Shear rate normalization is not essential for removing the dependency of flow-mediated dilation on baseline artery diameter: past research revisited

A ratio index (FMD%) is used ubiquitously to scale (by simple division) brachial artery flow-mediated dilation (D-diff) in direct proportion to baseline diameter (D-base). It is now known that D-diff is inversely proportional to D-base rendering FMD% wholly inappropriate. Consequently, FMD% is still substantially dependent on D-base. Although this problem is grounded in statistics, normalization of FMD% for the change in arterial shear rate (Delta SR) has been proposed to remove this D-base-dependency. It was hypothesized that, if the flow-mediated response is scaled properly to D-base in the first place, shear rate normalization would not be needed to remove D-base-dependency. Dedicated software (Digitizelt) was employed to extract the data from a seminal study on FMD% normalization. The underlying allometric relationship between D-base and peak diameter (D-peak) was described. The re-analyses revealed that the absolute change in arterial diameter was strongly inversely proportional to D-base (r=-0.7, P < 0.0005). The allometric exponent for the D-base-D-peak relationship was 0.82 (95% CI: 0.78-0.86) rather than the value of 1 needed for appropriate use of FMD%. The allometric approach completely eliminated the originally reported dependency on D-base without any need for Delta SR normalization (r=0.0, P=0.96). The correlation between Delta SR and FMD% reduced from 0.69 to 0.37, when adjusted for D-base. In conclusion, this new re-analysis of data from an influential study demonstrates that the FMD%-D-base correlation is caused by the inappropriate size-scaling properties of FMD% itself. Removal of D-base-dependency via FMD%/Delta SR normalization is not essential at all if allometric scaling is applied to isolate the flow-mediated response in the first place. Consequently, the influence of Delta SR on this properly scaled response can also be isolated and quantified accurately without the confounding influence of D-base.