Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Iraklis Pipinos

Second Advisor

George Casale

Third Advisor

Geoffrey Thiele

Fourth Advisor

B. Timothy Baxter

Abstract

Background: Peripheral Artery Disease (PAD) begins with atherosclerotic narrowing of arteries, including those that supply the legs. Individuals with PAD experience pain during walking, which becomes increasingly limiting. Studies from our group and others have shown that a myopathy is present in the skeletal muscle of PAD patients, and is characterized by myofiber degeneration, fibrosis, and remodeling of vessels ranging from 50 – 150 mm in diameter. However, microvascular pathology, particularly of the smallest microvessels (5 – 15 mm in diameter) remains poorly characterized. Furthermore, little is known about the relationships between microvascular architecture, microperfusion, and patient walking performance. We hypothesize that microvascular pathology is present in the terminal microvasculature of PAD muscle compared to control and worsens with PAD severity. Additionally, we hypothesize that microvascular architecture is associated with deficits in micro- and macro- perfusion and walking performance in PAD patients with intermittent claudication (IC).

Methods: Gastrocnemius biopsy specimens were collected from control, PAD patients with IC, and PAD patients with critical limb ischemia. Microvascular architecture, microvascular fibrosis, total collagen, and the abundance and phenotype of pericytes were quantified. Microvascular perfusion was assessed by Contrast Enhanced Ultrasonography (CEU). Gardner walking protocols were used to assess claudication onset time (COT) and peak walking time (PWT). Patients also completed the Walking Impairment Questionnaire (WIQ).

Results: Microvascular pathology increased with advancing PAD severity and included progressive increases in basement membrane thickening, abundance of aSMA+ pericytes, and microvessel density. In advanced PAD muscle, increases were observed in total fibrotic burden and peri-microvascular Collagen I and IV deposition. aSMA+ pericytes expressed TGF-b1. Relationships were observed between microvascular architecture and microperfusion both at rest and after ischemic stress. Microvascular architecture was associated with macrovascular hemodynamic restrictions. Microvascular architecture was associated with COT, PWT, and patient self-reports of walking speed, walking distance, and stair climbing ability.

Conclusions: Microvascular pathology worsens with PAD severity in association with fibrosis. Alteration of microvascular architecture contributes to microperfusion deficits and walking limitations in PAD.

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