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 (Ddiff) in direct proportion to baseline diameter (Dbase). It is now known that Ddiff is inversely proportional to Dbase rendering FMD% wholly inappropriate. Consequently, FMD% is still substantially dependent on Dbase. Although this problem is grounded in statistics, normalization of FMD% for the change in arterial shear rate (ΔSR) has been proposed to remove this Dbase-dependency. It was hypothesized that, if the flow-mediated response is scaled properly to Dbase in the first place, shear rate normalization would not be needed to remove Dbase-dependency. Dedicated software (Digitizelt) was employed to extract the data from a seminal study on FMD% normalization. The underlying allometric relationship between Dbase and peak diameter (Dpeak) was described. The re-analyses revealed that the absolute change in arterial diameter was strongly inversely proportional to Dbase (r= - 0.7, P < 0.0005). The allometric exponent for the Dbase-Dpeak 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 Dbase without any need for ΔSR normalization (r=0.0, P=0.96). The correlation between ΔSR and FMD% reduced from 0.69 to 0.37, when adjusted for Dbase. In conclusion, this new re-analysis of data from an influential study demonstrates that the FMD%-Dbase correlation is caused by the inappropriate size-scaling properties of FMD% itself. Removal of Dbase-dependency via FMD%/ΔSR 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 ΔSR on this properly scaled response can also be isolated and quantified accurately without the confounding influence of Dbase.