"To measure is to know": no relationship between cerebrovascular and peripheral shear-mediated dilation in young adults.

Abstract

Endothelial dysfunction is the first detectable manifestation of the atherosclerotic process, and its measurement is of both clinical and research importance. Vascular function in conduit arteries is promoted through shear-mediated dilation, where increases in shear-stress induce vasodilation through nitric oxide (NO) production. This is known as endothelium-dependent dilation, and is assessed in the peripheral vasculature through flow mediated dilation (FMD) of the brachial artery. This technique is associated with coronary artery endothelium-dependent vasodilation and is predictive of cardiovascular events. Endothelial dysfunction of the internal carotid artery (ICA) is a risk factor for cerebrovascular diseases (such as stroke, dementia and Alzheimer’s disease), but whether brachial FMD is associated with cerebral endothelium-dependent vasodilation is unknown. Typically, cerebrovascular function is assessed by cerebrovascular reactivity (CVR) of middle cerebral artery blood velocity (MCAv) to carbon dioxide (CO2). Although linked to FMD (Ainslie et al., 2007), this approach has poor predictive value in healthy populations, measures only blood velocity (not vessel dilation) and does not isolate a shear-mediated response. In a recent issue of The Journal of Physiology, Carr et al. (2020) explored the relationships between ICA and brachial artery shear-mediated dilation in 19 healthy adults (23±6 years). They also explored the endothelium-independent responses of these arteries, through glyceryl trinitrate (GTN) administration. Brachial artery shear-mediated dilation was assessed by FMD, and the authors utilised a cerebral-FMD protocol (cFMD) developed by Hoiland et al. (2017) for the ICA. In short, the cFMD test involved Duplex ultrasound imaging of the ICA during and following a rapid +9 mmHg increase in end-tidal CO2 (PETCO2) for 30 seconds. This test has been shown to be predominantly shear-stress mediated, with the subsequent ICA dilation significantly related to shear-rate area under the curve (SRAUC) (Hoiland et al., 2017). This provides a suitable “FMD-equivalent” for the cerebrovasculature, where ischemia-induced hyperaemia is not possible. This is in contrast to “traditional” CVR tests involving sustained hypercapnia (typically 3–5 minutes), where the relationships between shear stress and ICA diameter can be secondary to other confounding factors (e.g. increases in blood pressure and cardiac output). Indeed, another strength of the study by Carr et al., was the inclusion of a 5-minute hypercapnic CVR test to explore the relationships between ICA cFMD and commonly-used outcomes of MCAvand ICA-CVR. The primary finding was that ICA and brachial artery responses were not correlated in both the endotheliumdependent (FMD, r = 0.00, P = 0.93) and independent (GTN, r = 0.12, P = 0.19) tests, and this was maintained when data were allometrically scaled to account for between-artery differences in baseline diameter. Furthermore, ICA cFMD was not significantly related to MCAv or ICA blood flow CVR responses. These findings indicate that assessments of peripheral FMD and CVR cannot be used as surrogates of ICA endothelium-dependent function. These novel findings merit further discussion with respect to: (1) the lack of association between baseline cerebrovascular and peripheral artery shear-mediated function and (2) the lack of association between ICA endothelium-dependent function and traditional CVR outcomes. Lack of association between baseline cerebrovascular and peripheral artery shear-mediated function