Abstract 15726: Large-Scale Plasma Proteomics and Mendelian Randomization of Cardiovascular Performance and Peak Arterio-Venous Oxygen Difference Identify Novel Biology Related to VO 2 max

Abstract

Introduction: VO 2 max is the product of maximal cardiac output (Q) (maximal stroke volume (SVmax) x heart rate) and peak arterio-venous oxygen content difference (a-vO 2 diff). SVmax and peak a-vO 2 diff have important implications across the spectrum of human health and performance. However, the molecular mechanisms underlying SVmax and peak a-vO 2 diff remain largely unknown. We characterize SVmax and peak a-vO 2 diff using large-scale plasma proteomics and genotyping to identify circulating proteins and putative mediators of these traits. Methods: 763 physically inactive adults without overt cardiovascular disease underwent cardiopulmonary exercise testing with rigorous measurements of Q. High-throughput plasma proteomic profiling was performed to identify proteins associated with SVmax, a-vO 2 diff, and VO 2 max. cis-Mendelian Randomization (MR) analysis was conducted to assess causal relationships between protein markers and cardiovascular performance traits. Results: Proteomic profiling revealed associations between SVmax and several adiposity-related proteins, as well as secretory muscle factors (cathepsin B, α-actinin 2, and troponin I) (Figure). Proteins associated with peak a-vO2diff reflected oxygen-carrying capacity, muscle biology, and glucose metabolism (erythropoietin, myoglobin, fructose-1,6-bisphosphatase). Significant overlap was observed between proteins associated with SVmax, a-vO 2 diff, and VO 2 max. Cis-MR identified myocilin (MYOC) and caspase recruitment domain family member 9 (CARD9) as potential mediators of cardiovascular performance and VO 2 max. Conclusions: This study provides novel insights into the molecular influences of cardiovascular performance and VO 2 max. The identified protein markers associated with SVmax and a-vO 2 diff, along with the possible mediators MYOC and CARD9, merit further investigation into their role in endurance exercise capacity and cardiometabolic health.