In the present study, we demonstrate an inverse association of serum fetuin-A concentrations with MAC among a cohort with coronary heart disease and without severe kidney disease. A similar association was observed between fetuin-A and AS but was limited to participants without diabetes mellitus. These associations were moderately strong and were essentially unaltered after extensive statistical adjustment for traditional risk factors for cardiovascular disease and dystrophic calcification. These findings are consistent with the hypothesis that fetuin-A may be an inhibitor of dystrophic valvular calcification among persons with coronary heart disease and, in the context of prior research, suggest a novel mechanism for the regulation of dystrophic mineralization.
The lowest fetuin-A tertile had the highest prevalence of valvular calcification but the lowest prevalence of other previously recognized risk factors for dystrophic calcification, including diabetes mellitus, body mass index, low-density lipoprotein cholesterol, triglycerides, and calcium concentrations. These results suggest that fetuin-A may involve a regulatory mechanism of dystrophic valvular calcification that is independent of previously recognized mechanisms. Future research evaluating fetuin-A among persons with coronary heart disease may therefore provide novel insights into the biology of valvular heart disease.
The association between fetuin-A and MAC was evident regardless of diabetes status, whereas the association between fetuin-A and AS was limited to persons without diabetes mellitus. The mechanisms responsible for these disparate findings are uncertain; however, other risk factors for dystrophic calcification have previously been demonstrated to have differential associations with aortic and mitral valve calcification.21,27,28
Whereas prior research has consistently demonstrated a strong association between diabetes mellitus and MAC,29-31
diabetes and AS have not been strongly linked.21,28
Whether fetuin-A or other molecular promoters or inhibitors of dystrophic calcification may explain these disparate observations should be evaluated in future studies.
Separate from its function as an inhibitor of dystrophic calcification, fetuin-A also appears to promote insulin resistance by binding to the extracellular domain of insulin receptor tyrosine kinase in peripheral tissues and decreases the rate of autophosphorylation and subsequent downstream intracellular signaling cascades.32,33
Despite their extensive calcification, fetuin-A knockout mice are characterized by resistance to weight gain, lower free fatty acid and triglyceride concentrations, and improved insulin sensitivity.34
We previously demonstrated that higher fetuin-A concentrations are associated with the metabolic syndrome and an atherogenic lipid profile in humans.19
This dual role of fetuin-A may explain the differential relationship between fetuin-A and AS among the diabetic and nondiabetic participants. In line with this hypothesis, prior epidemiological studies in populations primarily without diabetes mellitus have demonstrated an inverse correlation of fetuin-A with vascular calcification14,15
but a direct correlation in diabetic cohorts.35
The cross-sectional study design does not allow us to investigate the longitudinal relationship of these associations; however, we hypothesize that factors promoting an insulin-resistant phenotype might result in higher serum fetuin-A concentrations, which may be protective in this setting by limiting the amount of dystrophic calcification conferred by an insulin-resistant state.36,37
Prior epidemiological studies evaluating the associations of fetuin-A with dystrophic calcification have largely been limited to populations with end-stage renal disease in which lower fetuin-A concentrations are associated with vascular14
and valvular calcification15
Here, we demonstrate an inverse association of fetuin-A with dystrophic valvular calcification among a population without severe kidney disease. We have previously demonstrated that fetuin-A concentrations are similar across the spectrum from normal to moderate kidney dysfunction.8
Together, these data suggest that fetuin-A may function as an inhibitor of dystrophic calcification among other populations and is not limited to persons with end-stage renal disease. However, all participants in the present study had coronary heart disease. Future studies are required to evaluate whether these observations are generalizable to the general population.
Among the strengths of the present study are its relatively large sample size and the measurement of a wide spectrum of potential confounding variables. However, several limitations should be considered in the interpretation of the results. First, the cross-sectional study design does not allow evaluation of the longitudinal direction of associations. Evaluation of the longitudinal association of fetuin-A with incidence and progression of calcification among persons with and without diabetes mellitus should be evaluated in futures studies. Detailed assessment of dietary calcium and phosphorus intake and measures of calcification in other vascular tissues were not available in the study sample. Whereas MAC was determined by direct visualization of an echo-dense structure on echocardiogram, AS was determined by measurements of flow across the aortic valve. The associations of fetuin-A and AS and the effect modification by diabetes status should be confirmed in future studies with direct measures of aortic valve calcification. All participants had coronary heart disease, and the mechanisms of dystrophic calcification may differ among other populations. Because of relatively small cell counts in persons with MAC within each fetuin-A tertile, we cannot exclude that the present study missed a modest interaction in the association of fetuin-A with MAC on the basis of diabetes. Finally, the majority of participants were elderly men, and our results may not necessarily generalize to younger persons or women.
In summary, fetuin-A concentrations are inversely associated with MAC among ambulatory persons with coronary heart disease and without severe kidney disease. Fetuin-A concentrations also were inversely associated with AS among participants without diabetes mellitus. In the context of prior studies, these data are consistent with the hypothesis that fetuin-A may function as an important inhibitor of dystrophic valvular calcification among persons with coronary heart disease and that this function does not require the presence of kidney disease or other traditional cardiovascular risk factors. Future studies are required to evaluate whether fetuin-A is associated with dystrophic calcification among other vascular tissues, whether the results may generalize to persons without coronary heart disease, and whether fetuin-A concentrations may predict longitudinal progression of dystrophic calcification.