| The dynamic interactions and coupling among the multiple components that collectively constitute the cardiovascular, respiratory, metabolic and sleep-wake regulation systems play important roles in determining the short-term and long-term physiological effects of sleep-disordered breathing. In previous and current studies, a computational model, named PNEUMA, has been continuously developed to be capable of simulating the complex dynamics of cardiorespiratory control during sleep and transient changes in sleep-wake state. PNEUMA includes the autonomic control of the cardiovascular system, chemoreflex and state-related control of breath-to-breath ventilation, state-related and chemoreflex control of upper airway potency, as well as respiratory and circulatory mechanics.Recent studies suggest that sleep-disordered breathing increases the risk of developing systemic hypertension and type 2 diabetes in the long term. To better understand the causal links, a computational metabolic model is developed to be capable of simulating glucose-insulin and free fatty acid (FFA) dynamics during sleep and wake states under normal breathing or sleep-disordered breathing conditions. The model incorporates the circadian regulation of epinephrine secretion, epinephrine regulation on the dynamic fluctuations in glucose and FFA in plasma, and metabolic coordination among tissues and organs provided by insulin, glucagon and epinephrine.While many respiratory cardiovascular and metabolic models exist in the literature, none thus far has focused on characterizing the interactions that involve the respiratory, cardiovascular, and metabolic systems with sleep-wake state regulation. By incorporating the metabolic model into PNEUMA, we have developed an integrative model of cardiovascular and respiratory control with interactions between the autonomic and metabolic control in sleep-disordered breathing.The extended integrative model provides realistic predictions of the physiological responses under a wide variety of conditions, including the day-to-day sleep-wake cycle, hypoxia-induced periodic breathing, Cheyne-Stokes respiration in congestive heart failure, obstructive sleep apnea (OSA) and sleep-disordered breathing effects on glucose insulin and FFA dynamics. It can be used to investigate the effects of virtual experiments and interventions such as isocapnic and hypercapnic and/or hypoxic gas administration, the Valsalva and Mueller maneuvers, the application of continuous positive airway pressure on OSA patients, insulin pump, and intravenous glucose tolerance test. The extended version of PNEUMA provides the foundation on which future modeling efforts to simulate disease progression and the long-term effects of pharmacological intervention can be based.Keywords---physiological model simulation autonomic pathways and reflexes circadian cycle sleep modeling sleep disordered breathing metabolic control. |
