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

Arterioscler Thromb Vasc Biol. 2020 Sep;40(9):2322-2331. doi: 10.1161/ATVBAHA.120.314824. Epub 2020 Jul 23.


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.

Keywords: epidemiology; fibrosis; inflammation; peripheral arterial disease.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Biomarkers / blood
  • C-Reactive Protein / analysis*
  • Critical Illness
  • Female
  • Fibrosis
  • Galectin 3 / blood*
  • Humans
  • Incidence
  • Inflammation Mediators / blood*
  • Intermittent Claudication / blood*
  • Intermittent Claudication / diagnosis
  • Intermittent Claudication / epidemiology
  • Intermittent Claudication / therapy
  • Ischemia / blood*
  • Ischemia / diagnosis
  • Ischemia / epidemiology
  • Ischemia / therapy
  • Male
  • Middle Aged
  • Peripheral Arterial Disease / blood*
  • Peripheral Arterial Disease / diagnosis
  • Peripheral Arterial Disease / epidemiology
  • Peripheral Arterial Disease / therapy
  • Prognosis
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • United States


  • Biomarkers
  • Galectin 3
  • Inflammation Mediators
  • LGALS3 protein, human
  • C-Reactive Protein