Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Carotid Artery Reactivity Predicts Events in Peripheral Arterial Disease Patients

van Mil, Anke C. C. M. MSc*,‡; Pouwels, Sjaak PhD; Wilbrink, Jelmer MSc*; Warlé, Michiel C. MD; Thijssen, Dick H. J. PhD*,‡

doi: 10.1097/SLA.0000000000002558

Objective: Patients with peripheral arterial disease (PAD) have increased risk on future cerebro- and cardiovascular events. Our aim was to examine whether carotid artery reactivity (CAR; a novel, simple procedure to examine endothelial function) predicts cardiovascular events in PAD patients.

Background: Increased risk for future cardiovascular events in PAD patients is likely related to endothelial dysfunction, highlighting the necessity for simple assessment of endothelial function.

Methods: A total of 172 PAD patients (68 ± 10 years, 67% male) underwent the CAR, which involves ultrasound measurement of carotid artery diameter during sympathetic stimulation produced by 90-second hand immersion in 4°C ice-water (ie, cold pressor test). CAR-responses were dichotomized into carotid constriction or dilation. We recorded cardiac and cerebrovascular events, mortality, and clinical progression to percutaneous transluminal angioplasty or loss of patency during 12-month follow-up.

Results: Eighty-two PAD patients demonstrated carotid constriction and 90 patients demonstrated dilation. PAD patients with carotid constriction showed more cardiovascular events compared to patients with dilation (Kaplan-Meier Log rank; P < 0.05). Cox proportional hazard models showed that patients with carotid constriction continued to show higher risk for cardiovascular events [hazard ratio: 4.1; 95% confidence interval (CI), 1.3–12.5] and clinical progression (hazard ratio: 2.0; 95% CI, 1.2–3.3), even after adjustment for other risk factors. Ankle brachial pressure index and carotid intima-medial thickness alone did not predict (cardiovascular) event or improve risk assessment beyond that provided by CAR.

Conclusion: Carotid vasoconstriction identifies PAD patients with a 4-fold increased risk for future cardiovascular events and 2-fold increased risk for clinical deterioration. CAR provides a simple, novel strategy to predict cardiovascular events and progression in PAD patients.

Clinical Trial Registration:, NTR-4117.

*Radboud Institute for Health Sciences, Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands

Radboud Institute for Health Sciences, Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands

Research institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom.

Reprints: Dick H. J. Thijssen, PhD, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street L3 3AF, Liverpool, United Kingdom. E-mail:

Disclosures: ACCM—Top Institute for Food and Nutrition-grant. ACCM is financially supported by a Top Institute for Food and Nutrition-grant.

Author Contributions: D.H.J.T. and M.W. designed the study. D.H.J.T. ensured funding of the project. A.C.C.M.M., M.W., S.P., and J.W. were involved in data collection. A.C.C.M.M. and D.H.J.T. performed the statistical analyses. All authors contributed to the interpretation of the data, writing of the manuscript and provided approval of the final version. The authors report no conflicts of interest.

M.C.W. and D.H.J.T. contributed equally to this work.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.