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QUARTERLY FOCUS ISSUE: PREVENTION/OUTCOMES: CARDIOVASCULAR GENOMIC MEDICINE

The Role of Biomarkers and Genetics in Peripheral Arterial Disease

Department of Medicine and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Manuscript received May 16, 2008; revised manuscript received March 16, 2009, accepted April 21, 2009.

^_* Reprint requests and correspondence: Dr. Mary M. McDermott, Northwestern University Feinberg School of Medicine, 750 North Lake Shore Drive, 10th Floor, Chicago, Illinois 60611 (Email: mdm608{at}northwestern.edu).

Men and women with lower extremity peripheral arterial disease (PAD) have higher levels of inflammatory biomarkers than those without PAD. Observational studies link higher levels of several inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, and soluble adhesion molecules, to 1 or more of the following outcomes in people with PAD: more severe PAD, greater lower extremity functional impairment, more adverse calf skeletal muscle characteristics, greater declines in the ankle brachial index, greater declines in lower extremity performance, and higher rates of cardiovascular morbidity and mortality. Higher levels of inflammatory biomarkers are also associated with poorer outcomes after lower extremity revascularization, including graft restenosis and mortality. Increasing levels of CRP are associated with increased mortality and faster functional decline among people with PAD. Statin therapies reduce cardiovascular event rates and may improve walking performance in men and women with PAD, perhaps in part because statins can reduce inflammation. However, no clinical trials have been performed to establish whether therapies that specifically block or lower inflammatory biomarkers improve outcomes in patients with PAD. Family studies show that heritability of PAD ranges from approximately 20% to 45% after adjusting for atherosclerotic risk factors. A genetic marker for PAD has the potential to identify individuals at increased risk for PAD and may also uncover proteins that can help determine mechanisms of development of lower extremity atherosclerosis. However, a genetic marker for PAD has not been identified.

Key Words: inflammatory biomarkers • ankle brachial index • peripheral arterial disease • genetics • atherosclerosis

Abbreviations and Acronyms   ABI = ankle brachial index   B2M = beta-2 microglobulin   CRP = C-reactive protein   ICAM = intracellular adhesion molecule   IL = interleukin   PAD = peripheral arterial disease   SAA = serum amyloid A   sICAM = soluble intercellular adhesion molecule   sVCAM = soluble vascular cellular adhesion molecule   VCAM = vascular cellular adhesion molecule

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