Experimental Models to Study End-Organ Morbidity in Sleep Apnea: Lessons Learned and Future Directions

Abstract

Sleep apnea (SA) is a very prevalent sleep breathing disorder mainly characterized by intermittent hypoxemia and sleep fragmentation, with ensuing systemic inflammation, oxidative stress, and immune deregulation. These perturbations promote the risk of end-organ morbidity, such that SA patients are at increased risk of cardiovascular, neurocognitive, metabolic and malignant disorders. Investigating the potential mechanisms underlying SA-induced end-organ dysfunction requires the use of comprehensive experimental models at the cell, animal and human levels. This review is primarily focused on the experimental models employed to date in the study of the consequences of SA and tackles 3 different approaches. First, cell culture systems whereby controlled patterns of intermittent hypoxia cycling fast enough to mimic the rates of episodic hypoxemia experienced by patients with SA. Second, animal models consisting of implementing realistic upper airway obstruction patterns, intermittent hypoxia, or sleep fragmentation such as to reproduce the noxious events characterizing SA. Finally, human SA models, which consist either in subjecting healthy volunteers to intermittent hypoxia or sleep fragmentation, or alternatively applying oxygen supplementation or temporary nasal pressure therapy withdrawal to SA patients. The advantages, limitations, and potential improvements of these models along with some of their pertinent findings are reviewed.

Chronic intermittent hypoxia‐induced cardiovascular and renal dysfunction: from adaptation to maladaptation

“…In rodents, the increase in BP is gradual and seen from the third day of exposure to CIH (Marcus et al, 2009(Marcus et al, , 2012, but the development of stable nocturnal and diurnal HTN was found between week 2 and 5, depending on the CIH paradigm and type of BP measurements (AlMarabeh et al, 2019;Coelho et al, 2020;Fletcher, Lesske, Qian et al, 1992;Takahashi et al, 2018). In humans, it is difficult to establish the total duration of OSA disease (Farré et al, 2022). In healthy volunteers, reversible increases in BP have been seen after 2-4 weeks of exposure to CIH (Gilmartin et al, 2010;Tamisier et al, 2009Tamisier et al, , 2011.…”

“…Cell cultures and animals subjected to CIH paradigms have been widely used to unravel mechanisms underlying the development and progression of obstructive and central sleep apnoea comorbidities (for a review see AlMarabeh et al., 2019; Farré et al., 2022). OSA coexists with autonomic responses to asphyxia, sleep fragmentation (Polotsky et al., 2006) and obesity (Wolk et al., 2003), but experimental CIH protocols have been mainly used to assess the isolated effects of intermittent hypoxia, representing a lean model with a slowing of body growth (Diogo, Pereira et al., 2015) and, according to some studies in mice, sleep fragmentation (Gozal et al., 2001; Kubin, 2014).…”

Low-Cost, Open-Source Device for Simultaneously Subjecting Rodents to Different Circadian Cycles of Light, Food, and Temperature

“…Figure 7A shows a general schematic of the box. The specific implementation we present herein (Figure 1) can accommodate either a conventional mouse cage (28 x 28 x 16 cm) or a cage (40.6 x 26.7 x 36.8 cm) for subjecting mice to sleep fragmentation/deprivation (model 80391, Lafayette Instruments, Lafayette, IN) [23,24]. To this end, we used an expanded polystyrene foam box (external 59.5 x 39.5 x 40 cm, 3 cm wall width; Broxon GmbH via Amazon) commercialized for food temperature maintenance.…”

The Effects of Volatile Anesthetics on Renal Sympathetic and Phrenic Nerve Activity during Acute Intermittent Hypoxia in Rats

“…Exposure to noxious stimuli, such as hypoxia and hypercapnia, leads to activation of the respiratory and sympathetic neurons in the brainstem and may strengthen the coordination of respiration and autonomic activity [3][4][5][6]. Intermittent hypoxia is a valuable model for studying obstructive sleep apnea (OSA) pathophysiology and implies repeated brief exposures to reduced oxygen levels interrupted by reoxygenation periods and, as such, has already been a subject of numerous studies [3,4,[7][8][9][10][11][12][13][14]. Previous findings indicate that chronic intermittent hypoxia (CIH), a common feature of OSA, is associated with sustained increases in sympathetic nerve activity and arterial blood pressure [8,12].…”