Validation of Exposure‐Response Modeling of Flow‐Mediated Dilation as a Less Biased and More Informative Measure of Endothelial Function
Authors: Hallow Karen Melissa , Van Brackle Charles H , Harris Ryan A 
Published: November 2023

The flow‐mediated dilation (FMD) test is the most widely used, non‐invasive method to evaluate endothelial function in humans. Currently, the endpoint obtained from this test is FMD%, calculated as the percentage change in brachial artery diameter. However, underutilized velocity and diameter time‐course data together with confounding effects of shear exposure, differences in baseline diameter, noise, and upward bias diminish the clinical utility of the FMD test. The purpose of this study was to develop and validate an exposure‐response model‐based approach that utilizes all of the available velocity and diameter data and overcomes several previously acknowledged challenges associated with current FMD methodology. Using FMD data obtained from 15 apparently healthy participants—each exposed to four different occlusion durations (2.5 min, 3.75 min, 5 min, and 10 min)—we developed our model to characterize both the velocity and diameter responses from the FMD test. The velocity response following occlusion was described by an exponential model with two parameters defining peak velocity and rate of decay. The shear exposure time profile was derived directly from velocity and was used to drive the diameter response model. The diameter response model consisted of additive terms describing constriction and dilation and is defined by three parameters characterizing distinct features of the vascular response to shear (magnitude of an initial constriction response, and magnitude and time constant of the dilation response). A second, more heterogeneous FMD dataset (5‐minute occlusion period) obtained from 18 participants diagnosed with chronic obstructive pulmonary disease (COPD) and 15 control participants was used for model validation. Parameter estimates for the first dataset at occlusion times of 2.5, 5, and 10 minutes were used to accurately predict a diameter response for the 3.75‐minute occlusion in each individual participant based on their corresponding shear exposure. The model's parameter estimates were found to be the same for a given participant regardless of occlusion time, thus demonstrating the model's ability to account for shear exposure. For both datasets, the model was able to successfully reproduce the velocity and diameter FMD responses for all participants and occlusion times. In conclusion, modeling of FMD yields identifiable and physiologically meaningful parameters which may provide greater information for comparing differences between experimental groups or over time, and provides a means to fully account for shear exposure. In addition, modeling of our validation data was able to reproduce both the velocity and diameter responses observed in patients with COPD, confirming the utility of this approach in quantifying endothelial function while fully accounting for shear exposure, eliminating artifact introduced by baseline diameter normalization, eliminating upward bias, and smoothing out error due to noise.