Exposure-response modeling of flow-mediated dilation provides an unbiased and informative measure of endothelial function

Abstract

The brachial artery flow-mediated dilation (FMD) test is the most widely utilized method to evaluate endothelial function noninvasively in humans by calculating the percent change in diameter (FMD%). However, the underutilized velocity and diameter time course data, coupled with confounding influences in shear exposure, noise, and upward bias, make the FMD test less desirable. In this study, we developed an exposure-response, model-based approach that not only quantifies FMD based on the rich velocity and diameter data, it overcomes previously acknowledged challenges. FMD data were obtained from 15 apparently healthy participants, each exposed to four different cuff occlusion durations. The velocity response following cuff release was described by an exponential model with two parameters defining peak velocity and rate of decay. Shear exposure derived from velocity was used to drive the diameter response model, which consists of additive constriction and dilation terms. Three parameters describing distinct aspects of the vascular response to shear (magnitude of the initial constriction response, and magnitude and time constant of the dilation response) were estimated for both the individuals and population. These parameters are independent of shear exposure. Thus this approach produces identifiable and physiologically meaningful parameters that may provide additional information for comparing differences between experimental groups or over time, and provides a means to completely account for shear exposure. While flow-mediated dilation (FMD) is a valuable tool for evaluating endothelial function, analytical challenges include confounding influences of shear exposure, upward bias, and underutilization of rich time course data collected during FMD testing. We have developed an exposure-response, model-based approach that quantifies endothelial function based on the velocity and diameter data and fully accounts for shear exposure. It produces physiologically meaningful parameters that may provide useful information for comparing differences between experimental groups or over time.

Association of Inflammation and Endothelial Dysfunction with Coronary Microvascular Resistance in Patients with Cardiac Syndrome X

“…Brachial artery FMD was measured using a standardized technique. 10 All subjects were studied in the morning, having abstained from alcohol, caffeine and food for 12 h before the test. The diameter of the artery was measured using high-resolution, two-dimensional ultrasound images obtained with a Doppler ultrasound device (HDI-ATL 5000, USA) with a 5 MHz to 12 MHz linear-array transducer.…”

The Delivery of Nitric Oxide in the Cardiovascular System: Implication for Clinical Diagnosis and Therapy

“…Aside from modeling the NO delivery from the small-scale mechanism, other studies modeled this process in large scale. For example, the exposure-response model was established based on the simplified physical formula to describe the NO delivery and vasodilation, which uniquely considers the FMD time course and excludes the interference of shear-exposure from the endothelial function [64]. This model was recently extended to quantitatively reveal the interfaces of blood pressure and arterial stiffness on assessing the endothelial function from FMD% [65,66].…”

An in silico simulation of flow-mediated dilation reveals that blood pressure and other factors may influence the response independent of endothelial function

“…There have been a few numerical models describing different physiological and hemodynamic aspects of the FMD test (4,34,38). Yamazaki et al (38) developed a mathematical model of the WSS-dependent vasomotor response involving both intra-and intercellular pathways, which was able to reproduce typical changes in arterial wall diameter during the FMD test.…”

“…They used the model to quantify changes in Young's modulus and peripheral resistance during the FMD test. In a recent study, Van Brackle et al (34) developed a model-based exposure response method for quantification of physiologically meaningful parameters that describe both the WSS exposure and diameter response during the FMD test and which was used in our study. None of these models were used to investigate the biophysical confounding factors studied here that may affect the FMD test results.…”

“…i, and i(x,t) ϭ Ϫ(11 Ui)/Ri the space-varying WSS in segment i computed at each time step. U i(x,t) and Ri(x,t) are the blood flow velocity and luminal radius, respectively, of the arterial segment i. ref is the right-arm, space-, and time-averaged WSS for the cardiac cycle just before cuff inflation.We then calculated the cumulative shear exposure, cum(t), for each cardiac cycle using the formula proposed by Van Brackle et al(34),…”