Abstract 4365000: Characterization of Plasma Proteins Associated with Arterial Stiffness and Pressure Pulsatility

Abstract

Background: Stiffening of large arteries is a key pathophysiologic precursor of micro- and macrovascular disease. Increased arterial stiffness (AoS) and central pressure pulsatility (CPP) can precede the development of atherosclerosis, heart failure, cardiometabolic disease, and renal failure. Further research into the underlying biology of arterial stiffening will improve our ability to target this important risk factor for disease. Proteome-wide evaluation of circulating factors may uncover insights into underlying mechanisms of AoS, as well as markers that modify its risk of disease. Objective: To identify plasma proteins related to and potential mediators of AoS and CPP as potential biomarkers and novel mechanistic mediators Methods: We evaluated 1072 participants from the Framingham Heart Study Generation 2 Exam 10 (2019-2021) who had completed proteomic profiling by SomaScan 7K platform and arterial tonometry measurements of AoS [carotid-femoral pulse wave velocity (CFPWV), augmentation index (AI)] and CPP. Using multiple linear regression, we assessed the association between 7335 detected proteins with (1) inverse-transformed CFPWV and log-transformed (2) CPP and (3) AI. Models were adjusted for either (1) batch and plate, or (2) batch, plate, and age. We subsequently identified proteins significantly associated with CFPWV, AI and CPP by multiplicity-corrected p-value < 0.05. Results: Mean age was 76±7 years, 45% were male. We identified 333 unique proteins significantly associated with elevated CFPWV, AI and CPP (Batch/plate: 319 proteins, Age-adjusted: 57 proteins) and 70 proteins with their reduction (Batch/plate: 62 proteins, Age-adjusted: 26 proteins). Many proteins are endocrine or paracrine factors in pathways important to alteration in the extracellular matrix of arterial vasculature (MMP12, CTSD, CHRDL1, CTSD, TAGLN), vascular calcification (SVEP1, PTN, HTRA1, SOST, MSC, BMP9, DDK2), endothelial dysfunction (FABP3, FABP4, RARRES2, ADAMTS13, PLAT, RSPO1, ANGPTL3, ADIPOQ), and inflammation (CRP, TREM2, LGALS3BP, NEGR1, APCS). Conclusions: We identified numerous circulating proteins strongly associated with change in AoS and CPP, many of which are paracrine and endocrine factors in mechanistic pathways leading to loss of arterial elasticity. Further investigations of these proteins may reveal putative biomarkers of AoS and CPP and new molecular pathways for therapeutic targeting.