A new approach to improve the specificity of flow-mediated dilation for indicating endothelial function in cardiovascular research

Abstract

Flow-mediated dilation (FMD) is a noninvasive indicator of endothelial function and is routinely expressed as the percentage change in arterial diameter (FMD%) from a resting baseline (D_base) to a postischemic peak (D_peak). This expression is equivalent to the ratio of D_peak/D_base and is, therefore, dependent on important statistical assumptions, which have never been analysed in the context of FMD%. We aimed to investigate these assumptions, via a comparison of FMD between samples of children and adults, as well as to explore other approaches to scaling diameter change for D_base. We found that FMD% did not scale accurately for interindividual differences in D_base but, as expected, overestimated endothelial function for low D_base and vice versa. We argue that this imprecise scaling of FMD% is predictable, not explained by physiology and is probably common. This problem is resolved by applying scaling principles, whereby the difference in diameter is the outcome and D_base is a covariate in a logarithmic-linked generalized linear model. A specific allometric expression of FMD can be derived and we found this to be D_peak/D_base^0.89 rather than a simple ratio in our particular dataset. We found that sample differences in endothelial function were inaccurate with FMD% versus our new allometric approach, and that FMD% misclassified participants into ‘high’ and ‘low’cohorts, which has implications for prognostic-type studies. We conclude that the general use of FMD% could have led to biased comparisons of different conditions and/or populations in past studies. Our new approach to scaling FMD is flexible for different datasets and is not based on the current assumption that a percentage change is appropriate in all circumstances.