Flow-mediated dilation and cardiovascular risk prediction: A systematic review with meta-analysis☆
Introduction
Endothelial cells form the inner lining of all blood vessels and play a central role in vascular homeostasis; they respond to stimuli such as hemodynamic changes or blood-borne signals by releasing vasoactive substances [1]. Disruption of the normal homeostatic endothelial condition is identified as endothelial dysfunction. The pathophysiological role of endothelial dysfunction in the development of atherosclerosis and cardiovascular disease (CVD) is well established [2], [3], [4].
Endothelial (dys)function can be quantified by the degree of flow-mediated dilation (FMD) of the brachial artery [5], [6]. This technique is widely used and non-invasive. FMD is determined by the change in brachial artery diameter in response to a blood flow stimulus. This stimulus is created by releasing an arm cuff that is inflated to supra-systolic blood pressure level. As a consequence, nitric oxide (NO) is released from the endothelial cells and mediates the relaxation of the smooth muscle cells with subsequent widening of the artery.
The association between brachial FMD and CVD risk has been investigated in several prospective studies. Although not conclusive [7], [8], the majority of these studies showed that FMD is inversely associated with future cardiovascular events [9], [10], [11], [12]. A meta-analysis summarizing the evidence of 14 prospective studies revealed that per 1% higher FMD, the risk of experiencing a cardiovascular event is 13% lower [13]. Since then, several large prospective studies have been published addressing the same research question, but adding to the evidence especially for asymptomatic populations [14], [15], [16], [17] and Asian populations [18], [19], [20]. Moreover, recent evidence in asymptomatic populations suggests that, in this specific population, the association between FMD and CVD risk may not be present [15], [16], [17]. Thus, the applicability of these data to populations not specifically being diagnosed for any disease remains to be determined. Therefore, we performed a meta-analysis on this association, with particular focus on the impact of underlying health status.
The purpose of the present study was to systematically review prospective studies that investigated the association between brachial FMD at baseline and future cardiovascular events in populations at different CVD risk. The relationship between FMD and CVD risk was quantitatively assessed, separately for studies that reported continuous relations (risk estimates expressed as the risk of CVD per 1% higher FMD) and for studies that reported categorical relations (risk estimates expressed as the risk of CVD for groups with high FMD compared to those with low FMD), by means of a meta-analysis of studies eligible for this purpose. Sources of variability in results across studies, especially underlying health status, were investigated.
Section snippets
Search strategy
Potentially relevant prospective studies investigating the association between FMD and CVD risk were searched in the databases Medline, Embase and Chemical Abstracts (through March 2011). Search terms related to the ‘exposure variable’ included: flow mediated vasodilation (or vasodilatation or dilation or dilatation) or endothelial (or endothelium) dependent vasodilation (or vasodilatation or dilation or dilatation) or endothelial (or endothelium) function (or dysfunction), or FMD or vascular
Selection process
In total, 1004 studies were obtained with the systematic search; an additional 16 studies were obtained via hand searching. After two selection steps, 29 prospective studies investigating the association between FMD and CVD events in adults were judged eligible for inclusion in the current review, of which 23 studies were suitable for a quantitative meta-analysis (Fig. 1).
Overview of included studies
In the 23 studies eligible for the meta-analysis, the number of subjects per study ranged from 73 to 3025 subjects, with
Discussion
In the current systematic review and meta-analysis, we observed a significant inverse association between brachial FMD at baseline and future cardiovascular events. The outcomes of our analysis are consistent with the findings from an earlier meta-analysis [13] that also observed a significant association between brachial FMD and CVD risk. Our analysis contributes to the existing evidence by showing significant associations for both continuously and categorically expressed risk estimates.
Conflict of interest
RTR, RD and PLZ are employed by Unilever R&D Vlaardingen. Unilever produces foods of which some are marketed to fit in a healthy diet and lifestyle. PLZ is senior scientist Cardiovascular Health Theme at the Top Institute Food and Nutrition, which is a public private partnership of science, industry and government that conducts strategic research in food and nutrition. MTS has no conflicts of interest.
Acknowledgments
The authors would like to acknowledge Ursula Garczarek (Unilever R&D Vlaardingen) for statistical input.
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These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.