A meta-analysis of published studies of endothelial dysfunction does not support its routine clinical use

Abstract

Background: Endothelial dysfunction is a marker of future cardiovascular disease (CVD) risk, yet epidemiological studies have yielded inconsistent results. We therefore studied the association between endothelial dysfunction and CVD under diverse circumstances. Methods and results: Literature-based meta-analysis of prospective observational studies with ≥ 12 months of follow-up published in Medline and having information on endothelial function and CVD outcomes. Tabular data on participant characteristics, endothelial function assessments and incident CVD outcomes were abstracted from individual studies. Random-effects meta-analysis was used to quantify pooled associations, and I 2 statistic to evaluate between-study heterogeneity. Potential sources of heterogeneity were explored by subgroup analyses and meta-regression. Thirty five studies involving 17,206 participants met the inclusion criteria. During more than 80,000 person-years of observation, up to 2755 CVD events were accrued, yielding a pooled relative risk (RR) of 1.25 (95% confidence interval 1.15-1.35) for CVD comparing top (i.e. more severe) vs. bottom (less severe) third of endothelial dysfunction. There was significant between-study heterogeneity and evidence of publication bias. RRs varied importantly according to the method used to ascertain endothelial function, and were higher among older individuals and among participants with risk factors for CVD or established CVD at baseline. Conclusions: Although endothelial dysfunction is an important determinant of cardiovascular outcomes in people with pre-existing CVD, current evidence base does not support its use as a potentially useful measurement for risk stratification in people at lower risk of CVD. Review criteriaEndothelial dysfunction has been proposed as a marker of incident cardiovascular disease (CVD) outcomes, and endothelial function assessments have been considered to represent a useful tool in the evaluation of cardiovascular risk among various individuals. However, epidemiological studies evaluating this association have yielded inconsistent results to date. Message for the clinicBy combining published information on over 17,000 individuals from 35 prospective studies, we found that people within the highest category of endothelial dysfunction had just 25% excess risk of CVD outcomes, as compared with those within the lowest category. Therefore, although endothelial dysfunction may be an important determinant of vascular disease outcomes in people with pre-existing CVD, current evidence does not support its use as a potentially useful measurement for risk stratification in people at lower risk of CVD.

Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials

“…Findings from our meta-analysis may be influenced by participants in the studies testing fenofibrate [21][22][23]33,35,37,38]: they were obese and/or dyslipidemic and all had endothelial dysfunction at baseline (basal FMD < 6%, range 3.1-5%), representing a high-risk category, where improvement in the lipid profile is expected to exert beneficial effects on vascular health. Taking into account that low HDL-C and high triglycerides levels have been associated with reduced post-ischemic endothelial vasodilation, as shown in a cohort of patients with metabolic syndrome [58], findings of the present meta-analysis might contribute to the interpretation of results of FIELD and ACCORD trials [58,58,61].…”

“…A recent Cochrane systematic review including 13 trials and 16,112 participants [4] demonstrates that fibrates exerts protective effects over the primary composite outcome (non-fatal stroke, non.fatal myocardial infarction and vascular death); however, after excluding clofibrate trials, the remaining class of fibrates were no longer effective in preventing the primary composite outcome but remained effective in preventing myocardial infarction. Furthermore, large-scale trials demonstrated that fenofibrate therapy reduces the rate of cardiovascular events only in patients at high risk, such as those with diabetes mellitus and atherogenic dyslipidemia (low levels of HDL-C and increased triglycerides) [58,58,61]. It is conceivable that trial results may considerably differ according to the background cardiovascular risk of participants.…”

Simultaneous Assessment of Systemic and Coronary Endothelial Function

“…10 Several studies indicate that impaired flow-mediated dilation is a hallmark of various clinical conditions associated with increased cardiovascular risk; as for its prognostic capability, this seems to have been established in patients with relatively high cardiovascular risk profile. [11][12][13][14] All set, then? Well, not quite.…”

“…Well, not quite. For one thing, there is controversy over the prognostic role of endothelial function assessment in subjects at the lower end of cardiovascular risk profile, 13,14 in whom refining of classical indicators of cardiovascular risk would be most helpful. In addition, a major issue has to do with an overarching question: is endothelial function of peripheral arteries representative of what occurs at the coronary artery level?…”

“…Overall, a recent meta-analysis points to a modest correlation between the 2 approaches. 13 However, meta-analysis findings provide indirect information, gathered through comparisons of cohorts, and not at individual patient level. Although differences in population characteristics may explain to some extent the underlying heterogeneity between the 2 approaches, it is also conceivable that the observed differences are in fact genuine, reflecting different behavior of different vessels.…”