Obstructive Sleep Apnea - An Obese Minipig Model



 DESCRIPTION (provided by applicant): The tongue base and soft palate constitute the anterior border of oropharynx and control the entrance into the larynx. Thus, their size, position, and mobility have a crucial influence on the upper airway (UA). Clinical data show that patients with obstructive sleep apnea or hypopnea (OSA) commonly have anatomic compromise of the UA due to either excessive tissue mass or neuromuscular compromise of the tongue base and/or soft palate. However, information about how shape and mobility of the tongue base and soft palate contribute to the UA collapse during sleep is very limited. Human study cannot address these critical questions underlying the pathogenesis and pathophysiology of OSA because of the invasive technology necessary. Thus, a suitable and reliable animal model is an imperative. This model must meet three basic criteria: 1) anatomical and functional similarity to humans; 2) presentation of spontaneous OSA with UA collapse; and 3) an appropriate size for physiological instrumentation and therapeutic interventions. Pigs have considerable similarity with humans in UA constitution and function, and spontaneous OSA occurs in obese minipigs. The obese minipig is especially appropriate because excess weight and obesity is the strongest risk factor for the development of OSA and an independent predictor of OSA in humans. This promising model has not yet been evaluated for UA collapse in OSA. Establishment of a validated large animal model would be foundational to our understanding of vital function and morphology of the tongue base and soft palate in respiration, would facilitate refinement of clinical treatment for breathing disorders, would allow study of the longitudinal consequences of mechanical and surgical treatment modalities, and would enable evaluation of controversial therapies such as neuromuscular stimulation and pharmacological application under well-controlled experimental conditions. Therefore, we propose this exploratory study to establish an obese minipig model for use in OSA research, and to determine the roles of the tongue base, soft palate, and pharyngeal wall in UA function and collapse during sleep. We will first validate OSA in obese minipigs, verify OSA absence in controls, and identify the obstructive site(s) in OSA to test the hypothesis that obese minipigs present spontaneous OSA with UA collapse, and non-obese controls have no sign of OSA (Aim 1). Using these validated OSA animals, we will determine the physical mechanism whereby obesity leads to UA collapse by comparing morphology and mobility of the tongue base and soft palate in controls and obese minipigs with OSA to test the hypothesis that compared to controls, obese OSA minipigs present excessive mass and stiffness, reduced mobility, and greater fat infiltration in the tongue base, soft palate, and pharyngeal wall, which in turn compress the UA and increase its resistance for respiration during sleep (Aim 2). The outcomes will establish a suitable and reliable animal model with well-characterized UA morphology and function to facilitate OSA studies in various fields.