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CLINICAL RESEARCH: PERIPHERAL VASCULAR DISEASE

Elevated Levels of Inflammation, D-Dimer, and Homocysteine Are Associated With Adverse Calf Muscle Characteristics and Reduced Calf Strength in Peripheral Arterial Disease

Mary M. McDermott, MD^_*,,_*, Luigi Ferrucci, MD, PhD, Jack M. Guralnik, MD, PhD, Lu Tian, ScD, David Green, MD, PhD^_*, Kiang Liu, PhD, Jin Tan, MS, Yihua Liao, MS, William H. Pearce, MD^||, Joseph R. Schneider, MD, PhD^||,¶, Paul Ridker, MD^#, Nader Rifai, PhD^#, Frederick Hoff, MD^_** and Michael H. Criqui, MD, MPH

^_* Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Laboratory of Clinical Epidemiology, National Institute on Aging, Bethesda, Maryland
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland
^|| Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
^¶ Division of Vascular Surgery, Department of Surgery, Evanston/Northwestern Hospital, Evanston, Illinois
^# Harvard Medical School, Boston, Massachusetts
^_** Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Department of Family and Preventive Medicine, University of California at San Diego, San Diego, California.

Manuscript received November 28, 2006; revised manuscript received April 2, 2007, accepted May 8, 2007.

^_* Reprint requests and correspondence: Dr. Mary M. McDermott, 676 N. St. Clair, Suite 200, Chicago, Illinois 60611. (Email: mdm608{at}northwestern.edu).

Objectives: This study determined whether increased levels of inflammatory blood markers, D-dimer, and homocysteine were associated with smaller calf skeletal muscle area, increased calf muscle percent fat, reduced calf muscle density, and poorer calf strength in persons with lower extremity peripheral arterial disease (PAD).

Background: Elevated levels of inflammatory markers and D-dimer are associated with greater functional impairment and functional decline in persons with PAD. Mechanisms of these associations are unknown.

Methods: Participants were 423 persons with PAD. Calf muscle area, percent fat, and density were measured with computed tomography. Physical activity levels were measured objectively over 7 days with the Caltrac (Muscle Dynamics Fitness Network, Inc., Rocklin, California) vertical accelerometer. Isometric plantarflexion strength was measured. Analyses were adjusted for age, gender, race, comorbidities, the ankle-brachial index, and other potential confounders.

Results: Higher levels of D-dimer (p = 0.014), C-reactive protein (CRP) (p = 0.002), interleukin (IL)-6 (p < 0.001), and soluble vascular cellular adhesion molecule (sVCAM)-1 (p = 0.008) were associated with smaller calf muscle area. Higher sVCAM-1 (p = 0.004) and IL-6 (p = 0.017) were associated with higher calf muscle percent fat. Higher D-dimer (p < 0.001), sVCAM-1 (p < 0.001), and homocysteine (p = 0.014) were associated with lower calf muscle density. These associations were generally unchanged after additional adjustment for physical activity. Higher sVCAM-1 (p = 0.013) was associated with lower calf strength.

Conclusions: These data show, for the first time, that higher levels of inflammation, D-dimer, and homocysteine are associated with more adverse calf muscle characteristics in persons with PAD. These associations may contribute to previously established associations between elevated biomarkers and functional impairment and functional decline in PAD.

Abbreviations and Acronyms   ABI = ankle-brachial index   BMI = body mass index   CRP = C-reactive protein   CT = computed tomography   ELISA = enzyme-linked immunosorbent assay   HDL = high-density lipoprotein   IL = interleukin   PAD = peripheral arterial disease   sICAM-1 = soluble intracellular adhesion molecule   sVCAM-1 = soluble vascular cellular adhesion molecule

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