Soluble P-selectin predicts lower extremity peripheral artery disease incidence and change in the ankle brachial index: the Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

Objective: To determine the association of circulating P-selectin with prevalent and incident peripheral artery disease (PAD), the ankle brachial index (ABI), and change in the ABI.

Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective population-based cohort study including 6814 European descent, African American, Hispanic and Chinese men and women aged 45-84 at baseline. Four clinical exams took place after the baseline exam. After excluding those with ABI>1.4, prevalent and incident PAD were defined as an ABI≤0.90. ABI progression was defined as progression from a normal ABI (0.91-1.4) to abnormal (≤0.90 or >1.4) at a later exam.

Results: In adjusted models, each SD (13 ng/mL) higher P-selectin was significantly associated with 0.007 lower ABI (95% CI ((-0.011, -0.004)), p < 0.001), and an average change in the ABI of -0.006 ((-0.010, -0.003, p < 0.001). P-selectin was significantly associated with a 1.17-fold greater odds of prevalent PAD ((1.02, 1.33), p = 0.03), and a 30% greater risk of incident PAD ((1.11, 1.53), p = 0.001), as well as progression from a normal ABI to an ABI≤ 0.90 (p = 0.003), but not to an ABI>1.4 (p = 0.96). Addition of P-selectin to models containing traditional PAD risk factors and markers of inflammation/coagulation significantly improved the net reclassification for ABI progression (p = 0.03), but was only marginally significant for incident PAD (p = 0.06).

Conclusions: P-selectin is significantly associated with the development of PAD. However, further research is needed in population-based studies to confirm prospective associations of P-selectin with incident PAD and change in the ABI, as well as its potential predictive ability.

Keywords: Ankle brachial index; Incidence; Net reclassification improvement; P-selectin; Peripheral artery disease; Prediction.

Figure 1. Mean Soluble P-selectin levels by ABI Category at Exam 3 and ABI progression from Exam 3 to Exam 5

Figure 1 shows least squares means of soluble P-selectin, adjusted for age, race/ethnicity and sex, by ABI category at Exam 3, and progression of ABI from normal at Exam 3 (0.91–1.4) to abnormal (≤0.90 or >1.4) at Exam 5. P-selectin in ng/mL is shown on the Y-axis, with ABI categories on the X-axis. ABI≤0.90 is represented by red bars, ABI>1.4 by green bars, and 0.90

Figure 2. Association of soluble P-selectin with progression of the ABI from Exam 3 to Exam 5

Figure 2 is a forest plot that displays the association of P-selectin per standard deviation for ABI progression from Exam 3 to Exam 5. Values shown are odds ratios with 95% CIs for varying levels of model adjustment as described in the text. Only participants with a normal ABI (0.91–1.4) at Exam 3 were included, and were evaluated for progression to an abnormal ABI at Exam 5 (ABI≤0.90 or ABI>1.4), with the reference group as participants who remained in the normal ABI category from Exam 3 to Exam 5 (ABI of 0.91–1.4). Model adjustments include demographics (age, race/ethnicity, and gender), with additional adjustment for body mass index, ever smoking, hypertension, diabetes, estimated glomerular filtration rate, fasting glucose, LDL cholesterol, HDL cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure; a final model additionally adjusts for CRP, IL-6, fibrinogen, and D-dimer.