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

Ning Ding, Chao Yang, Shoshana H. Ballew, Corey A. Kalbaugh, John W. McEvoy, Maya Salameh, David Aguilar, Ron C. Hoogeveen, Vijay Nambi, Elizabeth Selvin, Aaron R. Folsom, Gerardo Heiss, Josef Coresh, Christie M. Ballantyne, Kunihiro Matsushita

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish
Pages (from-to)2322-2331
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number9
StatePublished - Sep 1 2020

Bibliographical note

Publisher Copyright:
© 2020 American Heart Association, Inc.


  • epidemiology
  • fibrosis
  • inflammation
  • peripheral arterial disease

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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