Research Article: Reproducibility and validity of a novel invasive method of assessing peripheral microvascular vasomotor function

Date Published: January 25, 2019

Publisher: Public Library of Science

Author(s): Scott Kinlay, Mariah Bundy, Melissa Chin, Desiree Tobin, Margot Quinn, Jacquelyn-My Do, Shannon Johnson, Sara Temiyasathit, Samantha Ly, Carlos Zaragoza.


In healthy arteries, blood flow is regulated by microvascular tone assessed by changes in blood flow volume and vascular resistance to endothelium-dependent and -independent vasodilators. We developed a novel method of using intravascular ultrasound (IVUS) and a Doppler flow wire to measure changes in blood flow volume and vascular resistance of the profunda arterial bed. We assessed the variability over 6 months in measuring microvascular endothelium-dependent dilation to acetylcholine and endothelium-independent dilation to adenosine in 20 subjects who were part of a larger study of Gulf War Illness without obstructive peripheral artery disease. Vasomotor function was assessed by Infusions of control (dextrose), acetylcholine (10-6M), adenosine (50μg), and nitroglycerin (25μg/ml). 400 IVUS and 240 flow velocity images were measured a mean 6 (SD = 2) months apart blind to measurement and infusion stage. The mean (SD) baseline profunda flow was 227 (172) ml/min and vascular resistance 4.6 x 104 (2.4 x 104) dynes-s/cm5. The intraclass correlation coefficients for 6-month variability for vascular function were excellent (range 0.827–0.995). Bland-Altman analyses showed mean differences of less than 2% for microvascular endothelium-dependent function (flow volume and resistance) and less than 1% for macrovascular endothelium-dependent function with acceptable limits of agreement. In 49 subjects assessing concurrent validity of the technique against atherosclerosis risk factors, we observed greater impairment in microvascular endothelium-dependent function per year of age (flow volume = -1.4% (p = 0.018), vascular resistance = 1.5% (p = 0.015)) and current smoking (flow volume = -36.7% (p = .006), vascular resistance = 50.0% (p<0.001)). This novel method of assessing microvascular vasomotor function had acceptable measurement reproducibility and validity.

Partial Text

Blood flow to skeletal muscle increases with exercise due to increased metabolic demand. In healthy arteries, the increase in blood flow is regulated by microvascular tone (vascular resistance) and mean systemic blood pressure.[1] Vasodilation of the microvascular bed decreases vascular tone and is mediated by the endothelium-dependent and endothelium-independent dilators.[2]

Subjects were Veterans deployed to the Persian Gulf War (1990–1991) and enrolled in a larger study of Gulf War Illness (GWI) at the VA Boston. The larger study aims to assess whether endothelial dysfunction is related to the debilitating symptoms of fatigue associated with GWI. In this report we assessed the reproducibility and validity of our novel IVUS technique for measuring vascular function. Reproducibility was assessed in the initial 20 subjects in this study and validity in 49 subjects. Subjects were Veterans initially deployed from Fort Devens, MA, and were excluded if they had peripheral artery disease (ankle brachial indices ≤ 0.9), symptomatic coronary artery disease, disability of a limb, a serum creatinine > 1.5 mg/dL, a bleeding disorder or were on chronic anticoagulant therapy. The study was approved by the VA Boston IRB and all patients gave written informed consent.

In the 20 subjects included in the reproducibility analysis, the average time between the first and second measurement was 6 (SD = 2) months. The risk factors for atherosclerosis and average vasomotor function for the 49 subjects are listed in Table 1. Five subjects had a remote history of myocardial infarction or coronary intervention, but no subject had angina or prior peripheral artery interventions.

The assessment of endothelium-dependent and -independent microvascular function requires intra-arterial infusions of vasodilators and highly sensitive techniques to assess changes in blood flow and vascular resistance. Compared to raw film angiography, the image processing used with newer digital angiography in catheterization laboratories is a less reliable measure of the small changes in vascular function. IVUS and Doppler flow wires are readily available in most catheterization laboratories and are more sensitive measures of small changes in artery size. This study demonstrates that our novel IVUS method of measuring microvascular and macrovascular vasomotor function in a peripheral artery has excellent reproducibility over 6 months. The validity of our technique is supported by our observation that impaired microvascular endothelial function associated with increasing age and cigarette smoking–two factors known to cause atherosclerosis and impaired vascular function.




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