities for patient investigations, especially at the tissue level, have limited progress in the understanding of sleep apnea pathophysiology and in the development of specific treatments. Animal models make it possible to study the causative mechanisms (essentially upper airway dysfunction) and the consequences (cardiovascular, metabolic, and neurological alterations) of nocturnal respiratory events without the confounding factors that occur in humans. Such studies have revealed some of the pathophysiological mechanisms and enabled the recognition of IH as the most important sleep apnea component underlying cardiovascular complications. We review different animal models used to assess detrimental sleep apnea-related cardiovascular consequences: blood pressure elevation, impaired vasoreactivity, structural arterial remodeling leading to atherosclerosis, cardiac remodeling, and myocardial infarction. We also review experimental evidence of beneficial effects of IH. By combining clinical and experimental research, these models will contribute to the understanding of differential patient susceptibility and to the elaboration of prevention strategies and tailored treatments for sleep apnea patients.

Nonmuscle Myosin Light Chain Kinase: A Key Player in Intermittent Hypoxia‐Induced Vascular Alterations

“…Fraction of inspired oxygen in the hypoxic chambers was measured with a gas analyzer (ML206; ADInstruments) throughout the experiment. The IH stimulus consisted of a 60‐second cycle, with 30 seconds of hypoxia (hypoxic plateau at 5% fraction of inspired oxygen) and 30 seconds of normoxia (normoxic plateau at 21% fraction of inspired oxygen), as described 22. Normoxic mice were exposed to air flow turbulences related to gas circulation and noise stimuli similar to those undergone by animals submitted to IH.…”

Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice

“…However, it is well established that atherosclerosis is a chronic inflammatory disease 13 , and there is growing evidence that OSA is a chronic low grade inflammation. Therefore, IH-induced inflammation could be an additional link between OSA and atherosclerosis 9 , without the use of a dyslipidemic diet and even after a short-term of IH exposure, as we previously showed that 14 days of IH were sufficient to induce vascular alterations 14,15 .…”

“…IH was performed in experimental cages accommodating 10 mice each, as previously described 15 . The animals were exposed to IH (cyclic 21-5% FiO 2 , 60s cycle, both normoxic and hypoxic phases for 30s, 8h/day during daytime).…”

“…About 60% of OSA-patients develop systemic hypertension 22 , even in the absence of any other risk factors when including both clinical and masked hypertension 4,23 . Using animal models 15,24 and also applying IH in healthy humans 25 suggest that IH is a major factor determining blood pressure increase. We have previously shown in C57BL6 mice that blood pressure surges appear at each hypoxic episode, and are associated with increased sympathetic activation 14 .…”

“…We have previously shown in C57BL6 mice that blood pressure surges appear at each hypoxic episode, and are associated with increased sympathetic activation 14 . These hemodynamic changes are well known to induce functional and structural alterations of the vascular wall that could contribute to vascular remodeling and atherogenesis 15,26 . However in the present study, we found a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 slight elevation in blood pressure in 20-week-old mice, whereas hemodynamic parameters were unaffected in 15-week-old mice.…”