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European Heart Journal Advance Access originally published online on November 7, 2006
European Heart Journal 2007 28(3):292-298; doi:10.1093/eurheartj/ehl361
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Association between plasma adiponectin levels and unstable coronary syndromes

Robert Wolk1,*,{dagger}, Peter Berger1,{ddagger}, Ryan J. Lennon2, Emmanouil S. Brilakis1,, Diane E. Davison1 and Virend K. Somers1

1 Division of Cardiovascular Diseases, Mayo Clinic, 1216 Second Street SW, Rochester, MN 55902, USA
2 Division of Biostatistics, Mayo Clinic, Rochester, MN, USA

Received 5 April 2006; revised 11 October 2006; accepted 19 October 2006; online publish-ahead-of-print 7 November 2006.

* Corresponding author. Tel: +1 507 2551144; fax: +1 507 2557070. E-mail address: wolk.robert{at}mayo.edu

See page 274 for the editorial comment on this article (doi:10.1093/eurheartj/ehl454)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Aims Obesity is a risk factor for an acute coronary syndrome (ACS). The association between elevated body mass index (BMI) and ACS is independent of most traditional risk factors, suggesting a possible contribution of other body fat-related mediators. This study evaluated the association between adiponectin and ACS.

Methods and results Four hundred and ninety-nine patients undergoing coronary angiography were divided into a subgroup without (n = 331) and with ACS (n = 168). In multiple regression analysis, higher adiponectin levels were independently associated with a lower risk of ACS [odds ratio (OR) = 0.61; 95% CIs: 0.46–0.81; P < 0.001]. In contrast, a higher BMI, a history of myocardial infarction, C-reactive protein, and angiographic coronary artery disease severity were all associated with a higher risk. The greatest increase in risk for ACS was seen at adiponectin levels ≤ 5.5 µg/mL.

Conclusion Higher plasma adiponectin levels are independently associated with a lower risk of ACS.

Key Words: Adipokines • Adiponectin • C-reactive protein • Acute coronary syndrome • Atherosclerosis • Angiography


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgement
 References
 
The prevalence of obesity continues to increase rapidly worldwide.1 This epidemiological phenomenon has important clinical implications, because obesity contributes to increased morbidity and mortality,2,3 although the exact nature of this relationship remains to be established.4 While increased life expectancy and decreases in other risk factors over the last few decades may have led to a decreased epidemiological association of obesity with mortality, cardiovascular disease is still the leading cause of excess death among the obese.5

Obesity is a risk factor for the development of atherosclerosis.6,7 Furthermore, in those patients with established coronary atherosclerosis, body mass index (BMI) is an independent predictor of an acute coronary syndrome (ACS), with an increased risk even at mildly elevated BMI levels.8 Understanding the pathophysiology of the association between BMI and ACS is, therefore, of great clinical importance. However, the exact mechanisms of this association have not been fully elucidated.

The increased cardiovascular risk related to obesity has traditionally been ascribed to the presence of the metabolic syndrome, which includes hypertension, insulin resistance, and dyslipidaemia.9 However, in our previous study, the association between BMI and ACS was independent of several metabolic and cardiovascular risk factors such as age, gender, blood pressure, lipid levels, insulin resistance, leptin, fibrinogen, C-reactive protein, coronary artery disease (CAD) severity, smoking, history of myocardial infarction (MI), or hypertension,8 suggesting the contribution of some other BMI-related factors.

Adiponectin is an adipose tissue-derived bioactive mediator that is believed to have significant anti-atherogenic properties in humans. Low adiponectin has been linked to the presence of CAD10 and has been shown to be a risk factor for cardiovascular events.11,12 Low adiponectin levels are also independently associated with the progression of coronary artery calcification.13 In the present study, we tested the hypothesis that low adiponectin is an independent predictor of ACS.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgement
 References
 
This study was designed on the basis of a previous study.14 The study was approved by the Mayo Clinic IRB. All subjects were recruited prospectively in the cardiac catheterization laboratory at the Mayo Clinic, Rochester, MN, USA. The study group consisted of 504 patients who were undergoing coronary angiography for clinical indications (mainly chest pain, dyspnoea on exertion, or an abnormal nuclear imaging study). Almost all patients undergoing cardiac catheterization during the enrolment period were screened. More than 90% of eligible subjects agreed to participate and were enrolled. No patients were enrolled and no measurements were obtained; most or all data of interest were obtained in all of the 504 subjects.

The exclusion criteria were diabetes, a smoking history > 50 pack-years, a history of organ transplantation, prior coronary revascularization, bleeding disorders, blood transfusion within 30 days, HIV infection, renal failure, prior chest radiation therapy, and pregnancy. Since the aim of the original study14 was to look for novel risk factors, it was decided to exclude those known risk factors very strongly associated with CAD risk. For example, because diabetes is a very strong independent risk factor for both atherosclerosis and ACS, inclusion of diabetics might have been so powerful as to obscure the association of other risk factors with atherosclerosis.

Of the original 504 subjects, five did not have adiponectin measures. The remaining 499 subjects were included in this analysis. These patients were divided into a subgroup without (n = 331) and with ACS (n = 168). The subjects with ACS had a final clinical diagnosis of unstable angina (n = 127) or acute MI (n = 41). Patients were classified as having unstable angina if they had chest pain that was new in onset or if they had a significant unexplained change in the pattern of stable angina (such as increased frequency, increased intensity, increased duration, or decreased response to nitrates) in the previous 2 months. Patients were defined as having an acute MI if they had cardiac marker elevation (total CK more than three times the upper limit of normal or cardiac troponin T greater than the upper limit of normal) in association with chest pain or ischaemic electrocardiographic changes. The classification of a patient as having unstable angina or acute MI was done both prospectively at enrolment and retrospectively by review of the clinical histories of all patients, blinded to adiponectin level and clinical outcome.

Fasting morning blood samples were drawn at rest in the supine position. Adiponectin was measured by radioimmunoassay (Linco Research, St Charles, MO, USA). Leptin was measured by the human leptin double antibody radioimmunoassay kit (Linco Research, St Louis, MO, USA). High-sensitivity C-reactive protein was measured by a polystyrene particle-enhanced immunoturbidimetric assay (DiaSorin, Stillwater, MN, USA). Insulin measurements were based on a two-site immunoenzymatic assay (Beckman Instruments, Chaska, MN, USA). Insulin resistance was calculated using the homeostasis model assessment.

Statistical analysis
Continuous variables with little-to-mild skewness were summarized as mean ± SD and compared using Student's t-test. Continuous variables with skewed distributions were summarized as median (first and third quartiles) and were compared with the Wilcoxon rank-sum test. Discrete variables were represented as frequencies and group percentages. Nominal variables were tested with Pearson's {chi}2 test and ordinal variables were tested with the Wilcoxon rank-sum test. Spearman correlation coefficients were calculated to evaluate unadjusted (‘univariate’) associations between adiponectin and other variables. All tests were two-tailed with a 0.05 type I error rate.

Logistic regression models were used to estimate odds ratios (ORs). Owing to skewness, log transformations of C-reactive protein, insulin resistance, triglycerides, LDL/HDL ratio, and leptin were used. Continuous variables were inspected for deviations from linearity in the logistic model. Multiple logistic regression models were used to estimate the association between adiponectin and ACS adjusted for age and gender alone, plus a model with adjustments for age, gender, BMI, C-reactive protein, mean blood pressure, LDL/HDL cholesterol ratio, triglycerides, insulin resistance, smoking status, prior MI, leptin, insulin resistance, fibrinogen, hypertension, statin use, and number of coronary lesions with a ≥50% reduction in luminal diameter (used as an index of CAD severity).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgement
 References
 
Study groups' characteristics
The demographic and clinical characteristics of the study groups, as well as laboratory variables, are shown in Table 1. More subjects with ACS were males and current smokers, had somewhat higher BMI but lower systolic blood pressure, had a history of prior MI and statin use, and had more severe CAD as assessed by angiography. On average, subjects with ACS also had more cardiovascular risk factors, including higher glucose and insulin levels (as well as insulin resistance), dyslipidaemia (with higher LDL and lower HDL), inflammatory markers (higher C-reactive protein and fibrinogen). Adiponectin levels were lower in those with ACS.


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  		Table 1 Demographic and clinical characteristics of the study groups

 
Correlations of adiponectin
Significant associations were seen between adiponectin and several other variables. Adiponectin levels were lower in males (7.3 ± 3.8 vs. 10.4 ± 1 µg/mL in females, P < 0.001) and in subjects with prior MI (6.7 ± 3.5 vs. 8.8 ± 4.7 µg/mL in those without prior MI, P < 0.001). Adiponectin levels were negatively correlated with BMI (P < 0.001), triglycerides (P = 0.003), insulin resistance (P < 0.001), and LDL/HDL ratio (P < 0.001) and positively correlated with age (P < 0.001) and HDL (P < 0.001).

Associations of adiponectin with ACS
The ACS and non-ACS groups were compared in order to assess for any independent association between adiponectin and the risk of ACS. In age- and gender-adjusted analysis, most of the traditional CAD risk factors (higher BMI, history of MI, elevated C-reactive protein and fibrinogen, higher LDL/HDL ratio, insulin resistance, statin use, and CAD severity) had significant associations with ACS (Table 2). Higher adiponectin levels were associated with reduced OR of ACS, with OR = 0.59 (95% CIs: 0.46–0.76; P < 0.001) for each 5 µg/mL change in adiponectin (Figure 1).


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  		Table 2 ORs for ACS: CI, confidence interval

 

Figure 3611
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  		Figure 1 The trend for ACS in relation to adiponectin values for all the study subjects. The Y-axis reflects the estimated proportion of patients with ACS given their adiponectin level. The lines reflect the predicted probabilities of ACS from regression models with only age and gender (solid line) and with all covariates (dashed line). The smooth lines were fit to the data by means of a spline routine.38

 
In multiple regression models adjusted for all the covariates, higher adiponectin levels remained positively associated with a lower risk of ACS (OR = 0.61; 95% CIs: 0.46–0.81; P < 0.001) (Table 2; Figure 1). In contrast, higher BMI, history of MI, C-reactive protein, and angiographic CAD severity were all associated with a higher risk (Table 2). The protective association of adiponectin was independent of all the other risk factors, including BMI, C-reactive protein, dyslipidaemia, and insulin resistance. It was also independent of statin use and CAD severity. Indeed, when significant CAD (defined as the presence of > 50% stenosis in any coronary vessel) was used as a dependent variable in a separate model, adiponectin non-significantly decreased odds of CAD in an age–sex-adjusted model (OR = 0.81; 95% CIs: 0.64–1.02; P = 0.078), but not in the all-covariates model (OR = 1.17; 95% CIs: 0.86–1.59; P = 0.313). The association of adiponectin was attenuated primarily by the variables ACS and Log(LDL/HDL).

In order to identify a clinically useful cut-off level of adiponectin, the patients were divided into six groups based on adiponectin split by the 10th, 25th, 50th, 75th, and 90th percentiles. The results are shown in Table 3. The group with the adiponectin levels greater than 90th percentile was used as reference. As expected, OR for ACS increased with decreasing adiponectin levels. The greatest increase in risk for ACS was seen at adiponectin levels ≤ 5.5 µg/mL.


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  		Table 3 ORs for ACS for different adiponectin levels

 
Subgroup analysis
Additional exploratory analyses were performed in patient subgroups on the basis of the following characteristics: presence vs. absence of significant (≥50% stenosis) angiographic CAD; BMI lesser vs. greater than 30 kg/m2; smoker vs. non-smokers; prior MI vs. no prior MI; presence vs. absence of family history of CAD; males vs. females; statin use vs. no statin use; hypertension vs. no hypertension; C-reactive protein (≥3 vs. < 3 mg/L); insulin resistance (below vs. above the cohort median); age (below vs. above the cohort median); and presence vs. absence of the metabolic syndrome. Of the subgroups studied, significant interactions were found with the presence of angiographic CAD, gender, and C-reactive protein. For these three variables, in a model adjusting for other risk factors, the adiponectin ORs for each subgroup are shown in Table 4. These data suggest that the protective associations of adiponectin are more pronounced in men, patients with significant angiographic CAD, and those with higher C-reactive protein levels.


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  		Table 4 Covariate-adjusted adiponectin ORs (per 5 µg/mL) for ACS in patient subgroups

 
Patients with angiographic CAD
We also evaluated the association of adiponectin with ACS in a subgroup of subjects with CAD on angiography, defined as the presence of ≥10% coronary stenosis. This subgroup included 223 subjects without and 155 subjects with ACS. Similar to the entire study group, among the subjects with angiographic CAD, adiponectin decreased odds for ACS both in age–gender-adjusted models (OR = 0.52; 95% CIs: 0.38–0.71; P < 0.001) and in a model with all covariates (OR = 0.50; 95% CIs: 0.36–0.71; P < 0.001).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgement
 References
 
Protective association of adiponectin with ACS
Adiponectin is a unique protein specifically expressed in the adipose tissue and paradoxically lower in obesity.15 The novel and important finding of the present study is that using multiple logistic regression models, adiponectin was found to be positively associated with a lower risk of ACS (i.e. low adiponectin increased risk). This was true for the entire study population as a whole, as well as for a subset of subjects with CAD on angiography.

The protective association of adiponectin was independent of several other recognized cardiovascular risk factors, including BMI, insulin resistance, dyslipidaemia, and C-reactive protein, and it was also independent of statin use. Furthermore, not only was the association of adiponectin independent of CAD severity, but in a separate model with CAD as a dependent variable, adiponectin was not predictive of CAD severity after accounting for other risk factors. This suggests that the pathophysiological role of adiponectin is related more to the stability of atherosclerotic plaque rather than to atherosclerotic burden, although a role for adiponectin in the development of atherosclerosis is also likely.

Mechanisms of the protective associations of adiponectin
Although the exact mechanism of the protective association of adiponectin cannot be established on the basis of the present study, several possibilities should be considered. First, the protective association of adiponectin was more evident in patients with higher C-reactive protein levels (Table 4), suggesting that the anti-inflammatory properties of adiponectin may play an important role. Indeed, hypoadiponectinaemia has been shown to correlate with pro-inflammatory mediators that play a role in atherogenesis.16–20

Secondly, the observation that the adiponectin OR for ACS was lower among patients with significant angiographic CAD (Table 4) may indicate that adiponectin may be directly involved in the pathophysiology of atherosclerosis and/or thrombosis at the vascular wall level. Several experimental data support this supposition. For example, adiponectin suppresses the expression of endothelial adhesion molecules21 and interferes with many monocyte/macrophage functions,18,21 including their transition to foam cells.21–23 Furthermore, adiponectin suppresses the proliferation of vascular smooth muscle cells24 and neointimal thickening.25,26 In addition, adiponectin has been implicated in endothelial function,18,27,28 suppression of endothelial cell apoptosis,29 angiogenesis,30 and nitric oxide production.31 There is also evidence for a direct anti-thrombotic action of adiponectin in vivo, such that adiponectin deficiency may lead to enhanced thrombus formation and platelet aggregation.32

Thirdly, adiponectin may be important by modifying several recognized cardiovascular risk factors. Our present data, consistent with those from other authors,33,34 show that adiponectin levels are negatively correlated with triglycerides, insulin resistance, and LDL/HDL ratio and positively correlated with HDL.

On the basis of these multiple mechanisms of action, it is likely that the protective effects of adiponectin from ACS are multifactorial. This is consistent with the complex pathophysiology of coronary plaque instability. Coronary plaque rupture in ACS has been associated with vascular inflammation, macrophage infiltration, apoptosis, and activation of tissue metalloproteinases, leading to erosion and rupture of the fibrous cap, which is further accompanied by the production of tissue factor pro-coagulant and other haemostatic factors that increase the risk of thrombosis.35 Adiponectin adheres to injured vascular wall36 and the anti-inflammatory, anti-proliferative, and anti-apoptotic effects of adiponectin (as discussed earlier) may conceivably lead to greater plaque stability. Also consistent with the plaque stabilizing effects of adiponectin is the observation that adiponectin specifically increases tissue inhibitor of metalloproteinase-1 in human macrophages.37 In addition, adiponectin may be protective against ACS after plaque rupture through its anti-thrombotic effects.

Clinical implications
The significance of our results includes, first, that adiponectin may be helpful in the stratification of patients at risk of ACS. The greatest increase in risk for ACS was seen at adiponectin levels ≤ 5.5 µg/mL, suggesting a potential clinically useful cut-off value. Secondly, the finding of an independent association between adiponectin and ACS may have important therapeutic and preventive implications for decreasing the risk of acute coronary events. Such potential therapies would have to be based on understanding the specific mechanisms underlying the protective association of adiponectin.

Study limitations
One potential limitation of this study is that our sample is not representative of the general population of CAD patients at large because of the specific exclusion criteria. Namely, we excluded patients with diabetes, significant smoking history, prior revascularization, prior radiation to the chest, and renal failure. As these conditions are associated with an increased risk of CAD, they might influence clinical judgement and the threshold for angiography; thus, by excluding them, we minimized referral bias. In addition, the strict inclusion and exclusion criteria decrease the complexity of the pathophysiological processes involved and are therefore important for any mechanistic understanding of our results.

The validity of the identification of our study population and of our finding of adiponectin as a predictor of ACS is supported by our ability to demonstrate that other traditional risk factors (BMI, prior MI, C-reactive protein, and CAD severity) were also predictive of ACS in our population, consistent with what has been found in many other studies. Nevertheless, further studies are warranted to confirm the association between adiponectin and ACS in a non-selected population and to determine whether it exists in patients with diabetes.

Conclusions
Higher plasma adiponectin levels are associated with a lower risk of ACS, independent of other traditional metabolic and cardiovascular risk factors. These findings may have important implications both for understanding the pathophysiology of ACS and for the development of future therapeutic and coronary preventive approaches.


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
References
 
This study was supported by the Mayo Foundation, HL-61560, HL-65176, HL-70302, and MO1-RR00585.

Conflict of interest: none declared.


   Footnotes
 
{dagger} Present address. Pfizer, Global Research and Development, Groton, CT, USA. Back

{ddagger} Present address. Duke University School of Medicine, Durham, NC, USA. Back

Present address. University of Texas Southwestern Medical Center, Dallas, TX, USA. Back


   References
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 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
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