Date of Award

5-6-2009

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Alan Dardik

Abstract

Introduction: Mononuclear cells (MNCs) have been shown to increase neovascularization and ulcer healing after direct injection into the ischemic limbs of patients with unreconstructable peripheral vascular disease (PVD). Circulating MNCs are composed of lymphocytes (85%), monocytes (15%) and endothelial progenitor cells (EPCs; 0.03%). It is thought that MNCs may be effective in ameliorating ischemia since EPCs are a component of the monocyte fraction, and EPCs have been shown to participate in vascular healing. We hypothesized that ischemic areas secrete paracrine signals such as cytokines and growth factors that recruit bone marrow-derived monocytes into the circulation in order to augment vascular healing. For this reason we predicted that patients with critical limb ischemia (CLI) undergoing bypass surgery would have elevated preoperative monocyte counts compared to control subjects without CLI. In addition, since a successful surgical bypass procedure relieves ischemia, we expected a postoperative decrease in circulating monocyte numbers. Methods: We reviewed the records of all patients at the VA Connecticut Healthcare System undergoing lower extremity peripheral bypass surgery between 2002 and 2007. Patients were excluded if they did not have both preoperative and postoperative complete blood counts with differentials within a given time frame. Subjects were divided into two groups: those with preoperative critical limb ischemia (CLI) and those without. ANOVA and Chi-Square were used to compare counts, and multivariable logistic regression was used to determine risk factors. Results: Patients with CLI (n=24) had elevated preoperative monocyte counts compared to control patients (n=8) undergoing bypass for claudication or asymptomatic popliteal aneurysm (0.753 ± 0.04 vs. 0.516 ± 0.05; p=0.0046), but the preoperative lymphocyte count was not significantly different (1.979 ± 0.14 vs. 1.912 ± 0.22; p=0.814). After revascularization, ischemic patients had decreased monocyte counts compared to control patients (-20% vs. +55%; p=.0003) although lymphocyte ratios were unchanged in both groups (-10% vs. +1%; p=0.404). Diabetic patients also had reduced postoperative monocyte counts (-32% vs. +13%; p=0.035), however multivariable analysis demonstrated that the only factor that independently predicted reduced postoperative monocyte count was preoperative critical limb ischemia (p=0.038). Conclusions: Diminished numbers of circulating monocytes correlate with relief of ischemia after surgical revascularization. Circulating monocytes may be a clinically useful surrogate marker of circulating stem cells for patients undergoing vascular surgery.

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