Flow-mediated dilation and cardiovascular risk prediction: A systematic review with meta-analysis

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Abstract

Background

Flow-mediated dilation (FMD) is an accepted technique to quantify endothelial function and has shown to have prognostic value for future cardiovascular disease (CVD). The predictive strength of FMD in CVD patients compared to populations not diagnosed for CVD warrants further investigation. We systematically reviewed prospective studies that investigated the association between brachial FMD and future cardiovascular events, with particular focus on the role of underlying health status.

Methods

To obtain eligible studies, several literature databases were systematically searched through March 2011. Pooled overall risk estimates were calculated separately for continuous risk estimates for CVD (per 1% higher FMD) and for categorical risk estimates for CVD (having high vs. low FMD), based on random-effects models.

Results

A total of 23 studies including 14,753 subjects were eligible for inclusion in the meta-analysis. For studies reporting continuous risk estimates, the pooled overall CVD risk was 0.92 (95%CI: 0.88; 0.95) per 1% higher FMD. The observed association seemed stronger (P-value < 0.01) in diseased populations than in asymptomatic populations (0.87 (95%CI: 0.83; 0.92) and 0.96 (95%CI: 0.92; 1.00) per 1% higher FMD, respectively). For studies reporting categorical risk estimates, the pooled overall CVD risk for high vs. low FMD was similar in both types of populations, on average 0.49 (95%CI: 0.39; 0.62).

Conclusions

Our findings show that brachial FMD is inversely associated with future CVD events, with some indications for a stronger relation in diseased populations. Endothelial dysfunction may be considered relevant for classifying subjects in terms of CVD risk.

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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