CLINICAL RESEARCH: BIOMARKERS
Adipokines, Insulin Resistance, and Coronary Artery Calcification
Atif Qasim, MD*,
Nehal N. Mehta, MD*,
Mahlet G. Tadesse, ScD ,
Megan L. Wolfe, BS*,
Thomas Rhodes, MSPH ,
Cynthia Girman, DrPH and
Muredach P. Reilly, MB*,*
* Cardiovascular Institute and Institute for Translational Medicine and Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Department of Mathematics, Georgetown University, Washington, DC
Department of Epidemiology, Merck Research Laboratories, West Point, Pennsylvania.
Manuscript received January 29, 2008;
revised manuscript received April 25, 2008,
accepted April 28, 2008.
* Reprint requests and correspondence: Dr. Muredach P. Reilly, Cardiovascular Institute, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Boulevard, Philadelphia, Pennsylvania. (Email: muredach{at}spirit.gcrc.upenn.edu).
 |
Abstract
|
|---|
Objectives: We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary artery calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, metabolic syndrome, and plasma C-reactive protein (CRP).
Background: Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.
Methods: We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, nondiabetic participants in the SIRCA (Study of Inherited Risk of Coronary Atherosclerosis).
Results: Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance, and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjustment for age, gender, traditional risk factors, and Framingham risk scores (tobit regression ratio 2.42 (95% confidence interval [CI]: 1.48 to 3.95; p = 0.002) and further adjustment for metabolic syndrome and CRP (tobit regression ratio: 2.31; 95% CI: 1.36 to 3.94; p = 0.002). In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, interleukin-6, and soluble tumor necrosis factor receptor-2, as well as the homeostasis model assessment of insulin resistance (HOMA-IR) index, predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, metabolic syndrome, and CRP.
Conclusions: In SIRCA, although both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.
Key Words: adiponectin • leptin • coronary artery calcification • atherosclerosis • inflammation
|
Abbreviations and Acronyms
| | BMI = body mass index | | CAC = coronary artery calcium | | CAD = coronary artery disease | | CRP = C-reactive protein | | CVD = cardiovascular disease | | FRS = Framingham risk score | | HOMA-IR = homeostasis model assessment of insulin resistance | | IL = interleukin | | IMT = intima-media thickness | | LRT = likelihood-ratio test | | sol-TNFR2 = soluble tumor necrosis factor receptor-2 |
|
Adipokines are fat-secreted biomolecules with diverse signaling effects that modulate insulin resistance, hepatic lipoprotein production, and vascular inflammation (1). Two in particular, adiponectin and leptin, are almost exclusively fat derived and have antithetic actions in insulin resistance and in vascular signaling (2). Because of these properties, adiponectin and leptin have been proposed as biomarkers of adipose function that may add value in predicting cardiovascular disease (CVD) risk and provide targets for therapeutic interventions.
Levels of adiponectin, an insulin-sensitizing hormone with anti-inflammatory properties (3), are reduced in obesity, type 2 diabetes, and coronary artery disease (CAD) compared with controls (4–6). Indeed, several (7,8) but not all (9,10) epidemiologic studies suggest that reduced plasma adiponectin levels are independent predictors of CVD. Leptin, on the other hand, is a pleiotropic adipokine that modulates innate immune functions and vascular signaling in addition to its central role in regulation of appetite and energy expenditure (11). In contrast to adiponectin, leptin levels directly correlate with insulin resistance, obesity (12,13), and several CVD risk factors (14). Leptin levels have been associated with CVD beyond body mass index (BMI) in some (15–17) but not all studies (18).
We previously examined the association of plasma levels of C-reactive peptide (CRP), resistin, interleukin (IL)-6, and soluble tumor necrosis factor receptor-2 (sol-TNFR2), as well as metabolic syndrome, with coronary artery calcification (CAC) in the SIRCA (Study of Inherited Risk of Coronary Atherosclerosis) (19–22). In this report, we examined the association of adiponectin and leptin with CVD risk factors and CAC in SIRCA and then compared the relative value of all measured biomarkers of adiposity and insulin resistance in predicting CAC scores beyond traditional risk factors, metabolic syndrome, and plasma CRP.
|
Methods
|
|---|
Study participants.
SIRCA is a single-center, community-based, cross-sectional study of factors associated with CAC (21,23). Participants were healthy adults 30 to 75 years with family histories of premature CVD but without evidence of clinical CAD (defined as myocardial infarction, coronary revascularization, angiographic evidence of CAD, or ischemia seen on a cardiac stress test), diabetes, serum creatinine level >3.0 mg/dl, or elevated total cholesterol (>300 mg/dl). This report focuses on 860 unrelated, nondiabetic SIRCA participants.
Evaluated parameters.
Study subjects were evaluated in a fasting state at the General Clinical Research Center at the Hospital of the University of Pennsylvania, Philadelphia (21,23). Plasma levels of adiponectin, leptin, resistin, and insulin (Linco, St. Charles, Missouri), as well as IL-6 and sol-TNFR2 (R&D Systems, Minneapolis, Minnesota), were measured by enzyme-linked immunosorbent assays. The CRP levels were assayed as described (21). The intra-assay and interassay coefficients of variance for pooled human plasma were 5.7% and 9.9% for adiponectin; 5.5% and 12.4% for leptin; 4.6% and 4.3% for resistin; 4.1% and 11.6% for insulin; 8.7% and 10.9% for IL-6; 5.3% and 12.1% for sol-TNFR2; and 8.0% and 8.3% for CRP, respectively. Framingham risk scores (FRS) were calculated as described by Wilson et al. (24). Participants were classified as having metabolic syndrome using the National Cholesterol Education Program (NCEP) definition (25). The homeostasis model assessment of insulin resistance (HOMA-IR) index = fasting glucose (mmol/l) x fasting insulin (µU/ml)/22.5 (26) was used as a measure of insulin resistance. Global Agatston CAC scores (27), measured by electron beam tomography (Imatron, San Francisco, California) were determined as previously described (21,23).
Statistical analysis.
Data are reported as median with first and third quartiles (Q1 = 25th percentile, Q3 = 75th percentile) or mean ± standard deviation for continuous variables and as proportions for categoric variables. Spearman correlations of plasma adiponectin and leptin levels with other continuous variables are presented. Crude associations of adipokine levels with categoric variables were examined using the Kruskal-Wallis rank test. Tobit regression, using natural log (CAC+1) as the outcome, was used for the analysis of CAC data because of its marked right-skewed distribution and the presence of many zero scores (28). The tobit model is designed to assess the relationship between explanatory variables and a censored dependent variable at one end, at which many observations are clustered. We chose this modeling because CAC scores are censored at zero and the use of ordinary least-squares regression on such a nonnormal distribution would produce biased estimates and invalid inference. Tobit modeling has otherwise similar assumptions about error distributions as the linear regression model.
Because of potential gender differences in adipose associations with CVD, models are presented for each gender separately and combined when appropriate. The association between CAC and highest versus lowest quartile of adiponectin and leptin levels were assessed in incremental models including the variables age (age and age2), race, gender, family history of CAD, exercise (none vs. any), medications (aspirin, statins, angiotensin-converting enzyme inhibitors), FRS, metabolic syndrome, and CRP. Gender differences in the association of adipokines with CAC were assessed using the likelihood-ratio test (LRT). A priori BMI data were not included in the models because adipokines may be intermediate in the causal pathway between adiposity and subclinical atherosclerosis.
We used the likelihood-ratio test in nested models to assess the incremental value of each biomarker of adiposity and insulin resistance, adiponectin, leptin, resistin, IL-6, sol-TNFR2, HOMA-IR data (all included as log-transformed variables), and metabolic syndrome in predicting CAC scores beyond established risk factors. Statistical analyses were performed using Stata 9.0 software (Stata Corporation, College Station, Texas). A tobit regression model was fit in Stata (29) using the tobit command with the ll(0) option to indicate left censoring at a CAC score of 0.
|
Results
|
|---|
Characteristics of participants.
As previously described (19,21), the SIRCA sample is predominantly Caucasian (Table 1). Plasma levels of adiponectin and leptin were significantly higher in women than in men (p < 0.001 for both). Almost 40% had CAC scores above the 70th percentile, consistent with accelerated atherosclerosis most likely related to recruitment strategy based on a family history of CVD.
Differential association of adiponectin and leptin with cardiovascular risk factors.
Adiponectin and leptin correlated only modestly (and inversely) with each other, whereas associations with lipid, metabolic, and inflammatory variables were greater for both adipokines in women than men (Online Appendix Table A). Among all factors, adiponectin's strongest (direct) correlation was with plasma levels of high-density lipoprotein (HDL) cholesterol, whereas it was only modestly and inversely correlated with HOMA-IR, adiposity, and inflammatory markers. In contrast, leptin was strongly associated with BMI, waist circumference, and HOMA, moderately correlated with inflammatory markers, blood pressure, and apoB lipoproteins, but only weakly inversely related to HDL cholesterol.
Plasma levels of leptin, but not of adiponectin, are associated with CAC.
In simple models, adiponectin levels were not significantly correlated with CAC in either men or women, whereas leptin had a strong direct association with CAC across gender (Table 2). There were suggestive gender differences in the association of adipokines with CAC in cruder models, which were significant for adiponectin in age- and race-adjusted models (p < 0.01). In fully adjusted models, even after controlling for FRS, metabolic syndrome, and plasma CRP levels, the top quartile of leptin but not adiponectin was significantly associated with CAC scores (Table 2).
View this table:
[in this window]
[in a new window]
|
Table 2 Association of Plasma Levels of Adiponectin and Leptin With Coronary Artery Calcification in Tobit Multivariable Models
|
|
Comparison among adipocytokines, HOMA-IR, metabolic syndrome, and CRP in prediction of CAC scores.
In SIRCA, there was no evidence for major gender differences in the association of metabolic syndrome, HOMA-IR, IL-6, sol-TNFR2, and resistin with CAC in adjusted analyses (e.g., p = 0.10, 0.37, 0.68, and 0.18, respectively, for gender differences in age- and race-adjusted models). Therefore, except for adiponectin, results of these analyses are presented for both genders combined. The HOMA-IR index and plasma levels of leptin, IL-6, and sol-TNFR2, as well as the NCEP-defined metabolic syndrome (glucose cut point >110 mg/dl), provided significant improvements in the association with CAC beyond traditional risk factors and FRS (Table 3). After further adjustment for metabolic syndrome and CRP data, only HOMA-IR (LRT chi-square = 10.39, p < 0.01) and plasma leptin levels (LRT chi-square = 6.87, p < 0.01) significantly improved model prediction of CAC (Table 3).
View this table:
[in this window]
[in a new window]
|
Table 3 Incremental Value of Metabolic Syndrome, CRP, Adipocytokines, or HOMA-IR in Predicting Coronary Calcium Scores Beyond Established Risk Factors
|
|
|
Discussion
|
|---|
Adiponectin and leptin are fat-secreted hormones with opposing actions on insulin resistance and vascular inflammation. Plasma leptin and adiponectin had opposite correlations with lipid, metabolic, and inflammatory risk factors, but 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 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 because of resistance to its actions in the setting of increased production by adipose tissue (30). Leptin activates the endothelium and induces smooth muscle cell proliferation, and its receptors are expressed in atherosclerotic plaques (31). Recent studies suggest an association between plasma leptin levels and atherosclerotic CVD in humans, including angiographic CAD (32) and CVD events (33). In a case- (n = 377) control (n = 783) study nested within the WOSCOPS (West of Scotland Coronary Prevention Study), plasma leptin levels predicted CVD even after adjustments 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. (34) found no association between plasma leptin levels and carotid intima-media thickness (IMT) in 403 healthy elderly men, whereas Ciccone et al. (35) reported an association of leptin with IMT in 126 healthy Italians. We previously reported that leptin levels were associated with CAC in a type 2 diabetic sample even after controlling for established risk factors, including CRP and measures of subclinical vascular disease (16). Recently Iribarren et al. (36) reported an association of plasma leptin levels with CAC in older women in the ADVANCE (Atherosclerotic Disease, Vascular Function and Genetic Epidemiology) study, but this association was not significant after controlling for metabolic risk factors and BMI data. 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 (37). Atheroprotective effects may be directed through inhibition of the nuclear factor kappa-B inflammatory pathway in vascular cells (38) and by attenuation of foam cell formation (39). Plasma levels are depressed in patients with CAD (40) and are associated with clinical CVD in patients with diabetes (7). A nested case-control study by Maahs et al. (41) suggested that low levels of plasma adiponectin predict short-term CAC progression, more so in nondiabetics. 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. (42) looked at 589 men with fatal and nonfatal CAD and 1,231 controls and found no difference in median adiponectin levels despite adiponectin associations with HDL and CRP. A 7-study meta-analysis by the same authors failed to demonstrate a consistent relationship of adiponectin with CAD events (42).
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 as heterogeneous outcomes including subclinical atherosclerotic and different CVD outcomes. In fact, Steffes et al. (43) unexpectedly found a positive association of adiponectin with CAC in a study of more than 3,000 young adults age 33 to 45 years. Finally, several studies suggest that the high molecular weight adiponectin complex, but not the lower molecular weight hexamer, may be the active signaling molecule (44,45). Few epidemiologic 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 (46) studies that found that 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.
|
Study limitations
|
|---|
This study has several limitations. The study sample is cross-sectional, and causal relationships cannot be determined from the results. 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 (47). It has also been shown to be an independent predictor of CVD (48).
|
Conclusions
|
|---|
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 to establish which provide utility as metabolic biomarkers of clinical CVD.
|
Appendix
|
|---|
For a table on the Spearman correlations of plasma levels of adiponectin and leptin with cardiovascular risk factors, please see the online version of this article.
|
Footnotes
|
|---|
This work was supported by a Clinical and Translational Science Award (RFA-RM-06-002) from the National Center for Research Resources and by a Diabetes Endocrinology Research Award (P30 DK-019525) from the National Institutes of Health to the University of Pennsylvania, by RO1 HL-073278, RO1 DK-021224, P50 HL-083799 (SCCOR) and W.W. Smith Charitable Trust (grant H0204) awards to Dr. Reilly.
|
References
|
|---|
1. Mohamed-Ali V, Pinkney JH, Coppack SW. Adipose tissue as an endocrine and paracrine organ Int J Obes Relat Metab Disord 1998;22:1145-1158.[CrossRef][Web of Science][Medline]2. Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptin—the classical, resistin—the controversical, adiponectin—the promising, and more to come Best Pract Res Clin Endocrinol Metab 2005;19:525-546.[CrossRef][Medline] 3. Takemura Y, Ouchi N, Shibata R, et al. Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies J Clin Invest 2007;117:375-386.[CrossRef][Web of Science][Medline] 4. Behre CJ. Adiponectin, obesity and atherosclerosis Scand J Clin Lab Invest 2007;67:449-458.[CrossRef][Web of Science][Medline] 5. Kumada M, Kihara S, Sumitsuji S, et al. Association of hypoadiponectinemia with coronary artery disease in men Arterioscler Thromb Vasc Biol 2003;23:85-89.[Abstract/Free Full Text] 6. Pilz S, Maerz W, Weihrauch G, et al. Adiponectin serum concentrations in men with coronary artery disease: the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study Clin Chim Acta 2006;364:251-255.[CrossRef][Web of Science][Medline] 7. Schulze MB, Shai I, Rimm EB, Li T, Rifai N, Hu FB. Adiponectin and future coronary heart disease events among men with type 2 diabetes Diabetes 2005;54:534-539.[Abstract/Free Full Text] 8. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men JAMA 2004;291:1730-1737.[Abstract/Free Full Text] 9. Lawlor DA, Davey Smith G, Ebrahim S, Thompson C, Sattar N. Plasma adiponectin levels are associated with insulin resistance, but do not predict future risk of coronary heart disease in women J Clin Endocrinol Metab 2005;90:5677-5683.[Abstract/Free Full Text] 10. Lindsay RS, Resnick HE, Zhu J, et al. Adiponectin and coronary heart disease: the Strong Heart Study Arterioscler Thromb Vasc Biol 2005;25:e15-e16.[Free Full Text] 11. Hamann A, Matthaei S. Regulation of energy balance by leptin Exp Clin Endocrinol Diabetes 1996;104:293-300.[Web of Science][Medline] 12. Segal KR, Landt M, Klein S. Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men Diabetes 1996;45:988-991.[Abstract] 13. Chu NF, Spiegelman D, Rifai N, Hotamisligil GS, Rimm EB. Glycemic status and soluble tumor necrosis factor receptor levels in relation to plasma leptin concentrations among normal weight and overweight US men Int J Obes Relat Metab Disord 2000;24:1085-1092.[CrossRef][Web of Science][Medline] 14. Haynes WG. Role of leptin in obesity-related hypertension Exp Physiol 2005;90:683-688.[Abstract/Free Full Text] 15. Wallace AM, McMahon AD, Packard CJ, et al. Plasma leptin and the risk of cardiovascular disease in the West Of Scotland Coronary Prevention Study (WOSCOPS) Circulation 2001;104:3052-3056.[Abstract/Free Full Text] 16. Reilly MP, Iqbal N, Schutta M, et al. Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes J Clin Endocrinol Metab 2004;89:3872-3878.[Abstract/Free Full Text] 17. Soderberg S, Ahren B, Jansson JH, et al. Leptin is associated with increased risk of myocardial infarction J Intern Med 1999;246:409-418.[CrossRef][Web of Science][Medline] 18. Couillard C, Lamarche B, Mauriege P, et al. Leptinemia is not a risk factor for ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Diabetes Care 1998;21:782-786.[Abstract] 19. Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ. Resistin is an inflammatory marker of atherosclerosis in humans Circulation 2005;111:932-939.[Abstract/Free Full Text] 20. Reilly MP, Rohatgi A, McMahon K, et al. Plasma cytokines, metabolic syndrome, and atherosclerosis in humans J Invest Med 2007;55:26-35.[CrossRef][Web of Science][Medline] 21. Reilly MP, Wolfe ML, Localio AR, Rader DJ. C-reactive protein and coronary artery calcification: the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA) Arterioscler Thromb Vasc Biol 2003;23:1851-1856.[Abstract/Free Full Text] 22. Reilly MP, Wolfe ML, Rhodes T, Girman C, Mehta N, Rader DJ. Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis Circulation 2004;110:803-809.[Abstract/Free Full Text] 23. Reilly MP, Wolfe ML, Localio AR, Rader DJ. Coronary artery calcification and cardiovascular risk factors: impact of the analytic approach Atherosclerosis 2004;173:69-78.[CrossRef][Web of Science][Medline] 24. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories Circulation 1998;97:1837-1847.[Abstract/Free Full Text] 25. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement Circulation 2005;112:2735-2752.[Free Full Text] 26. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man Diabetologia 1985;28:412-419.[CrossRef][Web of Science][Medline] 27. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte Jr M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography J Am Coll Cardiol 1990;15:827-832.[Abstract] 28. Tobin J. Estimation of relationships for limited dependent variables Econometrica 1958;26:24-36.[CrossRef][Web of Science] 29. UCLA Academic Technical Services. Stata Data Analysis Examples Tobit Analysis. Available at: http://www.ats.ucla.edu/stat/stata/dae/tobit.htm. Accessed April 25, 2008. 30. Enriori PJ, Evans AE, Sinnayah P, Cowley MA. Leptin resistance and obesity Obesity (Silver Spring) 2006;14(Suppl 5):254S-258S. 31. Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL. Leptin enhances the calcification of vascular cells: artery wall as a target of leptin Circ Res 2001;88:954-960.[Abstract/Free Full Text] 32. Stangl K, Cascorbi I, Laule M, et al. Elevated serum leptin in patients with coronary artery disease: no association with the Trp64Arg polymorphism of the beta3-adrenergic receptor Int J Obes Relat Metab Disord 2000;24:369-375.[CrossRef][Web of Science][Medline] 33. Wolk R, Berger P, Lennon RJ, Brilakis ES, Johnson BD, Somers VK. Plasma leptin and prognosis in patients with established coronary atherosclerosis J Am Coll Cardiol 2004;44:1819-1824.[Abstract/Free Full Text] 34. van den Beld AW, Bots ML, Janssen JA, Pols HA, Lamberts SW, Grobbee DE. Endogenous hormones and carotid atherosclerosis in elderly men Am J Epidemiol 2003;157:25-31.[Abstract/Free Full Text] 35. Ciccone M, Vettor R, Pannacciulli N, et al. Plasma leptin is independently associated with the intima-media thickness of the common carotid artery Int J Obes Relat Metab Disord 2001;25:805-810.[Web of Science][Medline] 36. Iribarren C, Husson G, Go AS, et al. Plasma leptin levels and coronary artery calcification in older adults J Clin Endocrinol Metab 2007;92:729-732.[Abstract/Free Full Text] 37. Stefan N, Stumvoll M. Adiponectin—its role in metabolism and beyond Horm Metab Res 2002;34:469-474.[CrossRef][Web of Science][Medline] 38. Ouchi N, Kihara S, Arita Y, et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway Circulation 2000;102:1296-1301.[Abstract/Free Full Text] 39. Ouchi N, Kihara S, Arita Y, et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages Circulation 2001;103:1057-1063.[Abstract/Free Full Text] 40. Liang KW, Sheu WH, Lee WL, et al. Decreased circulating protective adiponectin level is associated with angiographic coronary disease progression in patients with angina pectoris Int J Cardiol 2007Jul 23 [e-pub ahead of print]. 41. Maahs DM, Ogden LG, Kinney GL, et al. Low plasma adiponectin levels predict progression of coronary artery calcification Circulation 2005;111:747-753.[Abstract/Free Full Text] 42. Sattar N, Wannamethee G, Sarwar N, et al. Adiponectin and coronary heart disease: a prospective study and meta-analysis Circulation 2006;114:623-629.[Abstract/Free Full Text] 43. Steffes MW, Gross, MD, Lee DH, Schreiner PJ, Jacobs Jr DR. Adiponectin, visceral fat, oxidative stress, and early macrovascular disease: the Coronary Artery Risk Development in Young Adults Study Obesity (Silver Spring) 2006;14:319-326.[Medline] 44. Pajvani UB, Du X, Combs TP, et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J Biol Chem 2003;278:9073-9085.[Abstract/Free Full Text] 45. Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis J Biol Chem 2003;278:2461-2468.[Abstract/Free Full Text] 46. Bertoni AG, Wong ND, Shea S, et al. Insulin resistance, metabolic syndrome, and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA) Diabetes Care 2007;30:2951-2956.[Abstract/Free Full Text] 47. Mautner GC, Mautner SL, Froehlich J, et al. Coronary artery calcification: assessment with electron beam CT and histomorphometric correlation Radiology 1994;192:619-623.[Abstract/Free Full Text] 48. Kondos GT, Hoff JA, Sevrukov A, et al. Electron-beam tomography coronary artery calcium and cardiac events: a 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults Circulation 2003;107:2571-2576.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. Zeadin, M. Butcher, G. Werstuck, M. Khan, C. K. Yee, and S. G. Shaughnessy
Effect of Leptin on Vascular Calcification in Apolipoprotein E-Deficient Mice
Arterioscler Thromb Vasc Biol,
December 1, 2009;
29(12):
2069 - 2075.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Martin, A. N. Qasim, N. N. Mehta, M. Wolfe, K. Terembula, S. Schwartz, N. Iqbal, M. Schutta, R. Bagheri, and M. P. Reilly
Apolipoprotein B but not LDL Cholesterol Is Associated With Coronary Artery Calcification in Type 2 Diabetic Whites
Diabetes,
August 1, 2009;
58(8):
1887 - 1892.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. K. Chatterjee, L. L. Stoll, G. M. Denning, A. Harrelson, A. L. Blomkalns, G. Idelman, F. G. Rothenberg, B. Neltner, S. A. Romig-Martin, E. W. Dickson, et al.
Proinflammatory Phenotype of Perivascular Adipocytes: Influence of High-Fat Feeding
Circ. Res.,
February 27, 2009;
104(4):
541 - 549.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Martin, A. Qasim, and M. P. Reilly
Leptin Resistance: A Possible Interface of Inflammation and Metabolism in Obesity-Related Cardiovascular Disease
J. Am. Coll. Cardiol.,
October 7, 2008;
52(15):
1201 - 1210.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods