Adiponectin and leptin are fat secreted hormones with opposing actions on insulin resistance and vascular inflammation. While plasma leptin and adiponectin had opposite correlations with lipid, metabolic and inflammatory risk factors, we found that only plasma leptin levels were independently associated with CAC. Further, in a comparison of several metabolic biomarkers, leptin and the HOMA-IR index of insulin resistance had the most robust associations with CAC scores beyond traditional risk factors, NCEP defined metabolic syndrome and plasma levels of CRP.
Leptin is an important negative regulator of body weight (11
). Paradoxically, obesity is associated with increased plasma leptin levels, most likely due to resistance to its actions in the setting of increased production by adipose tissue (29
). Leptin activates the endothelium, induces smooth muscle cell proliferation and its receptors are expressed in atherosclerotic plaques (30
). Recent studies suggest an association between plasma leptin levels and atherosclerotic CVD in humans including angiographic CAD (31
) and CVD events (32
). In a case (n=377) control (n=783) study nested within the WOSCOPS clinical trial, plasma leptin levels predicted CVD even after adjusting for traditional risk factors, BMI and plasma CRP levels (15
). However, in a nested case-control study from the Quebec Cardiovascular Study Cohort, plasma leptin levels were not related to CVD events (18
Few data are available on the association between leptin and direct measures of atherosclerosis in humans. Van den Beld et. al. found no association between plasma leptin levels with carotid intima-media thickness (IMT) in 403 healthy elderly men (33
), while Ciccone et. al. reported an association of leptin with IMT in 126 healthy Italians (34
). We previously reported that leptin levels were associated with CAC in a type-2 diabetic sample even after controlling for establish risk factors including CRP and measures of sub-clinical vascular disease (16
). Recently, Iribarren et. al. reported an association of plasma leptin levels with CAC in older women in the ADVANCE study, but this association was not significant after controlling for metabolic risk factors and BMI data (35
). In SIRCA, we found an association of plasma leptin with CAC even after controlling for metabolic syndrome and CRP.
Adiponectin has emerged as a unique fat secreted hormone that regulates insulin sensitivity (36
). Atheroprotective effects may be directed through inhibition of the NF-κB inflammatory pathway in vascular cells (37
) and by attenuation of foam cell formation (38
). Plasma levels are depressed in patients with CAD (39
) and are associated with clinical CVD in diabetics (7
). A nested case control study by Maahs and colleagues suggested low plasma adiponectin predicted short term CAC progression, more so in non diabetics (40
). Several recent prospective studies of clinical CVD, however, have been negative. In a nested case-control study from the Strong Heart Study, there was no association with incident CAD events (10
). Similarly, in the British Women's Heart and Health Cohort Study, adiponectin levels were not associated with CVD (9
). More recently, Sattar et. al looked at 589 men with fatal and non fatal CAD and 1231 controls and found no difference in median adiponectin levels despite adiponectin associations with HDL and CRP. A seven-study meta-analysis by the same authors failed to demonstrate a consistent relationship of adiponectin with CAD events (41
Despite correlations with lipids, metabolic factors and insulin resistance, we also did not find an inverse association of adiponectin levels with CAC. The reasons for conflicting study findings are uncertain but may reflect differences in study design and populations as well heterogeneous outcomes including sub-clinical atherosclerotic and different CVD outcomes. In fact, Steffes and colleagues unexpectedly found a positive association of adiponectin with CAC in a study of over 3,000 young adults aged 33 to 45 years (42
). Finally, several studies suggest that the high molecular weight adiponectin complex, but not the lower molecular weight hexamer, may be the active signaling molecule (43
). Few epidemiological studies, however, have assayed the different circulating forms of adiponectin.
We also determined which of several metabolic biomarkers predicted CAC scores beyond established clinical CVD risk factors. Leptin, HOMA-IR, and, to a lesser extent, IL-6 and sol-TNFR2, provided incremental value beyond FRS, metabolic syndrome and CRP. Our finding that HOMA-IR levels are associated with CAC beyond all other risk factors is consistent with most (22
) but not all (45
) studies which found hyperinsulinemia and insulin resistance indices were independently associated with atherosclerosis and CVD. The clinical application of insulin-based measures, however, is challenging given the lack of assay standardization and because of ultradian and circadian variation in circulating insulin.
This study has several limitations. The study sample is cross-sectional and is not capable of determining causal relationships. Moreover, it is a study of a population consisting primarily of Caucasians with a family history of premature CVD who are otherwise deemed to be at low risk, therefore the generalizability of our findings across other populations and ethnic groups is uncertain. In addition, CAC is not a direct measure of coronary atherosclerosis. In autopsy studies, however, CAC has been shown to be a quantitative estimate of coronary atherosclerosis (46
). It has also been shown to be an independent predictor of CVD (47
In summary, we found that plasma levels of leptin but not adiponectin were associated with CAC after controlling for traditional cardiovascular risk factors, metabolic syndrome and CRP levels. Whether leptin signaling promotes human atherosclerotic CVD directly remains to be established. Finally, leptin levels and the HOMA-IR index had stronger associations with CAC scores than other adipocytokines in this asymptomatic sample. A systematic comparison of multiple adipocytokine and insulin resistance biomarkers across diverse clinical settings is warranted in order to establish which provide utility as metabolic biomarkers of clinical CVD.