Endothelium-Dependent Dilatation Is Impaired in Young Healthy Subjects With a Family History of Premature Coronary Disease

BACKGROUND: A family history of premature coronary artery disease (CAD) in a first-degree relative is an independent risk factor for coronary disease. Both genetic and environmental influences are likely to be responsible and may interact, but their relative importance is unclear. METHODS AND RESULTS: We studied endothelial function in 50 first-degree relatives (31 men, 19 women; mean age, 25+/-8 years) of patients (men < or = 45 years, women < or = 55 years) with proven CAD. All subjects were well, lifelong nonsmokers, not diabetic, and not hypertensive and took no medications. Using high-resolution external vascular ultrasound, we measured brachial artery diameter at rest and in response to reactive hyperemia (with increased flow causing an endothelium-dependent vasodilatation) and to sublingual glyceryltrinitrate (GTN, an endothelium-independent dilator). Vascular responses were compared with those of 50 healthy control subjects matched for age and sex. Flow-mediated dilatation (FMD) was impaired in the family history group (4.9+/-4.6% versus 8.3+/-3.5% in control subjects, P<.005). In contrast, GTN caused dilatation in all subjects (family history, 17.1+/-8.8%; control subjects, 19.0+/-6.3%; P=NS), suggesting that reduced FMD was due to endothelial dysfunction. When the family history subjects were subdivided, those found to have a serum cholesterol > 4.2 mmol/L (group A, n=10) had mildly impaired FMD compared with control subjects (5.5+/-5.1% versus 8.3+/-3.5%). In others whose affected relative had coronary risk factors (group B, n=24), FMD was also only slightly reduced (6.2+/-4.8% versus 8.3+/-3.5%). In contrast, subjects with no risk factors and whose affected relative had a normal cardiovascular risk factor profile (group C, n=16) had markedly impaired FMD (2.9+/-3.7% versus 8.3+/-3.5%). Although ANOVA of the three family history subgroups did not reach statistical significance (F=2.55, P=.09), pairwise analysis showed that FMD in group C was significantly impaired compared with group B (P=.026). CONCLUSIONS: Healthy young adults with a family history of premature coronary disease may have impaired endothelium-dependent dilatation, even in the absence of other cardiovascular risk factors. Those subjects, who were free of risk factors and whose affected first-degree relative was free of risk factors, had the most impaired endothelial function, suggesting a genetic influence on early arterial physiology that may be relevant to later clinical disease.