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Endothelial Function and Atherosclerosis
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Source: Halcox JP, et al. Endothelial function predicts progression of carotid intima-media thickness. Circulation. 2009;119;1005-1012.
Many reports evaluating coronary risk factors in overtly healthy individuals have been highlighted in a variety of preventative cardiology programs, guidelines, and sources. The Framingham Study gave an amazingly powerful kick start to the recognition of coronary risk factors. This somewhat sophisticated article suggests that the vascular endothelium is an important piece of the risk-factor puzzle, and supports a relatively new methodology for coronary risk-factor identification as it relates to endothelial function status.
Halcox et al state, "the vascular endothelium has a central role in the maintenance of vascular health and the nature of endothelial cell function...recognizing and responding to local physical and chemical signals, endothelial cells are able to influence vasomotor, thrombotic, inflammatory, and cellular pathways that affect the short- and long-term biology of the vessel wall." Thus, disordered endothelial function and vascular dysfunction may predict cardiovascular (CV) outcome in high-risk subjects.
Halcox et al in London have assessed the implications of atheroma progression in the carotid arteries using carotid intima media thickness (CIMT) in asymptomatic subjects selected from the Whitehall II study population. The protocol features a serial assessment of CV risk factors. The study subjects consisted of healthy, older non-smokers without diabetes or CV disease. The main Whitehall II study consists of more than 10,000 subjects, of which 282 participants were selected for this vascular protocol (phase 5, 1997-1999); initial enrollment took place from 1985 to 1987. Halcox et al sought to prospectively evaluate the influence of endothelial dysfunction (ED) on the progression of CV disease and CIMT thickness. Subjects underwent a complete CV risk-factor analysis, including CIMT (right and left common carotid artery) and brachial artery vasomotor function with arterial diameter and high-resolution ultrasound, with reassessment at a mean of 6.2 years (phase 7 - 2003-2005). A total of 213 participants completed the two studies.
Risk Factor Measurement: Blood pressure, waist circumference, fasting plasma glucose, cholesterol, and standard lipid particles were measured. Vascular studies included brachial artery function (flow mediated dilation or FMD) and CIMT, measured by experienced staff. Statistical analysis indicated that CIMT and the annual rate of CIMT progression were normally distributed. The value of using FMD to predict adverse progression of CIMT was also assessed.
Results: At baseline, age, blood pressure, and waist circumference were all inversely related to FMD. Women increased CIMT after menopause. Framingham risk score was strongly correlated with CIMT and, inversely, with FMD. Mean annual rate of progression of CIMT was similar in both men and women, and correlated with age. After adjustment for age and sex, FMD was the sole parameter that remained associated with CIMT. Other markers did not affect the relationship between FMD and CIMT. Reactive hyperemia was not associated with IMT progression.
Halcox et al claim, "... for the first time, we can now demonstrate that impaired endothelial function is associated with more rapid progression of structural arterial disease in a general, middle-aged population." The data indicate that the findings are robust and independent of conventional risk factors and the Framingham risk score. Endothelial function testing with FMD may, therefore, have a role in identifying those individuals at increased of CV risk. They conclude that a blunted FMD is associated with more rapid progression of development of arterial disease in this middle-aged population without clinical CV disease. Furthermore, they suggest, as noted, that endothelial function testing may be able to identify subjects at a high or increased risk of disease progression, including those with increased and/or progression of disease.
This study explored whether endothelial testing can help identify preclinical disease. Although these conclusions only apply to low- and intermediate-risk individuals, endothelial dysfunction is well known to be associated with a poorer prognosis. The results suggest that the combination of both CIMT and FMD are markers of progression. FMD testing is an attractive measure of vascular status in the assessment in both the earlier and later stages of atherosclerotic disease.
Of interest, women and men had equal rates of CIMT progression (women had a lower initial CIMT, which increased after menopause), with similar subsequent progression of increased CIMT. FMD was most closely associated with a change in CIMT over a six-year period, suggesting endothelial factors are a causal determinant of atherosclerosis.
This large, detailed study is consistent with the concept that endothelial pathobiology may identify presymptomatic coronary disease. Increased CIMT indicates an abnormal vessel wall, presumably due to atherosclerotic disease. The methodology for obtaining accurate FMD and CIMT are feasible in high-quality clinical practices or clinical research units. It is critical to have highly trained technicians and strict adherence to testing methods. Flow-mediated dilatation is more labor intensive, with fewer publications than with CIMT. In conclusion, we all need to become educated about these emerging vascular diagnostic techniques in carotid and coronary arterial studies.