Bed to bench evaluation of cardiac and vascular impact of OSA

PROJECT SUMMARY Obstructive sleep apnea (OSA) is known to be correlated with cardiovascular diseases (CVD), yet controlled clinical trials showed that CPAP treatment was insufficient to alleviate CVD risk in all patients. Current tools fail to identify the mechanistic pathways involved in OSA-related CVD pathophysiology, and residual CVD risk may persist despite CPAP treatment. Conversely, some studies have identified OSA as possibly protective against myocardial infarction consequences, highlighting significant knowledge gaps in understanding the mechanisms linking OSA and CVD. This research project aims to elucidate the complex relationship between OSA and CVD through an innovative "bed to bench" approach, integrating clinical, in silico, and in vitro techniques. Specifically, we will develop and validate a novel mathematical model to quantify tissue-specific hypoxia burden in OSA patients, correlating this with clinical outcomes and traditional OSA metrics. This model will be validated using superoxide expression in microvascular tissue from patient skin biopsies and further refined with large-scale sleep study databases from the Sleep Heart Health Study (SHHS). Second, we will optimize in vitro microvascular models, including an endothelial cell model and an advanced Vascularized Micro-Organ (VMO) platform, to study the direct effects of intermittent hypoxia (IH) on the microvasculature. The IH protocol will be developed to match gene expression profiles of IH-exposed endothelial cells to patient biopsy profiles to ensure physiological relevance. Third, we will employ a "heart-on-a-chip" model to investigate the direct impact of OSA- induced IH on cardiac structure and function, providing insights into OSA-specific cardiovascular pathways. Throughout these aims, we will leverage data from the National Sleep Research Resource to inform our models and validate our findings against real-world patient outcomes. This comprehensive approach addresses current limitations in OSA research by providing more accurate risk assessment tools and physiologically relevant in vitro models. Our strategy has the potential to uncover new biomarkers, identify novel therapeutic targets, and ultimately improve the clinical management of OSA patients at risk for cardiovascular complications.