Endothelial Dysfunction: A Useful Tool?
Endothelial Dysfunction: A Useful Tool?
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 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.
Endothelial dysfunction represents an early step in the development of atherosclerosis and has been proposed as a marker of cardiovascular disease (CVD) outcomes. However, its association with CVD has not been reliably quantified under diverse circumstances. As reviewed recently, the clinical usefulness of endothelial function assessment is not yet firmly established, nor is any specific method for measuring endothelial dysfunction recommended in guidelines for primary or secondary prevention. In this respect, interpretation of the findings from individual studies can be problematic because of differences in: baseline prevalence of CVD and associated risk factors; the extent and severity of underlying ischaemic heart disease and diagnostic techniques used to assess endothelial (dys)function.
A previous meta-analysis of 23 cohort studies reported a significant association between endothelial dysfunction assessed using brachial artery flow-mediated dilatation (FMD) and CVD outcomes. However, it was importantly limited because: several contributing studies had combined all-cause mortality along with CVD in their primary end-point resulting in potentially misleading estimates of association; results of the meta-analysis were based solely on FMD measurements precluding any comparisons with other techniques; and, the associations were calculated separately for studies reporting continuous vs. categorical risk estimates, i.e. without any attempts to standardise the risk ratios (RRs). We therefore sought to quantify more precisely than previously possible, the association between endothelial dysfunction and the composite end-point of all CVD outcomes under diverse circumstances, by analysing data from 35 prospective studies including over 17,000 participants with up to 2755 CVD events. Studies included in our meta-analysis were based on five distinct population subtypes: essentially general populations (involving participants not selected on the basis of pre-existing CVD risk factors or baseline CVD); individuals at moderate-to-high risk of CVD; individuals with suspected coronary heart disease (CHD), defined as those undergoing diagnostic cardiac catheterisation for suspected coronary artery disease (CAD) or those with a positive exercise stress test; participants with established CHD (defined as a previous diagnosis of any CAD according to standard criteria); and, patients with known congestive heart failure (CHF).
Abstract and Introduction
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 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.
Introduction
Endothelial dysfunction represents an early step in the development of atherosclerosis and has been proposed as a marker of cardiovascular disease (CVD) outcomes. However, its association with CVD has not been reliably quantified under diverse circumstances. As reviewed recently, the clinical usefulness of endothelial function assessment is not yet firmly established, nor is any specific method for measuring endothelial dysfunction recommended in guidelines for primary or secondary prevention. In this respect, interpretation of the findings from individual studies can be problematic because of differences in: baseline prevalence of CVD and associated risk factors; the extent and severity of underlying ischaemic heart disease and diagnostic techniques used to assess endothelial (dys)function.
A previous meta-analysis of 23 cohort studies reported a significant association between endothelial dysfunction assessed using brachial artery flow-mediated dilatation (FMD) and CVD outcomes. However, it was importantly limited because: several contributing studies had combined all-cause mortality along with CVD in their primary end-point resulting in potentially misleading estimates of association; results of the meta-analysis were based solely on FMD measurements precluding any comparisons with other techniques; and, the associations were calculated separately for studies reporting continuous vs. categorical risk estimates, i.e. without any attempts to standardise the risk ratios (RRs). We therefore sought to quantify more precisely than previously possible, the association between endothelial dysfunction and the composite end-point of all CVD outcomes under diverse circumstances, by analysing data from 35 prospective studies including over 17,000 participants with up to 2755 CVD events. Studies included in our meta-analysis were based on five distinct population subtypes: essentially general populations (involving participants not selected on the basis of pre-existing CVD risk factors or baseline CVD); individuals at moderate-to-high risk of CVD; individuals with suspected coronary heart disease (CHD), defined as those undergoing diagnostic cardiac catheterisation for suspected coronary artery disease (CAD) or those with a positive exercise stress test; participants with established CHD (defined as a previous diagnosis of any CAD according to standard criteria); and, patients with known congestive heart failure (CHF).
