Project Summary/Abstract Coronavirus 2019 (COVID-19) has infected more than 29 million globally. While the majority of individuals experience mild symptoms, the presence of obesity among other factors identifies a particularly high-risk group of individuals for development of severe COVID-19. Severe COVID-19 is characterized by exuberant inflammation and vascular dysfunction, but long-term cardiovascular effects remain unclear. We hypothesize that COVID-19 infection has widespread and long-lasting deleterious effects on endothelial function, including molecular pathways of cellular senescence and inflammation among obese individuals. We propose to prospectively study 100 obese and non-obese individuals with history of COVID-19 infection and 50 age- and sex-matched controls. To gain further insights into underlying mechanisms of vascular dysfunction, we will pursue three related lines of investigation: In Aim 1, we will study the effect of COVID-19 across vascular beds including peripheral and coronary microvascular function. In Aim 2, we will investigate the association of COVID-19 and molecular pathways of endothelial activation and senescence using circulating proteomic profiling, gene expression profiling of freshly isolated human endothelial cells, complemented by interrogation of targeted endothelial pathways. In Aim 3, we will conduct a prospective longitudinal observational study to examine the effect of COVID-19 on trajectories of peripheral and coronary microvascular function and endothelial phenotype over the course of 6 months. This proposal leverages a unique and highly experienced multidisciplinary team of investigators with expertise in obesity-related cardiovascular disease, endothelial and aging biology, coronary microvascular dysfunction, and bioinformatics. Importantly, our investigative team has a track record of successfully enrolling minority participants across two medical centers. With a disproportionate burden of severe COVID-19 among racial and ethnic minority groups, we will be uniquely positioned to examine race/ethnic differences in exploratory analyses. These studies have the potential to provide important insights into mechanisms driving endothelial inflammation and cardiovascular consequences of COVID-19 among obese individuals and will lay the foundation for future studies focused on long-term cardiovascular complications and therapeutic strategies.

Project Narrative (Public Health Relevance) One of the most prominent clinical features of severe COVID-19 is exuberant inflammation and endothelial dysfunction. The proposed research investigates the effects of COVID-19 on cardiovascular function using deep phenotyping approaches including human endothelial cell gene expression profiling. These studies will provide the unique opportunity to investigate molecular underpinnings of long-term endothelial effects among patients with obesity and could have important preventive and therapeutic implications in understanding disease susceptibility to COVID-19.