Fibrosis and Inflammatory Markers and Long-Term Risk of Peripheral Artery Disease

Objective: Inflammatory markers, such as hs-CRP (high-sensitivity C-reactive protein), have been reported to be related to peripheral artery disease (PAD). Galectin-3, a biomarker of fibrosis, has been linked to vascular remodeling and atherogenesis. However, its prospective association with incident PAD is unknown; as is the influence of inflammation on the association between galectin-3 and PAD. Approach and Results: In 9851 Atherosclerosis Risk in Communities Study participants free of PAD at baseline (1996–1998), we quantified the association of galactin-3 and hs-CRP with incident PAD (hospitalizations with PAD diagnosis International Classification of Diseases - Ninth Revision : 440.2–440.4 or leg revascularization eg, International Classification of Diseases - Ninth Revision : 38.18) as well as its severe form, critical limb ischemia (PAD cases with resting pain, ulcer, gangrene, or leg amputation) using Cox models. Over a median follow-up of 17.4 years, there were 316 cases of PAD including 119 critical limb ischemia cases. Log-transformed galectin-3 was associated with incident PAD (adjusted hazard ratio, 1.17 1.05–1.31 per 1 SD increment) and critical limb ischemia (1.25 1.05–1.49 per 1 SD increment). The association was slightly attenuated after further adjusting for hs-CRP (1.14 1.02–1.27 and 1.22 1.02–1.45, respectively). Log-transformed hs-CRP demonstrated robust associations with PAD and critical limb ischemia even after adjusting for galectin-3 (adjusted hazard ratio per 1 SD increment 1.34 1.18–1.52 and 1.34 1.09–1.65, respectively). The addition of galectin-3 and hs-CRP to traditional atherosclerotic predictors (C statistic of the base model 0.843 0.815–0.871) improved the risk prediction of PAD (ΔC statistics, 0.011 0.002–0.020). Conclusions: Galectin-3 and hs-CRP were independently associated with incident PAD in the general population, supporting the involvement of fibrosis and inflammation in the pathophysiology of PAD.