The Coronary Artery Risk Development in Young Adults Study
- Joel A. Simon1,2,
- Maureen A. Murtaugh3,
- Myron D. Gross4,
- Catherine M. Loria5,
- Stephen B. Hulley2 and
- David R. Jacobs Jr.4,6
Ascorbic acid is an antioxidant nutrient possibly related to the development of atherosclerosis. To examine the relation between ascorbic acid and coronary artery calcium, an indicator of subclinical coronary disease, the authors analyzed data from 2,637 African-American and White men and women aged 18–30 years at baseline who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (1985–2001). Participants completed diet histories at enrollment and year 7, and plasma ascorbic acid levels were obtained at year 10. Coronary artery computed tomography was performed at year 15. The authors calculated odds ratios in four biologically relevant plasma ascorbic acid categories, adjusting for possible confounding variables. When compared with men with high plasma ascorbic acid levels, men with low levels to marginally low levels had an increased prevalence of coronary artery calcium (multivariate odds ratio = 2.68, 95% confidence interval: 1.31, 5.48). Among women, the association was attenuated and nonsignificant (multivariate odds ratio = 1.50, 95% confidence interval: 0.58, 3.85). Ascorbic acid intakes from diet alone and diet plus supplements were not associated with coronary artery calcium. Low to marginally low plasma ascorbic acid levels were associated with a higher prevalence of coronary artery calcium among men but not among women..
Overall, our study produced mixed findings. The main positive finding was that low to marginally low plasma ascorbic acid levels (measured at year 10) were associated with an approximately threefold higher prevalence of coronary artery calcium (ascertained at year 15) among men independently of other cardiovascular disease risk factors, including smoking. We did not, however, observe a similar relation among women, perhaps because fewer women had coronary artery calcium, thereby limiting our statistical power to detect such an association. We also cannot exclude the possibility that our findings resulted from chance or residual confounding. The findings among men concur with findings from cross-sectional and longitudinal analyses of participants in the Second National Health and Nutrition Examination Survey (NHANES II) (7, 15). Simon et al. (15) reported previously that NHANES II participants with low to marginally low serum ascorbic acid levels had an increased prevalence of self-reported coronary heart disease. In the NHANES II Mortality Study, which followed participants for a mean of 14 years, Simon et al. (7) found a trend toward increased cardiovascular disease mortality among individuals with low to marginally low serum ascorbic acid levels. Similar to our current findings, those from the NHANES II Mortality Study did not reflect a relation between dietary intake of ascorbic acid and cardiovascular disease endpoints (7).
Our current findings are also consistent with results from some observational studies that also reported low blood ascorbic acid levels to be a risk factor for coronary heart disease (3–5, 8, 16, 17). Not all observational studies have reported such an association (6, 18), and the few randomized trials examining the effect of vitamin C supplementation on coronary heart disease endpoints, typically in combination with other antioxidants, have produced inconsistent results, ranging from decreased risk to no effect to increased risk (19–22). Specifically determining whether marginal vitamin C deficiency is a factor in the development of atherosclerotic coronary disease would be of considerable public health importance, since blood levels consistent with marginal deficiency are prevalent in the population (7) and readily modifiable.
Conclusions based on our findings are qualified by limitations in the study design. We collected information on plasma levels of ascorbic acid 5 years before the coronary artery calcium measurement, but we do not have coronary artery calcium scores before year 15. Therefore, we cannot be certain that differences in plasma ascorbic acid preceded the development of coronary artery calcium since we cannot exclude the possibility that subclinical coronary disease lowered plasma ascorbic acid levels. The concern about the direction of causality is underscored in part because we were unable to find an association between dietary ascorbic acid intake (measured at baseline and year 7) and coronary artery calcium; that is, since blood levels of ascorbic acid are generally correlated with intake, a similar association between lower ascorbic acid intakes and coronary artery calcium would have been expected.
There are several potential explanations for these findings. Because the dietary assessments were performed at baseline and year 7 and plasma ascorbic acid levels were assayed at year 10, we cannot exclude the possibility that dietary and supplement use changed during the intervening period, although we did find a weak, albeit statistically significant, correlation between dietary ascorbic acid intake and plasma ascorbic acid levels (r = 0.14; p < 0.0001). It is also possible that the dietary assessments were not sufficiently accurate or precise to permit the detection of the association. Prospective studies that examined dietary intake of ascorbic acid as a predictor of cardiovascular disease have produced contradictory results. An analysis of data from the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study found that individuals with the highest intakes of ascorbic acid had 25–50 percent lower cardiovascular disease mortality (23). Dietary ascorbic acid intake was also associated with a lower risk of coronary heart disease death among Finnish women (24) and a group of 747 noninstitutionalized elderly Massachusetts residents (25). The Nurses’ Health Study (26), the Health Professionals Follow-up Study (27), and others (28, 29), however, found no significant association between ascorbic acid intake and risk of coronary heart disease.
Ascorbic acid may reduce the risk of cardiovascular disease by a number of mechanisms. Antioxidant status has been hypothesized to be an important factor in atherogenesis, and ascorbic acid is a highly effective water-soluble antioxidant capable of inhibiting lipid peroxidation (30, 31). In some studies, ascorbic acid blood levels and dietary intake have been associated with increased levels of high density lipoprotein cholesterol and decreased levels of total cholesterol (1, 32, 33). The inverse relation between plasma ascorbic acid levels and coronary artery calcium that we observed, however, was independent of cholesterol levels. Ascorbic acid promotes endothelial prostacyclin production (34), improves endothelium-dependent vasodilation (2), and is essential for vascular collagen formation, all factors that may be associated with cardiovascular disease risk. Despite the potential for ascorbic acid to lower the risk for cardiovascular disease, recent clinical trials using antioxidant cocktails that contain ascorbic acid have failed to lower cardiovascular disease risk (19–22). We are unaware, however, of clinical trials using ascorbic acid supplementation specifically among individuals with low to marginally low blood levels, our postulated high-risk group.
In addition to the limitations discussed, we were also limited by having only a single measurement of plasma ascorbic acid, which may not reflect long-term plasma concentrations optimally. However, plasma ascorbic acid levels reflect at least the previous several months of dietary intake, even during periods of seasonal variation (35), and are strongly correlated with leukocyte ascorbic acid levels, an indicator of tissue ascorbic acid levels (36, 37). We cannot exclude the possibility that our findings were affected by residual confounding (especially from smoking) or that plasma ascorbic acid levels were simply a healthy diet or lifestyle marker. The association of low plasma ascorbic acid levels with higher prevalence of coronary artery calcium among men was, however, independent of the effects of other lifestyle-related variables, such as education and exercise.
In conclusion, we found that low to marginally low plasma ascorbic acid levels were independently associated with a higher prevalence of coronary artery calcium in young adult men but not in young adult women. Because we cannot exclude chance or residual confounding as an explanation of our findings, our results need to be confirmed by other investigators.