Multiple Flow-Mediated Dilation Paradigms Provide a Robust and Potentially Clinically Relevant Test of Endothelial Function

Abstract

Brachial artery Flow-Mediated Dilation (FMD) is the most common method utilized in research to non-invasively assess endothelial function. Although the recent advancement of normalizing FMD for shear has profoundly improved inter-subject variability as well as our understanding of this technique, the population FMD/ shear relationship (r2 = ∼0.6 - 0.8) is still not sufficient to a allow a reliable clinical interpretation. PURPOSE: This investigation aimed to evaluate the feasibility of multiple FMD measurements of varied shear stimuli in a single testing session to provide a more complete and rigorous assessment of endothelial function that may ultimately be embraced clinically. METHODS: Apparently healthy non-smoking young adult males (ages 24±1) reported to the laboratory following an overnight fast, and having abstained from exercise, caffeine, or vitamin supplementation for 12 hours prior to the start of the investigation. To elicit different shear rate profiles, four occlusion paradigms (150s, 225s, 300s, and 300s + 120s of superimposed handgrip exercise) were randomly performed and each paradigm was separated by 30 minutes. For each subject and each paradigm, FMD was plotted against shear area under the curve (AUC) until maximal vessel dilation, and the slope and fit of this regression analysis were recorded. RESULTS: All data are reported as mean±SE. The cuff duration for 150, 225, 300, and 300 s + handgrip exercise produced a shear rate (AUC) of 7919±1032, 9570±2549, 11123±305, and 20752±3178 s−1, respectively. The FMD for 150, 225, 300, and 300 s + handgrip exercise was 3.6±0.5, 4.5±2.1, 6.1±1.1, and 10.4±3.1%, respectively. The r2 and slope for the individually developed FMD/shear relationship was 0.96±0.006 and 0.51±.08, respectively. CONCLUSIONS: This work has provided evidence that four FMD paradigms evoking different shear stimuli yield a very tight individualized relationship between FMD and shear. In addition, the subsequent slope of the FMD/shear relationship is a far more robust marker of endothelial function than a single FMD. This methodology may allow better test-retest evaluations on individuals and provide methodology for comparisons of age, sex, and disease based norms in the clinical setting. Supported by TRDRP 15RT-0100 and Parker B Francis Fellowship Program