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Endothelium-Dependent Dilation in the Systemic Arteries of Asymptomatic Subjects Relates to Coronary Risk Factors and Their Interaction

Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE
Journal of the American College of Cardiology 1994 24(6):1468-1474

Bibliography

PubMed
PMID 7930277
DOI
10.1016/0735-1097(94)90141-4
Funding
Dr Celermajer was supported by the British Heart Foundation and Dr Sorensen by the Danish Heart Foundation. The project was supported in part by a grant from Corda, a UK paediatric cardiac research charity. No pharmaceutical or commercial industry funding is disclosed.
Competing interests
No formal conflict-of-interest statement is included in this 1994 publication (it predates modern journal COI disclosure requirements). No commercial or pharmaceutical affiliations are apparent from the authors' listed affiliations (paediatric cardiology and cardiothoracic units).

Study snapshot

DesignCross-sectional observational study of vascular physiology
ModelHuman volunteers, children and adults (mean age 36 +/- 15 years, range 5-73), clinically well and free of known cardiovascular disease
Sample500 subjects (252 men, 248 women); 454 brachial artery studies, 46 superficial femoral artery studies
InterventionN/A - observational; endothelium-dependent dilation assessed via reactive hyperaemia (flow-mediated dilation) and endothelium-independent dilation via sublingual nitroglycerin, using high-resolution ultrasound
DurationN/A - single-visit cross-sectional measurement
EndpointsFlow-mediated (endothelium-dependent) dilation of the brachial or superficial femoral artery; Nitroglycerin-induced (endothelium-independent) dilation; Association between dilation responses and cardiovascular risk factors (smoking, cholesterol, blood pressure, age, sex, family history)

What the study showed, in plain terms

This landmark 1994 study measured how well the blood vessels of 500 healthy people could relax and widen in response to increased blood flow, a direct physical test of nitric-oxide-driven endothelial function. It found that cigarette smoking, older age, male sex and larger vessel size independently predicted a blunted vasodilation response, and that combining several risk factors made the impairment worse than any one risk factor alone. Notably, heavy smoking blunted vessel relaxation regardless of a person's cholesterol level, showing that smoking's damage to the vessel lining can occur even when other risk factors look favourable.

Key findings

  • In 500 clinically well subjects, flow-mediated (endothelium-dependent) dilation was significantly reduced with higher cholesterol, cigarette smoking, higher blood pressure, positive family history, older age, male sex, and larger vessel size on univariate analysis.
  • On multivariate analysis, only cigarette smoking, older age, male sex and larger vessel size remained independently associated with reduced flow-mediated dilation; cholesterol, blood pressure and family history did not remain independent predictors once other factors were accounted for.
  • Flow-mediated dilation was inversely related to smoking dose, measured in pack-years.
  • A composite risk factor score was independently and strongly related to flow-mediated dilation (r = -0.30, p < 0.0001), and adding it to the model did not eliminate the significance of individual risk factors, indicating that risk factors interact rather than acting in isolation.
  • In lifelong non-smokers, higher cholesterol was linked to significantly reduced flow-mediated dilation; in heavy smokers, flow-mediated dilation was impaired regardless of cholesterol level, showing smoking can override or mask cholesterol's effect on endothelial function.
  • Nitroglycerin-induced (endothelium-independent) dilation was related only to vessel size, not to any of the risk factors examined, confirming the risk-factor effects were specific to endothelial (nitric oxide-dependent) function rather than smooth-muscle responsiveness in general.

What this study can and cannot tell us

This is a cross-sectional, single time-point study, not a longitudinal or interventional one; it establishes association, not causation, and the authors explicitly state they do not recommend flow-mediated dilation testing as a clinical diagnostic tool given the absence of prospective outcome data linking impaired dilation to later cardiovascular events.

The risk-factor model explained only about 40% of the observed variability in flow-mediated dilation between subjects, indicating other unmeasured factors (the authors suggest genetic factors and lipid subfractions such as lipoprotein(a)) likely also matter. The study population had relatively low average cholesterol levels (only 25% had cholesterol at or above 215 mg/dl), which may have limited the ability to detect cholesterol's independent effect.

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