Fibrosis-related biomarkers and large and small vessel disease: The Cardiovascular Health Study

Objective: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels. Methods: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998. Results: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR]=1.36 per doubling of TGF-β, 95% confidence interval [CI]=1.04, 1.78) and retinal venular diameter (1.63μm per doubling of TGF-β, CI=0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102mm per doubling of PIIINP, CI=0.029, 0.174) and impaired brachial artery reactivity (-0.20% change per doubling of PIIINP, CI=-0.39,-0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy. Conclusions: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.