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European Heart Journal Advance Access originally published online on February 9, 2008
European Heart Journal 2008 29(5):649-657; doi:10.1093/eurheartj/ehn009
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study

Renate Schnabel1,*, Claudia M. Messow2, Edith Lubos1, Christine Espinola-Klein1, Hans J. Rupprecht1, Christoph Bickel3, Christoph Sinning1, Stergios Tzikas1, Till Keller1, Sabine Genth-Zotz1, Karl J. Lackner4, Thomas F. Münzel1 and Stefan Blankenberg1

1 Department of Medicine II, Johannes Gutenberg-University Mainz, Germany
2 Institute of Medical Biostatistics, Epidemiology, and Informatics, Johannes Gutenberg-University Mainz, Germany
3 Innere Abteilung, Bundeswehrzentralkrankenhaus Koblenz, Koblenz, Germany
4 Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg-University, Mainz, Germany

Received 20 June 2007; revised 20 December 2007; accepted 7 January 2008; online publish-ahead-of-print 9 February 2008.

* Corresponding authors. Tel: +49 6131 175992, Fax: +49 6131 175691, Email: blankenberg{at}2-med.klinik.uni-mainz.de (S.B.); Tel: +49 6131 175992, Fax: +49 6131 175691, Email: schnabelr{at}gmx.de (R.S.)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Aims: In primary prevention, the adipocytokine adiponectin seems to be protective against diabetes mellitus and cardiovascular disease. Data in patients with manifest coronary artery disease (CAD) are scant stimulating the investigation of the association of adiponectin concentrations and cardiovascular outcome in a prospective CAD cohort.

Methods and results: In 1890 consecutive patients with documented CAD [1130 with stable angina (SAP) and 760 with acute coronary syndrome (ACS)] baseline concentrations of adiponectin were measured by enzyme-linked immuno assay. During a median follow-up of 2.5 years cardiovascular events were registered (cardiovascular deaths 70; non-fatal myocardial infarction 46).

Baseline adiponectin concentrations were similar in patients presenting with SAP [9.03 µg/mL (6.7, 13.45)] or ACS [9.19 µg/mL (6.72, 13.15)], P = 0.779. Kaplan–Meier survival analysis showed a stepwise decrease in event-free survival across quartiles of adiponectin baseline concentration (Plog rank = 0.0188). A similar pattern was observed in both subgroups of patients (SAP P = 0.075 and ACS P = 0.254). In univariate analyses, continuous adiponectin concentration was related to event-free survival in all patients [HR 1.02 (95% confidence interval 1.0–1.04), P = 0.012] as well as in the subgroup of SAP subjects [1.03 (1.01–1.05), P = 0.012]. The relation was less strong in the subgroup presenting with ACS [1.014 (0.99–1.04), P = 0.280]. A correlation of adiponectin with high density cholesterol (r = 0.39) and a negative relation to triglyceride levels (r = –0.22) could be described.

An increase of one interquartile distance in adiponectin concentration was associated with a 1.17-fold risk for future cardiovascular events (P = 0.013), in B-type natriuretic peptide (BNP) it meant a 1.13-fold risk (P < 0.001). In the overall patient group, this risk association remained robust after the adjustment for classical risk factors, clinical presentation and cardiac medication. Only after adjustment for BNP adiponectin lost its independent predictive value.

Conclusion: In contrast to studies including initially healthy individuals, the current prospective study demonstrates that adiponectin is associated with adverse cardiovascular outcome in patients with manifest CAD.

Key Words: Adiponectin • Risk stratification • Coronary artery disease


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
White fatty tissue is not only an energy depot but also a most active organ in chronic disease processes like coronary artery disease (CAD). Adiponectin is one of the most intensively discussed secretion products of white fat cells, the so-called adipocytokines, a regulator exclusively derived from mature adipocytes,1 discovered in the mid-90s in context with the human genome project.2–5

It belongs to the collagen superfamily and shares striking homologies with collagens, complement factors, and TNF-alpha. Once secreted, it acts via two recently discovered receptors which are ubiquitously expressed in human tissue.6 Experimental data have revealed that key features of the atherosclerotic process like pro-inflammatory activities, upregulation of cellular adhesion molecules, foam cell formation, smooth muscle cell migration, proliferation and activation of immune cells, and oxidative stress7,8 are modulated by various not yet fully established mechanisms exerted by adiponectin. Furthermore, it has been attributed insulin-sensitizing characteristics and seems to reduce the risk of type 2 diabetes.9–11 Data on the prospective impact of adiponectin plasma concentration determination in cardiovascular disease in humans are evolving. First evidence in asymptomatic middle-aged individuals showed that elevated blood concentrations tend to be protective against the incidence of cardiovascular disease though not consistently and only with borderline significance.12–15 On the contrary, in subjects at high risk for cardiovascular events or with manifest cardiac disease like chronic heart failure, chronic kidney disease, and elderly men, high adiponectin concentrations are a predictor of mortality independent of risk factors of heart failure severity.16–19 Based on these divergent data, the aim of the present study was to elucidate the role of adiponectin for long-term cardiovascular risk prediction in patients with documented CAD and preserved systolic function. Further, the predictive strength of adiponectin was set into relation to traditional risk markers, C-reactive protein, and B-type natriuretic peptide (BNP), which has been shown to be one of the strongest risk predictors over the whole spectrum of CAD irrespective of left ventricular function.20–23


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 Acknowledgements
 References
 
Study participants
Between June 1999 and February 2004, 3500 patients who presented with chest pain at the Department of Medicine II of the Johannes Gutenberg-University Mainz or at the Bundeswehrzentralkrankenhaus Koblenz and who had at least one stenosis >30% diagnosed in a major coronary artery were enrolled in the AtheroGene study registry. For the study all patients undergoing cardiac catheterization who met the inclusion criteria were primarily eligible. Exclusion criteria were evidence of haemodynamically significant valvular heart disease, surgery, or trauma within the previous month, known cardiomyopathy, known cancer, febrile conditions, or use of oral anticoagulant therapy within the previous 4 weeks which were the reason for non-eligibility in about 5% of consecutive patients. Only 4% of patients were not willing to participate. Most patients remained in the study after initial assessment (>98%). Baseline blood specimen and coronary angiography results were available in all subjects; adiponectin measurements were successfully performed in 1924 consecutive participants. Patients who were on antihypertensive treatment or who had blood pressure measurements above 140/90 mm Hg were considered to have hypertension. Patients were classified as currently smoking, as having smoked in the past (if they had stopped more than 4 weeks and less than 40 years earlier), or as never having smoked (if they had never smoked or had stopped 40 or more years earlier).

Acute coronary syndrome (ACS) patients presented with ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina. The latter was defined according to the Braunwald classification (classes I–IIIB).

The patients were followed for a median of 2.5 years (maximum 5 years). Follow-up information was obtained on death from cardiovascular causes (n = 70), death from causes not related to heart disease (n = 32), and non-fatal myocardial infarction (n = 46). Information on the cause of death or clinical events was obtained from hospital or general practitioner charts. Follow-up information was obtained for 1890 (98%) of the patients.

Participation was restricted to German nationality and Caucasian origin. The study was approved by the local ethics committee. Participation was voluntary, and each subject gave written, informed consent.

Laboratory methods
Blood was drawn under standardized conditions before coronary angiography was performed. Control subjects underwent venipuncture after a 12 h fast. Samples were immediately processed and stored at –80°C until analysis.

Adiponectin was analysed by human adiponectin ELISA (BioVendor, Heidelberg, Germany). The detection limit reported is 0.2 µg/mL. No relevant cross reactivity has been observed for human leptin, leptin receptor, and resistin. The intra-assay coefficient of variation measured was 7.0% and the inter-assay coefficient of variation was 8.2%. Plasma BNP was measured by using a fluorescence immunoassay (Biosite, Inc., San Diego, CA, USA). The detection limit for this assay is less than 5 pg/mL. The assay has an inter-assay coefficient of variation of nearly 10% and a recovery of 100% of added peptide was found. Cross reactivity with other natriuretic peptides is negligible. C-reactive protein was determined by a highly sensitive, latex particle-enhanced immunoassay (detection range of 0–20 mg/L, Roche Diagnostics, Mannheim, Germany). Lipid serum levels and creatinine were measured immediately by standardized routine methods.

Statistical analysis
Continuous variables are summarized as median and 25th and 75th percentile. For discrete variables, absolute and relative frequencies per category are given. The association between adiponectin and other continuous variables is described by Spearman correlation coefficients along with 95%-confidence intervals (determined through bootstrap).

The relation of the different variables to survival is tested with log-rank test for categorical variables, with proportional hazards regression for continuous variables. The association of adiponectin with survival is examined in different proportional hazard regression models, first a univariate model, then in a model adjusting for classical risk factors (age, sex, BMI, presence or absence of hypertension, diabetes, smoking, HDL-cholesterol, family history, and presence or absence of ACS). A third model additionally adjusts for medication with β-blockers and statins and a fourth model additionally for BNP. Proportional hazards assumption was checked using standard methods based on testing for significant slope of the smooth curve through the scatter of the rescaled Schoenfeld residuals vs. time.

Kaplan–Meier curves according to quartiles of adiponectin levels are shown. Survival was compared by log-rank test between the groups based on quartiles.

To compare the prognostic value of adiponectin with BNP, C-reactive protein, and serum creatinine, each variable is entered separately into a proportional hazard regression model adjusting for classical risk factors. To obtain results that are comparable between the different variables hazard ratios associated with an increase in one interquartile distance are given.

For all survival analyses the hazard ratios, associated confidence intervals and P-values are reported. The endpoint in those analyses is cardiovascular death or myocardial infarction.

All survival analyses are carried out for the total population and separately for patients with ACS and patients with SAP.

All analyses were performed using SPSS 12 or R2.2.0 (R Development Core Team (2005). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org). As P-values are not adjusted for multiple testing they have to be considered as descriptive.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 Acknowledgements
 References
 
A summary of the baseline characteristics of the study population is given in Table 1, along with the P-values for the univariate association with survival of each variable. In addition to the variable distribution in the overall study population data are shown separately for patients according to clinical presentation. A higher age (P = 0.021) and a lower left ventricular ejection fraction (P < 0.001) were associated with shorter event-free survival. Prognosis was worse if patients presented with ACS at enrolment (P = 0.004). Of the classical risk factors, insulin-dependent diabetes mellitus was associated with cardiovascular events (P < 0.001) and a positive family history and the number of diseased vessels showed a borderline relation. With regard to biomarkers, adiponectin was associated with adverse cardiovascular outcome (P = 0.012). Concentrations were similar in patients presenting with SAP [9.03 µg/mL (6.7, 13.45)] or ACS [9.19 µg/mL (6.72, 13.15)], P = 0.779.


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  		Table 1 Baseline characteristics of the study population according to clinical presentation and for the overall cohort

 
As expected, the biomarkers BNP, C-reactive protein, and serum creatinine were indicative of an increased risk of future events as well.

The relation of adiponectin to other variables measured in this study is described in Table 2. A positive correlation with HDL cholesterol (0.39) could be observed whereas no relevant correlation with other lipid parameters was seen. Adiponectin levels seemed to be higher in women (median of 13.08 vs. 8.529 µg/mL in men, P < 0.001). They differ between smokers, ex- and non-smokers, with highest levels found in non-smokers (P < 0.001). Patients who were treated with β-blockers (P < 0.001) or statins (P = 0.002) revealed lower adiponectin levels. In this study, Spearman’s correlation coefficient with BNP was 0.19, the interaction term of adiponectin and BNP was not significant (P = 0.14).


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  		Table 2 Relation of adiponectin concentration to other variables

 
Figure 1 shows Kaplan–Meier curves and Plog rank values for event-free survival for all patients (A), stable patients (B), and unstable patients (C) divided into subgroups according to quartiles of adiponectin levels. A decrease of event-free survival over quartiles was observed with highest event-rates in the upper quartiles. This association was strong in the overall patient population and could be seen as a tendency in the subgroups. Moreover, there seemed to be a threshold effect since the risk of adverse events was relatively similar in the lower three quartiles and a clear risk increase could be observed for subjects in the upper quartile.


Figure 1
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  		Figure 1 Kaplan–Meier curves for event-free survival for the overall study population (A) and in the subgroups of patients with stable angina (B) and acute coronary syndrome (C) according to adiponectin quartiles. Adiponectin concentrations are provided in µg/mL

 
The results of the analyses of the relation of adiponectin to event-free survival are summarized in Table 3. In univariate analyses, adiponectin treated as a continuous variable is related to event-free survival in all patients [HR 1.02 (95% confidence interval 1.0–1.04), P = 0.012] as well as in the subgroup of stable angina subjects [1.03 (1.01–1.05), P = 0.012]. The relation is less strong in the subgroup with ACS [1.014 (0.99–1.04), P = 0.280]. These associations remain nearly unchanged in all populations if adjusted for classical risk factors (model 2) and for classical risk factors and medication (model 3). If BNP is included in the model, adiponectin no longer provides relevant prognostic information in addition to the other variables. Testing for interaction with sex showed that the effect of adiponectin on outcome seems to be stronger in men (coefficient 0.0534, standard error 1.055; P = 0.022). Considering the results for stable and acute patients separately, it can be demonstrated that adiponectin is not significantly associated with outcome in the analyses for ACS patients. In stable angina patients it provides risk information, even after adjustment for BNP and C-reactive protein. Highest event-rates were observed in patients in whom both markers, adiponectin and BNP, were elevated into the upper quartile (data not shown). Figure 2 reveals that in the overall population, one quartile increase in adiponectin concentration is associated with a 1.17-fold (95% confidence interval 1.04–1.31, P = 0.013) increased risk for future cardiovascular events. In the current analyses, this predictive power is comparable to BNP (HR 1.13, 95% confidence interval 1.08–1.19, P < 0.001) and serum creatinine (HR 1.27, 95% confidence interval 1.07–1.50, P = 0.007). In contrast, the inflammatory marker C-reactive protein does not provide significant risk information. In the subgroup analysis, adiponectin remains predictive in stable angina whereas its predictive value is less strong in the small subgroup of unstable patients. Similar results are seen for serum creatinine. In contrast, BNP proves to be a strong risk factor in stable CAD as well as in ACS. Overall the hazard ratios for one quartile increase in biomarker concentration seem to be slightly lower in the ACS subgroup which consists of 760 subjects.


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  		Table 3 Hazard ratios for future cardiovascular events according to adiponectin baseline concentration in continuous analysis (increase of one unit of adiponectin concentration)

 

Figure 2
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  		Figure 2 Cox-regression analysis for event-free survival. Provided are the hazard ratios and 95% confidence intervals according to an increase in one interquartile range in biomarker concentrations for the overall study cohort (A) and separate analyses for patients with stable angina (B) and acute coronary syndrome (STEMI, NSTEMI, and unstable angina) (C)

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 Acknowledgements
 References
 
In this prospective study in 1890 consecutive patients over the whole spectrum of CAD increased baseline adiponectin concentrations are related to future cardiovascular events in patients presenting with stable angina and preserved systolic function. It could be demonstrated that in this setting, adiponectin is an indicator of adverse outcome in addition to classical risk factors. Due to the consecutive enrolment of patients in the cath lab, the AtheroGene cohort is representative of a mid-European CAD population especially in the proportion of diabetics and female participants which may be of interest in the context of adiponectin metabolism.

Various vasoprotective mechanisms have been discussed for adiponectin including insulin-sensitizing characteristics, anti-oxidative and anti-inflammatory properties.11,24–28 Despite its favourable characteristics almost consistently reported in experimental data, animal models and human studies on vascular function in subjects free of symptomatic cardiovascular disease, increasing evidence suggests that elevated adiponectin levels may represent a risk marker in patients with manifest cardiovascular disease.

It is generally accepted that plasma adiponectin levels are related to most classical risk factors independent of the presence of cardiovascular disease.29–33 These formerly reported associations could be confirmed in the present cohort with similar strength. A trend of a beneficial effect of increased plasma adiponectin concentrations was observed in the Health Professionals Follow-up Study (HPFS) and the MONICA/KORA Augsburg study in healthy middle-aged men independent of blood lipids and C-reactive protein levels during long-term follow-up in the primary prevention setting. These findings have not remained unopposed.12,15,33 In the Strong Heart Study (SHS), no significant association with later development of CAD could be found in American Indians which has been explained by the potential impact of a higher prevalence of diabetes mellitus in this study cohort.13 Furthermore, ethnic differences in adiponectin levels have to be considered and may, at least in part, account for a discrepancy of the data. Meanwhile, polymorphisms with different distribution according to ethnicity have been examined. Some mutations show associations with disorders of the metabolic syndrome and the onset of CAD.34–37 The strength of the data in the AtheroGene registry in this respect is that solely Caucasian participants were enrolled.

Recently, further input to the discussion of adiponectin in context with CAD was provided by a meta-analysis of seven prospective studies in which overall only a moderate association between adiponectin levels and CAD risk could be revealed.38

In patients with manifest CAD, adiponectin seems to play a different role. Whereas in clinically asymptomatic subjects, high adiponectin levels appear to be protective against atherosclerotic disease, this adipocytokine, if elevated in patients with symptomatic CAD, becomes associated with an increased risk for cardiovascular events.39 Presuming a beneficial influence of adiponectin on atherosclerotic disease, this would imply that adiponectin concentrations are elevated in a counter-regulatory fashion as a response to excessive pro-atherosclerotic processes with a net excess of adverse impact despite elevated adiponectin concentrations, indicating an imbalance of the whole system. This may contribute to the so-called risk factor reversal which has first been described for the obesity paradox when high BMI can result in a reverse, beneficial association with outcome as seen in advanced kidney disease and congestive heart failure.40 Rathman and Herder41 explained the reverse epidemiology of adiponectin by the futile attempt of the body to counter-regulate a systemic inflammatory assault which is over-whelmed by the severity of the underlying disease.

In addition, recent findings in patients with manifest CAD showed that adiponectin is associated with the presence of pro-atherogenic dyslipidaemia and revealed a positive correlation with N-terminal pro-B-type natriuretic peptide (Nt-proBNP)42 which represents one of the strongest currently known risk markers in CAD patients.43 A significant association with all-cause mortality and myocardial infarction has been suggested in a study comprising 325 male CAD patients with a follow-up of 2 years.44 However, that population consisted of a mixture of patients with both normal and reduced LV systolic function. We are now able to extend these data towards a large general CAD population with maintained left ventricular ejection fraction, thus removing a potential confounding effect of congestive heart failure and left ventricular dysfunction on outcome predicted by adiponectin measurement. We had the opportunity to directly compare the predictive value of adiponectin with novel risk markers like C-reactive protein and BNP. Statistical analyses demonstrated that the strength of adiponectin in risk prediction cannot compete with that of BNP as an indicator of cardiovascular outcome. No significant interaction of adiponectin with BNP could be shown. A similar trend has been observed in a study by Pilz et al.39 in which adiponectin concentrations weakly correlated with Nt-proBNP in the overall study group of patients undergoing coronary angiography but showed a relevant correlation in participants with severely impaired left ventricular function. A strong correlation with Nt-proBNP in chronic heart failure patients had been described earlier.16 These findings suggest that the relation of these two biomarkers seen in these groups may in fact be due to the association between adiponectin and left ventricular dysfunction and/or congestive heart failure which has to be investigated in more detail in future studies.

Limitations
As expected, only a relatively small number of events have been registered during follow-up in this intermediate risk cohort which may lead to unstable results especially in the multivariable survival analysis. The number of patients in the subgroup presenting with ACS does not allow final conclusions and may, at least in part, account for the fact, that in the prospective analyses only a trend was observed and we could not reproduce the strength of earlier findings.44 In addition, to not further reduce the number of individuals, we did not perform separate analyses for patients with troponin-negative ACS. For acute myocardial infarction patients, a drop of adiponectin concentrations during the first hours after the acute event has been reported.45 This may lead to falsely low adiponectin values in these individuals which may additionally dilute the strength of the results. However, as all results reveal similar trends, they seem to be relatively reliable.

The models containing BNP have to be interpreted carefully, as the group of patients with measurements of BNP is only a subgroup of the original population. Although missing values did occur for technical reasons and not due to patient characteristics, a selection bias cannot be excluded.

To date, all adiponectin isoforms were recognized by commercial assay kits measuring the total adiponectin concentrations.46 The ELISA used in this study detects the globular and full-length isoforms. Recent studies demonstrated that adiponectin circulates as a trimer with each isoform playing a different biological role. The proportion of isoform expression is altered in various physiological and pathological conditions. For mortality risk prediction, total adiponectin has been recommended in heart failure populations.47 Newly developed adiponectin assays measure each isoform separately and further research is needed to establish the role of the different isoforms in diverse pathologies.48

In conclusion, the current study supports an association of adiponectin with adverse cardiovascular outcome during long-term follow-up in patients with CAD and preserved left ventricular systolic function. The clinical relevance of these findings needs further evaluation. These data should stimulate experimental and epidemiological studies to further elucidate the complex role of the adipocytokine adiponectin in atherosclerosis and CAD.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
Acknowledgements
 References
 
The AtheroGene study is supported by a grant of the ‘Stiftung Rheinland-Pfalz für Innovation,’ Ministry for Science and Education (AZ 15202–386261/545), Mainz.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
References
 
We are indebted to Margot Neuser for her graphical work.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 

  1. Korner A, Wabitsch M, Seidel B, Fischer-Posovszky P, Berthold A, Stumvoll M, Bluher M, Kratzsch J, Kiess W. Adiponectin expression in humans is dependent on differentiation of adipocytes and down-regulated by humoral serum components of high molecular weight. Biochem Biophys Res Commun (2005) 337:540–550.[CrossRef][Web of Science][Medline]
  2. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem (1995) 270:26746–26749.[Abstract/Free Full Text]
  3. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun (1996) 221:286–289.[CrossRef][Web of Science][Medline]
  4. Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem (Tokyo) (1996) 120:803–812.[Abstract/Free Full Text]
  5. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem (1996) 271:10697–10703.[Abstract/Free Full Text]
  6. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature (2003) 423:762–769.[CrossRef][Medline]
  7. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med (1999) 340:115–126.[Free Full Text]
  8. Libby P. Inflammation in atherosclerosis. Nature (2002) 420:868–874.[CrossRef][Medline]
  9. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem (2002) 277:25863–25866.[Abstract/Free Full Text]
  10. Duncan BB, Schmidt MI, Pankow JS, Bang H, Couper D, Ballantyne CM, Hoogeveen RC, Heiss G. Adiponectin and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes (2004) 53:2473–2478.[Abstract/Free Full Text]
  11. Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Adiponectin and protection against type 2 diabetes mellitus. Lancet (2003) 361:226–228.[CrossRef][Web of Science][Medline]
  12. 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]
  13. Lindsay RS, Resnick HE, Zhu J, Tun ML, Howard BV, Zhang Y, Yeh J, Best LG. Adiponectin and coronary heart disease: the Strong Heart Study. Arterioscler Thromb Vasc Biol (2005) 25:e15–e16.[Free Full Text]
  14. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol (2003) 23:85–89.[Abstract/Free Full Text]
  15. Koenig W, Khuseyinova N, Baumert J, Meisinger C, Lowel H. Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany. J Am Coll Cardiol (2006) 48:1369–1377.[Abstract/Free Full Text]
  16. Kistorp C, Faber J, Galatius S, Gustafsson F, Frystyk J, Flyvbjerg A, Hildebrandt P. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation (2005) 112:1756–1762.[Abstract/Free Full Text]
  17. George J, Patal S, Wexler D, Sharabi Y, Peleg E, Kamari Y, Grossman E, Sheps D, Keren G, Roth A. Circulating adiponectin levels predict outcome in patients with severe congestive heart failure. Heart (2006) 92:1420–1424.[Abstract/Free Full Text]
  18. Menon V, Li L, Wang X, Greene T, Balakrishnan V, Madero M, Pereira AA, Beck GJ, Kusek JW, Collins AJ, Levey AS, Sarnak MJ. Adiponectin and mortality in patients with chronic kidney disease. J Am Soc Nephrol (2006) 17:2599–2606.[Abstract/Free Full Text]
  19. Wannamethee SG, Whincup PH, Lennon L, Sattar N. Circulating adiponectin levels and mortality in elderly men with and without cardiovascular disease and heart failure. Arch Intern Med (2007) 167:1510–1517.[Abstract/Free Full Text]
  20. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med (2001) 345:1014–1021.[Abstract/Free Full Text]
  21. Morrow DA, de Lemos JA, Sabatine MS, Murphy SA, Demopoulos LA, DiBattiste PM, McCabe CH, Gibson CM, Cannon CP, Braunwald E. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol (2003) 41:1264–1272.[Abstract/Free Full Text]
  22. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med (2005) 352:666–675.[Abstract/Free Full Text]
  23. Schnabel R, Lubos E, Rupprecht HJ, Espinola-Klein C, Bickel C, Lackner KJ, Cambien F, Tiret L, Munzel T, Blankenberg S. B-type natriuretic peptide and the risk of cardiovascular events and death in patients with stable angina: results from the AtheroGene study. J Am Coll Cardiol (2006) 47:552–558.[Abstract/Free Full Text]
  24. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation (1999) 100:2473–2476.[Abstract/Free Full Text]
  25. Matsushita K, Yatsuya H, Tamakoshi K, Wada K, Otsuka R, Zhang H, Sugiura K, Kondo T, Murohara T, Toyoshima H. Inverse association between adiponectin and C-reactive protein in substantially healthy Japanese men. Atherosclerosis (2006) 188:184–189.[CrossRef][Medline]
  26. Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol (2004) 24:29–33.[Abstract/Free Full Text]
  27. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. 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]
  28. Hattori S, Hattori Y, Kasai K. Hypoadiponectinemia is caused by chronic blockade of nitric oxide synthesis in rats. Metabolism (2005) 54:482–487.[CrossRef][Web of Science][Medline]
  29. Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Buemi M, Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol (2002) 13:134–141.[Abstract/Free Full Text]
  30. Huang KC, Lue BH, Yen RF, Shen CG, Ho SR, Tai TY, Yang WS. Plasma adiponectin levels and metabolic factors in nondiabetic adolescents. Obes Res (2004) 12:119–124.[Web of Science][Medline]
  31. Miyazaki T, Shimada K, Mokuno H, Daida H. Adipocyte derived plasma protein, adiponectin, is associated with smoking status in patients with coronary artery disease. Heart (2003) 89:663.[Free Full Text]
  32. Kim OY, Koh SJ, Jang Y, Chae JS, Kim JY, Kim HJ, Cho H, Lee JH. Plasma adiponectin is related to other cardiovascular risk factors in nondiabetic Korean men with CAD, independent of adiposity and cigarette smoking: cross-sectional analysis. Clin Chim Acta (2006) 370:63–71.[CrossRef][Web of Science][Medline]
  33. 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]
  34. Ohashi K, Ouchi N, Kihara S, Funahashi T, Nakamura T, Sumitsuji S, Kawamoto T, Matsumoto S, Nagaretani H, Kumada M, Okamoto Y, Nishizawa H, Kishida K, Maeda N, Hiraoka H, Iwashima Y, Ishikawa K, Ohishi M, Katsuya T, Rakugi H, Ogihara T, Matsuzawa Y. Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. J Am Coll Cardiol (2004) 43:1195–1200.[Abstract/Free Full Text]
  35. Yang WS, Chuang LM. Human genetics of adiponectin in the metabolic syndrome. J Mol Med (2006) 84:112–121.[CrossRef][Web of Science][Medline]
  36. Bacci S, Menzaghi C, Ercolino T, Ma X, Rauseo A, Salvemini L, Vigna C, Fanelli R, Di Mario U, Doria A, Trischitta V. The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients. Diabetes Care (2004) 27:2015–2020.[Abstract/Free Full Text]
  37. Filippi E, Sentinelli F, Romeo S, Arca M, Berni A, Tiberti C, Verrienti A, Fanelli M, Fallarino M, Sorropago G, Baroni MG. The adiponectin gene SNP+276G >T associates with early-onset coronary artery disease and with lower levels of adiponectin in younger coronary artery disease patients (age <or=50 years). J Mol Med (2005) 83:711–719.[CrossRef][Web of Science][Medline]
  38. Sattar N, Wannamethee G, Sarwar N, Tchernova J, Cherry L, Wallace AM, Danesh J, Whincup PH. Adiponectin and coronary heart disease: a prospective study and meta-analysis. Circulation (2006) 114:623–629.[Abstract/Free Full Text]
  39. Pilz S, Mangge H, Wellnitz B, Seelhorst U, Winkelmann BR, Tiran B, Boehm BO, Marz W. Adiponectin and mortality in patients undergoing coronary angiography. J Clin Endocrinol Metab (2006) 91:4277–4286.[Abstract/Free Full Text]
  40. Kopple JD. The phenomenon of altered risk factor patterns or reverse epidemiology in persons with advanced chronic kidney failure. Am J Clin Nutr (2005) 81:1257–1266.[Abstract/Free Full Text]
  41. Rathmann W, Herder C. Adiponectin and cardiovascular mortality: evidence for ‘reverse epidemiology. Horm Metab Res (2007) 39:1–2.[CrossRef][Web of Science][Medline]
  42. von Eynatten M, Hamann A, Twardella D, Nawroth PP, Brenner H, Rothenbacher D. Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease. Clin Chem (2006) 52:853–859.[Abstract/Free Full Text]
  43. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet (2003) 362:316–322.[CrossRef][Web of Science][Medline]
  44. Cavusoglu E, Ruwende C, Chopra V, Yanamadala S, Eng C, Clark LT, Pinsky DJ, Marmur JD. Adiponectin is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction in patients presenting with chest pain. Eur Heart J (2006) 27:2300–2309.[Abstract/Free Full Text]
  45. Kojima S, Funahashi T, Sakamoto T, Miyamoto S, Soejima H, Hokamaki J, Kajiwara I, Sugiyama S, Yoshimura M, Fujimoto K, Miyao Y, Suefuji H, Kitagawa A, Ouchi N, Kihara S, Matsuzawa Y, Ogawa H. The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction. Heart (2003) 89:667.[Free Full Text]
  46. Ebinuma H, Miyazaki O, Yago H, Hara K, Yamauchi T, Kadowaki T. A novel ELISA system for selective measurement of human adiponectin multimers by using proteases. Clin Chim Acta (2006) 372:47–53.[CrossRef][Web of Science][Medline]
  47. Tsutamoto T, Tanaka T, Sakai H, Ishikawa C, Fujii M, Yamamoto T, Horie M. Total and high molecular weight adiponectin, haemodynamics, and mortality in patients with chronic heart failure. Eur Heart J (2007) 28:1723–1730.[Abstract/Free Full Text]
  48. Takemura Y, Osuga Y, Koga K, Tajima T, Hirota Y, Hirata T, Morimoto C, Harada M, Yano T, Taketani Y. Selective increase in high molecular weight adiponectin concentration in serum of women with preeclampsia. J Reprod Immunol (2007) 73:60–65.[CrossRef][Web of Science][Medline]

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