implications for the assessment of endothelial function
Kyra E Pyke 1, Michael E Tschakovsky Affiliations expand
Abstract Endothelium-dependent flow-mediated dilatation (FMD) describes the vasodilatory response of a vessel to elevations in blood flow-associated shear stress. Nitric oxide (NO), one of many vasoactive substances released by the endothelium in response to shear stress, is of particular interest to researchers as it is an antiatherogenic molecule, and a reduction in its bioavailability may play a role in the pathogenesis of vascular disease. The goal of many human studies is to create a shear stress stimulus that produces an NO-dependent response in order to use the FMD measurements as an assay of NO bioavailability. The most common non-invasive technique is the 'reactive hyperaemia test' which produces a large, transient shear stress profile and a corresponding FMD. Importantly, not all FMD is NO mediated and the stimulus creation technique is a critical determinant of NO dependence. The purpose of this review is to (1) explain that the mechanisms of FMD depend on the nature of the shear stress stimulus (stimulus response specificity), (2) provide an update to the current guidelines for FMD assessment, and (3) summarize the issues that surround the clinical utility of measuring both NO- and non-NO-mediated FMD. Future research should include (1) the identification and partitioning of mechanisms responsible for FMD in response to various shear stress profiles, (2) investigation of stimulus response specificity in coronary arteries, and (3) investigation of non-NO FMD mechanisms and their connection to the development of vascular disease and occurrence of cardiovascular events.
Figure 1. Hypothetical schematic of temporal recruitment of mechanisms for FMD
If a shear stress stimulus is prolonged the mechanisms primarily responsible for the observed vasodilatory response may change. The time courses of the mechanisms for FMD (i.e. when one begins and when it ceases to contribute) are currently unknown. It is also unknown how many mechanisms may be recruited over time in response to a sustained stimulus
Figure 2 In vessels with different diameters the same flow may represent a very different shear stress stimulus
Figure 3. Peak flow versus peak shear rate demonstrating no relationship
Data from reactive hyperaemia tests performed in 8 healthy subjects (2 tests on 2 separate days) from the data set published in Pyke et al. (2004). These data illustrate that flow and shear rate cannot be used interchangeably as the stimulus for FMD when the subject pool has a range of baseline diameters.
Figure 4. Relationship of baseline diameter to bloodflow, shear rate and FMD
A, baseline diameter versus peak shear rate demonstrating an inverse relationship. B, baseline diameter versus peak flow demonstrating a direct relationship. C, baseline diameter versus peak FMD response demonstrating an inverse relationship. Data from reactive hyperaemia tests performed on 8 healthy subjects (2 tests on 2 separate days) from the data set published in Pyke et al. (2004).
Figure 5. Schematic diagram of the area under the curve (AUC) of the stimulus (shear stress or shear rate) until the time of peak diameter measurement
Continuous line, stimulus; dashed line, response.