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CLINICAL RESEARCH: ASSESSING VASCULAR FUNCTION

Methodological Approaches to Optimize Reproducibility and Power in Clinical Studies of Flow-Mediated Dilation

Ann E. Donald, AVS^_*,_*, Julian P. Halcox, MD, MA, FRCP^_*, Marietta Charakida, MD, PhD^_*, Clare Storry, BSc, AVS^_*, Sharon M.L. Wallace, BA, DipHE, RN^_*, Tim J. Cole, ScD, Peter Friberg, MD, PhD^_* and John E. Deanfield, BA, BChir, MB, FRCP^_*

^_* Vascular Physiology Unit, UCL Institute of Child Health, London, United Kingdom
Centre for Pediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, United Kingdom.

Manuscript received October 31, 2007; revised manuscript received January 7, 2008, accepted February 5, 2008.

^_* Reprint requests and correspondence: Ms. Ann E. Donald, Vascular Physiology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. (Email: A.Donald{at}ich.ucl.ac.uk).

Objectives: Our aim was to determine reproducibility of the flow-mediated dilation (FMD) response profile, and discriminatory ability of the components.

Background: Brachial FMD is widely used to study conduit artery endothelial function. Automated B-mode image edge detection (B-ED) provides a full response profile. Reproducibility and biological relevance of these additional components have not been fully explored.

Methods: Forty-two healthy adults underwent FMD using B-ED repeated at fixed time intervals up to 3 months. The FMD profile was assessed for diameter changes, area under the curve, and time course. Measures were compared in 25 adults with hypercholesterolemia, 25 subjects with diabetes, and 50 matched control subjects.

Results: The maximum change in FMD was the most reproducible (coefficient of variation = 9.8%, 10.6%, 6.6%, and 9.2% at 4 to 6 h, 1 week, 1 month, and 3 months, respectively). Most of the variability occurred between subjects rather than within. All FMD measures except time course were significantly reduced in hypercholesterolemia and diabetes. Power curves were generated to indicate the appropriate number of subjects for parallel and crossover study designs.

Conclusions: Maximum FMD percentage change from baseline is the most reproducible of the response curve measures and best identifies those with risk factors. Flow-mediated dilation measured by B-ED is robust and practical to assess the effect of interventions on endothelial function in clinical trials.

Abbreviations and Acronyms   A-WT = A-mode wall tracking   B-ED = B-mode edge detection   CV = coefficient of variation   FMD = flow-mediated dilation   FMDmax = maximum flow-mediated dilation percentage change from baseline   NO = nitric oxide   T2DM = type 2 diabetes mellitus

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