Response to Letter from Tremblay & King: Near‐infrared spectroscopy: can it measure conduit artery endothelial function?

We thank Tremblay & King (2016) for their interest in our publication (McLay et al. 2016a), which has since been followed up with studies by McLay and colleagues (McLay et al. 2016c,b). In these studies, it is suggested that the near-infrared spectroscopy (NIRS)-derived measure of tissue oxygen saturation (), specifically the reperfusion rate (slope 2) following a brief period of ischaemia, can be easily applied as a reliable, non-invasive measure of vascular reactivity (McLay et al. 2016a,b,c). As mentioned by Tremblay & King (2016), the reperfusion rate, being measured distal to the site of occlusion, provides insight on microvascular reperfusion, and it was an error in our wording that wrongfully implied that the NIRS measure of slope 2 could be used as a surrogate for conduit artery endothelium-dependent vasodilatation. We appreciate this opportunity to clarify the interpretation of the present study to avoid further confusion on this topic. The primary concern raised by Tremblay & King (2016) is that microvascular and macrovascular function are different entities, and they conclude that the significant correlation observed in the present study is likely to reflect the fact that the reperfusion rate is related to the stimulus for flow-mediated dilation (FMD). This is true and was discussed in our paper; refer to paragraph 2 of the Discussion in McLay et al. (2016a). We accept that our statement in the Abstract and New Findings section that ‘NIRS-derived slope 2 can be used as a measure of vascular endothelial function’ was a poorly crafted sentence, as we offered no evidence to support an endothelium-dependent mechanism from this NIRS-derived measure. However, it is evident to us that there are different mechanisms governing the responses being measured by the two methods, and that the reperfusion slope is a microvascular response, whereas %FMD is measuring the arterial vascular responsiveness of a conduit artery (i.e. macrovascular response). Indeed, we stated that the significant correlation between the two measures was most likely to be a result of the relationship between what is being measured at the microvascular level by NIRS and the stimulus for FMD. The focus of this paper (McLay et al. 2016a) was not FMD, which was used primarily as an indirect means of validation, but instead to discuss the new NIRS technique for assessing vascular reactivity. Owing to space limitations, we chose not to emphasize and discuss in detail the shear stress stimulus for FMD. It is unfortunate that our understanding of the different mechanisms at play for the two measures was not clearly delivered, and we appreciate the opportunity to discuss them in more detail here. Although other researchers using similar NIRS measurements have concluded that the slope 2 represents endothelial function, we tried not to do so because we are aware that measurements distal and proximal to the site of occlusion evoke different mechanisms of vasodilation, even at the same level of the vasculature. The FMD of a conduit artery is an endothelium-dependent response, and the mechanisms governing this response have been heavily researched. As mentioned by Tremblay & King (2016), the majority of studies consider this dilatory response to an ischaemic challenge to be largely nitric oxide (NO) dependent; however, some studies have been unable to abolish a vasodilatory response through pharmacological blockades targeting the NO pathway (Pyke et al. 2009). Although we would accept that the FMD response to ischaemia is largely attributable to a single dilatory pathway, the mechanisms governing the control of microvascular blood flow distribution are not fully understood, and there are multiple different mechanisms influencing the microvascular response. The endothelium appears to play a major role both by detecting reductions in local oxygen availability and by inducing vasodilatation in the microcirculation by releasing NO (Blitzer et al. 1996; Justice et al. 2000). However, additional pathways that may be influencing the reperfusion rate may include metabolites, and even red blood cells themselves have been identified as regulators of oxygen delivery and distribution rather than merely transporters (Bergfeld & Forrester, 1992). Thus, even though endothelium-dependent mechanisms cannot be directly linked to the reperfusion responses, some lines of research suggest that they might have a certain degree of participation. Further research is needed to elucidate the mechanistic components that control the response following a period of blood flow occlusion. With this in mind, we would like to point out that we do not consider the reperfusion rate of the signal (as assessed by the graphical display of the slope 2 over a given period of time) simply as an indicator of the stimulus for conduit artery FMD but also as an autonomous indicator of vascular reperfusion within the microcirculation. It seems evident that this measure reflects vascular responsiveness within the microvasculature (independently of the mechanisms that control it) and, given that the microcirculation plays a critical role in the redistribution of blood flow, evaluating vascular responsiveness within the microcirculation is crucial. In other words, measures of FMD have been widely used as these vessels are easily accessible in humans. However, we argue that the main focus of interest in terms of vascular responsiveness lies within the microcirculation. Although measurements of FMD provide information on the dilator function of peripheral conduit arteries, which relates to the function of coronary arteries and clinical macrovascular events, a measurement of responsiveness in the microcirculation provides important information on ‘functional’ perfusion at the ever-important capillaries. In expressing their hesitation for the use of NIRS to measure vascular responsiveness, Tremblay & King (2016) also addressed a follow-up investigation that should be done to correlate the reperfusion rate with the stimulus for FMD by measuring blood velocity to calculate the postischaemic shear rate response. As our NIRS technique is very much in its infancy, we agree that there are several studies that should, and are being done. Again, in the interest of keeping the discussion succinct, we did not include ‘future directions’, but welcome the opportunity to address some of the exciting possibilities in more detail here. We agree that would be likely to correlate with the postischaemic shear rate response, and although that was not the purpose of the present study, it may be helpful in confirming that the reperfusion rate is closely linked with the stimulus for FMD. Future investigations might consider this topic. That being said, the administration of pharmacological vasodilatory agents and blockades in combination with the measure throughout a vascular occlusion test might be more beneficial in elucidating the governing mechanisms of microvascular responsiveness distal to the site of occlusion. Finally, we are glad that this letter provided us with the opportunity to clarify the interpretation and implications of our study. None declared.

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