Aims: Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper is to assess FMD values in apparently healthy individuals and provide reference values to facilitate wider clinical use.

Methods and Results: In 1,579 apparently healthy individuals (aged 18-76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body-mass-index, glucose, cholesterol, blood pressure, and brachial artery diameter. Significant multivariate predictors of FMD were age (-0.4%/decade), BMI (0.04%/kg/m²), smoking (-0.7%), and brachial artery diameter (-0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (>6.8%) were younger, had smaller brachial artery diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (<5.4%). After adding data from 385 patients with stable coronary artery disease (CAD), ROC analysis (c=0.841, p<0.001) showed that FMD of >6.5% excluded CAD (95% sensitivity; 60% specificity) and FMD <3.1% excluded 95% healthy individuals (95% specificity, 31% sensitivity). A meta-analysis and meta-regression of 82 clinical trials (11 countries, n=3,509) using similar FMD methodology showed that despite considerable heterogeneity (I²=0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (-0.3%/decade, R²=0.13).

Conclusions: We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of CV health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.