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J Am Coll Cardiol, 2006; 48:1155-1162, doi:10.1016/j.jacc.2006.05.054 (Published online 25 August 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: BIOMARKERS AND CORONARY DISEASE

Plasma Adiponectin Levels Are Associated With Coronary Lesion Complexity in Men With Coronary Artery Disease

Fumiyuki Otsuka, MD*, Seigo Sugiyama, MD, PhD*,*, Sunao Kojima, MD, PhD*, Hidetomo Maruyoshi, MD*, Tohru Funahashi, MD, PhD{dagger}, Kunihiko Matsui, MD, MPH{ddagger}, Tomohiro Sakamoto, MD, PhD*, Michihiro Yoshimura, MD, PhD*, Kazuo Kimura, MD, PhD§, Satoshi Umemura, MD, PhD§ and Hisao Ogawa, MD, PhD*

* Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
{dagger} Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
{ddagger} Department of General Medicine, Kumamoto University Hospital, Kumamoto, Japan
§ Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan.

Manuscript received November 29, 2005; revised manuscript received May 9, 2006, accepted May 16, 2006.

* Reprint requests and correspondence: Dr. Seigo Sugiyama, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556, Japan. (Email: ssugiyam{at}kumamoto-u.ac.jp).


   Abstract
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Methods
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 Discussion
 References
 
OBJECTIVES: We sought to assess whether plasma adiponectin levels correlate with angiographic coronary lesion complexity in patients with coronary artery disease (CAD).

BACKGROUND: Metabolic disorders, including diabetes mellitus and metabolic syndrome, are important risk factors for acute cardiovascular events, and adiponectin is a key molecule of metabolic disorders, with anti-atherogenic properties. Low plasma adiponectin levels are associated with CAD and future incidence of myocardial infarction. The involvement of adiponectin in coronary plaque vulnerability, which may be reflected by angiographic complex lesions, remains to be elucidated.

METHODS: We measured plasma adiponectin levels in 207 men (152 with stable CAD and 55 with acute coronary syndromes [ACS]). Coronary lesions were classified as of simple or complex appearance.

RESULTS: Plasma adiponectin levels were significantly lower in stable CAD patients with complex coronary lesions (n = 60) than in those with simple lesions (n = 92) (4.14 [range 2.95 to 6.02] vs. 5.27 [range 3.67 to 8.12] µg/ml, p = 0.006). Multiple logistic regression analysis demonstrated that adiponectin level was independently associated with complex lesions (odds ratio 0.514, 95% confidence interval 0.278 to 0.951; p = 0.034). Polytomous logistic regression revealed that adiponectin correlated independently with both single and multiple complex lesions. Among patients with ACS, who had lower adiponectin levels than stable CAD patients, those with multiple complex lesions had significantly lower adiponectin than those with a single complex lesion (3.26 [range 2.26 to 4.46] vs. 4.21 [range 3.36 to 5.41] µg/ml, p = 0.032).

CONCLUSIONS: Plasma adiponectin levels are significantly associated with coronary lesion complexity in men with CAD. Low adiponectin levels may contribute to coronary plaque vulnerability.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  CAD = coronary artery disease
  CI = confidence interval
  hs-CRP = high-sensitivity C-reactive protein
  MI = myocardial infarction
  OR = odds ratio

The incidence of diabetes mellitus, a major and important risk factor for cardiovascular events including acute coronary syndromes (ACS), is increasing worldwide (1). Similarly, the metabolic syndrome, a clustering of cardiovascular disease risk factors characterized by abdominal obesity, insulin resistance, dyslipidemia, and hypertension, is associated with increased cardiovascular morbidity and mortality (2). There is increasing evidence that adiponectin, an adipocyte-derived plasma protein, plays an important role in the development of diabetes mellitus and metabolic syndrome, with anti-diabetic and anti-atherogenic properties (3). Plasma levels of adiponectin are significantly decreased in obesity (4), in type 2 diabetes (5), and in patients with coronary artery disease (CAD) (6). In addition, we recently reported a significant association between plasma adiponectin levels and atherosclerotic burden (7).

Hypoadiponectinemia is considered an independent risk factor for CAD (8), and a recent study demonstrated that plasma adiponectin levels in patients with ACS were significantly lower than those in patients with stable CAD (9). Moreover, it has been shown (10) that lower levels of plasma adiponectin are associated with increased risk of future myocardial infarction (MI). Thus, low adiponectin may contribute to the development of atherosclerosis and acute vascular complications including ACS.

The vulnerability of coronary plaques is implicated in the pathogenesis of ACS (11). Vulnerable atheromatous plaques lead to coronary plaque disruption with superimposed thrombosis (12), which is often manifested as angiographically complex lesions (13). The presence of complex coronary lesions is associated with acute coronary events (14,15) concomitant with rapid progression of coronary stenosis (15–18). Thus, evaluation of coronary lesion complexity is clinically useful for the estimation of plaque instability. Although complex lesions are frequently observed in ACS patients (19), coronary angiography may also reveal these lesions in patients with stable CAD (17,18); therefore, symptomatic stability does not always reflect coronary plaque stability. Practical evaluation of coronary plaque instability, in addition to the degree of luminal stenosis, is important in assessing clinical disease activity and the risk of subsequent vascular complications in patients with CAD. Diabetes mellitus and metabolic syndrome have been shown to contribute to the development of ACS; however, the mechanisms of such metabolic disorders involving plaque vulnerability remain to be fully elucidated. In this regard, adiponectin may be involved in the pathogenesis of coronary lesions’ vulnerability.

The hypothesis tested in the present study was that adiponectin is associated with the presence of complex coronary lesions, reflecting coronary vulnerability. To investigate this hypothesis, we measured plasma levels of adiponectin and evaluated angiographic coronary stenosis morphology in men with CAD.


   Methods
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Study population.   Those eligible for entry in this study were male patients who underwent coronary angiography at Kumamoto University Hospital from January 2000 through June 2005 because of an abnormal electrocardiogram or angina-like chest symptoms. Patients with a previous history of coronary intervention or coronary artery bypass graft surgery were excluded to avoid artificial bias from such procedures. We also excluded patients with malignant disease, infectious disease, inflammatory disease such as collagen disease, advanced liver disease, and advanced renal disease. None of the patients was taking any type of thiazolidinedione, which is an insulin-sensitizing agent known to increase plasma concentrations of adiponectin (20).

According to these criteria, this study enrolled 207 consecutive men with CAD (55 patients with ACS and 152 patients with stable CAD). Patients with ACS included 31 with acute MI (who were catheterized within 6 h from the onset of chest pain) and 24 patients with unstable angina pectoris. A diagnosis of acute MI was made if the patient had typical chest pain with ST-segment elevation on the electrocardiogram and an increase in the serum level of creatine kinase-MB isoenzyme to greater than twice the upper limit of the normal range. A diagnosis of unstable angina (Braunwald’s class IIB or IIIB [21]) was made if the patient had characteristic chest symptoms at rest associated with transient ischemic ST-segment shifts and normal serum level of creatine kinase-MB isoenzyme. Stable CAD was defined as no episodes of angina at rest but angiographically documented organic stenosis of >50% in at least one of the major coronary arteries and no previous MIs. Written informed consent was obtained from each patient before study participation. The study was conducted in accordance with guidelines approved by the ethics committee of our institution.

Coronary angiography.   Angiographic scoring system (extent score)
All patients underwent selective coronary angiography, and the extent of coronary stenosis was assessed using the scoring system previously described by Sullivan et al. (22). The length proportion of each vessel involved by angiographically detectable atheroma was evaluated and multiplied by a factor for each vessel: left main stem, 5; left anterior descending artery, 20; main diagonal branch, 10; first septal perforator, 5; left circumflex artery, 20; obtuse marginal and posterolateral vessels, 10; right coronary artery, 20; and main posterior descending branch, 10. When the major lateral wall branch was a large obtuse marginal or intermediate vessel, this was given a factor of 20 and the left circumflex artery a factor of 10. When a vessel was occluded and the distal segments were not fully visualized by collateral flow, the proportion of vessel not visualized was given the mean extent score of the remaining vessels. The scores for each vessel or branch were added to give a total score up to a maximum of 100, representing the percentage of the coronary luminal surface area involved by atheroma, as described in previous studies (22,23).

Angiographic morphology of coronary stenosis
Coronary stenosis was assessed morphologically according to the Ambrose classification (19,24) and was classified as either simple or complex. A simple lesion was defined as stenosis with smooth and regular borders without intraluminal filling defects, whereas a complex lesion comprised stenosis with irregular, rough borders; ulceration with or without intraluminal filling defects, suggestive of thrombus formation; and long atherosclerotic lesions with severe narrowing in series. Angiographic evaluations were performed independently by 2 cardiologists who were blinded to the clinical features of the patients and, in case of disagreement, the decision was based on the judgment of a third, more experienced observer. The interobserver reproducibility for morphologic assessment of coronary lesions was 95%.

Blood sampling and measurement of plasma adiponectin
Venous blood samples were obtained just before the emergency coronary angiography in patients with ACS and were obtained in the early morning after a 12-h fast in patients with stable CAD. The serum profile, including fasting blood glucose, hemoglobin A1c, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, creatinine, and high-sensitivity C-reactive protein (hs-CRP) levels, was measured in the hospital laboratory. Plasma samples were immediately stored at –80 °C for subsequent assay for adiponectin levels by enzyme-linked immunosorbent assay as described previously (4,7).

Statistical analysis.   Results of normally distributed continuous variables are expressed as the mean value ± SD, and those for continuous variables with skewed distribution are expressed as the median value (interquartile range). Comparisons of continuous variables were analyzed with the unpaired t test and the Mann-Whitney U test, as appropriate. Categorical variables are presented by frequency counts, and intergroup comparisons were analyzed by the chi-square test. Associations between the presence of complex lesions and all other parameters were first analyzed by simple logistic regression analysis and then by multivariate analysis. The base-2 logarithms (log2) of the plasma levels of adiponectin, triglycerides, and hs-CRP were used in all the logistic regression analysis to account for skewed distribution of these parameters (25). Thus, odds ratios (ORs) for these variables reflect the change in odds for an increase of 1 log2 (the equivalent of a doubling of the value) in the measure. We performed polytomous logistic regression analysis to calculate the ORs and 95% confidence intervals (CIs) for single and multiple complex lesions, as compared with simple lesions, in relation to all parameters. In this analysis, factors that were associated with the dependent variable at p < 0.20 in the univariate analysis were entered into the multivariate model and eliminated using a backward procedure. Statistical significance was defined as p < 0.05. All analyses were performed using Stat View-5.0 software (SAS Institute Inc., Cary, North Carolina) and SPSS 14.0J for Windows (SPSS Inc., Tokyo, Japan).


   Results
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Discussion
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Plasma levels of adiponectin in patients with stable CAD and ACS.   Figure 1 shows plasma levels of adiponectin in patients with stable CAD and ACS. Patients with ACS had significantly lower plasma levels of adiponectin than those with stable CAD (3.81 [range 2.66 to 5.22] vs. 4.60 [range 3.36 to 7.36] µg/ml, p = 0.003).


Figure 1
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  		Figure 1 Plasma levels of adiponectin in patients with stable coronary artery disease (CAD) (n = 152, blue circles) and acute coronary syndromes (ACS) (n = 55, yellow circles). Box-and-whisker plot showing plasma levels of adiponectin in patients with stable CAD and ACS. In these plots, lines within boxes represent median values; the upper and lower lines of the boxes represent the 25th and 75th percentiles, respectively; and the upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively.

 
Characteristics of patients with stable CAD.   We assessed the association between plasma levels of adiponectin and coronary lesion complexity in patients with stable CAD. The baseline clinical characteristics of the 152 men with stable CAD are summarized in Table 1. Complex coronary lesions were angiographically identified in 60 patients (39%), and simple lesions were identified in the remaining 92 patients (61%). Coronary multi-vessel involvement was noted in 76 patients (50%), and multiple complex lesions were observed in 30 of these patients (20%).


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  		Table 1. Baseline Clinical Characteristics and Coronary Angiographic Findings of 152 Men With Stable Coronary Artery Disease
 
Comparison of adiponectin levels in stable CAD patients with simple and complex lesions.   Stable CAD patients with complex lesions had significantly lower plasma levels of adiponectin than those with simple lesions (4.14 [range 2.95 to 6.02] vs. 5.27 [range 3.67 to 8.12] µg/ml, p = 0.006) (Table 1, Fig. 2). Low-density lipoprotein cholesterol, triglyceride levels, and the extent score were significantly higher, and left ventricular ejection fraction was significantly lower in patients with complex lesions than in those with simple lesions (Table 1).


Figure 2
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  		Figure 2 Box-and-whisker plot showing plasma levels of adiponectin in stable coronary artery disease patients with simple (n = 92, blue) and complex lesions (n = 60, red). In these plots, lines within boxes represent median values; the upper and lower lines of the boxes represent the 25th and 75th percentiles, respectively; and the upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively. Abbreviations as in Figure 1.

 
Adiponectin and presence of complex coronary lesions in patients with stable CAD.   Simple logistic regression analysis showed that low-density lipoprotein cholesterol concentrations (OR 1.010, 95% CI 1.001 to 1.020; p = 0.037), hs-CRP (OR 1.305, 95% CI 1.015 to 1.679; p = 0.038), left ventricular ejection fraction (OR 0.970, 95% CI 0.943 to 0.999; p = 0.041), extent score (OR 1.163, 95% CI 1.107 to 1.222; p < 0.001), and plasma adiponectin levels (OR 0.531, 95% CI 0.347 to 0.811; p = 0.003) were associated with the presence of complex coronary lesions (Table 2). Multiple logistic regression analysis revealed that the extent score was strongly associated with the presence of complex coronary lesions (OR 1.158, 95% CI 1.098 to 1.222; p < 0.001); however, plasma adiponectin levels remained as a significant and independent predictor of complex lesions (OR 0.514, 95% CI 0.278 to 0.951; p = 0.034) (Table 2). Furthermore, hypoadiponectinemia, which was defined by using a cutoff value for plasma adiponectin of 4.0 µg/ml (8), was a significant risk factor for the presence of complex coronary lesions in patients with stable CAD (OR 2.138, 95% CI 1.090 to 4.194; p = 0.027).


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  		Table 2. Logistic Regression Analysis for the Presence of Complex Coronary Lesions in Patients With Stable Coronary Artery Disease
 
Moreover, the ORs and 95% CIs for single and multiple complex lesions as compared with simple lesions in relation to all parameters were assessed using polytomous logistic regression analysis (Table 3). Univariate analysis showed that adiponectin levels were significantly associated with both single and multiple complex lesions, and ORs for multiple complex lesions were lower than those for single complex lesions (OR 0.565, 95% CI 0.336 to 0.948; p = 0.031 for single complex lesions, OR 0.463, 95% CI 0.273 to 0.784; p = 0.004 for multiple complex lesions). Multivariate analysis demonstrated that extent score and plasma adiponectin level were significantly and independently associated with both single and multiple complex lesions (extent score; OR 1.135, 95% CI 1.075 to 1.199; p < 0.001 for single complex lesions, OR 1.199, 95% CI 1.126 to 1.277; p < 0.001 for multiple complex lesions, adiponectin; OR 0.505, 95% CI 0.261 to 0.979; p = 0.043 for single complex lesions, OR 0.290, 95% CI 0.128 to 0.658; p = 0.003 for multiple complex lesions) (Table 3).


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  		Table 3. Polytomous Logistic Regression Analysis of Factors Associated With Single and Multiple Complex Lesions in Patients With Stable Coronary Artery Disease
 
Comparison of adiponectin levels in ACS patients with single and multiple complex lesions.   Finally, we evaluated the association between plasma levels of adiponectin and coronary lesion complexity in patients with ACS. Of the 55 ACS patients, 47 had angiographically complex lesions. Acute coronary syndrome patients with multiple complex lesions (n = 24) had significantly lower plasma levels of adiponectin than those with single complex lesions (n = 23) (3.26 [range 2.26 to 4.46] vs. 4.21 [range 3.36 to 5.41] µg/ml, p = 0.032) (Fig. 3).


Figure 3
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  		Figure 3 Box-and-whisker plot showing plasma levels of adiponectin in acute coronary syndrome patients with single (n = 23, blue) and multiple complex lesions (n = 24, red). In these plots, lines within boxes represent median values; the upper and lower lines of the boxes represent the 25th and 75th percentiles, respectively; and the upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively. Abbreviations as in Figure 1.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
In the present study, we demonstrated that men with stable CAD and complex coronary lesions had significantly lower plasma adiponectin levels than those with simple lesions, and that the plasma level of adiponectin was an independent predictor of angiographically complex coronary lesions. Furthermore, among patients with ACS (who had significantly lower adiponectin levels than stable CAD patients), those with multiple complex lesions had significantly lower adiponectin levels than those with single complex lesions. Thus, hypoadiponectinemia is associated with coronary lesion complexity, and our results suggest that the extent of hypoadiponectinemia may provide valuable information about coronary plaque vulnerability.

Vulnerable coronary plaques, which include rupture-prone plaques and atheromatous plaques with high likelihood of thrombotic complications and rapid progression, play crucial roles in the development of ACS (11). Inflammation and metabolic disorders are thought to be implicated in the pathogenesis of coronary plaque vulnerability (26). Previous studies demonstrated that inflammatory serologic markers, serum neopterin, and pregnancy-associated plasma protein A are associated with coronary lesion complexity (23,27). In addition to such inflammatory processes, metabolic disorders, including diabetes mellitus, may also affect coronary plaque vulnerability (26,28). Indeed, pathologic studies demonstrated that coronary plaques of diabetic patients exhibited increased infiltration of macrophages and thrombus formation (29), indicating vulnerable and activated plaque condition.

Adiponectin, an adipocyte-derived plasma protein with anti-diabetic and anti-atherogenic properties, may be a key molecule in the pathogenesis of diabetes mellitus and metabolic syndrome (3). Adiponectin suppresses macrophage-to-foam cell transformation (30,31) and increases the expression of tissue inhibitor of metalloproteinase-1 in monocyte-derived macrophages through induction of interleukin-10 (32), suggesting that adiponectin may be a positive contributor to the stabilization of atherosclerotic plaques.

To our knowledge, the present study represents the first report demonstrating that low adiponectin levels are significantly associated with coronary lesion complexity, reflecting plaque vulnerability, in men with CAD. This finding may in part help explain the missing link between metabolic disorders and cardiovascular complications resulting from the disruption of vulnerable plaques.

Several lines of evidence point to the role of adiponectin in atherogenesis, and it is conceivable that the low adiponectin levels in patients with complex coronary lesions in the present study can be the cause and consequence of active atherosclerosis. Adiponectin could reduce atherosclerosis by inhibiting endothelial expression of adhesion molecules (6), modulation of macrophage functions (30,31), and suppression of vascular smooth muscle cell proliferation (33). Plasma levels of adiponectin are reduced in patients with CAD (6), and a previous study (9) reported significantly lower adiponectin levels in patients with ACS than those with stable CAD. A recent report found that low levels of plasma adiponectin were associated with future development of MI in men without cardiovascular disease (10), suggesting that low adiponectin may contribute to the development of ACS. We have recently reported (34) the reduction of plasma adiponectin in the early phase of acute MI, and accumulation of adiponectin has been demonstrated in the walls of injured vessels, but not in intact vessels (30,35). Therefore, increased consumption of circulating adiponectin in active atheroma might lower the plasma levels of this molecule in patients with complex lesions.

Based on the mechanisms of acute coronary events, we have recognized the clinical importance of evaluating not only the degree of coronary luminal stenosis but also plaque vulnerability in determining disease activity and the risk of subsequent vascular complications (11). Angiographically, the presence of complex coronary lesions correlates with pathologic plaque rupture and thrombus formation (13). Clinical observations demonstrated that complex lesions were associated with accelerated progression of plaque stenosis (15–18), and they were also predictive of future cardiac events (14,15). Angiographic assessment of the morphology of coronary stenosis is well established and considered to be clinically useful for risk stratification of CAD patients (15). In the present study, we showed that adiponectin is significantly associated with coronary lesion complexity in men with CAD. Our results may indicate that low plasma adiponectin could perhaps be used to predict the occurrence of future cardiovascular events; however, further prospective studies are required to clarify this issue because we did not assess clinical outcomes in the present study.

It is widely accepted that inflammation plays an important role in the pathogenesis of atheromatous plaque vulnerability (36). In our present study, hs-CRP levels in patients with stable CAD were significantly associated with the presence of complex coronary lesions in simple logistic regression analysis. Furthermore, hs-CRP levels in patients with complex lesions were higher than those with simple lesions, though the difference was not statistically significant. Previous studies have demonstrated that hs-CRP levels correlate with coronary lesion complexity in patients with unstable angina (37,38), whereas such associations cannot be observed consistently in patients with stable CAD (27,39,40). In part, our results were in line with the previous observations; however, the rather weak association between hs-CRP and coronary lesion complexity in patients with stable CAD is intriguing.

This study was limited by the relatively small number of patients studied. We demonstrated that plasma adiponectin level is an independent predictor of complex lesions in men with stable CAD in multiple logistic regression analysis, though it was barely statistically significant. Further studies in a large number of patients should confirm our results. There was some overlap of distribution in adiponectin levels between patients with complex and simple lesions, however, hypoadiponectinemia (<4.0 µg/ml) (8) was a significant risk factor for the presence of complex coronary lesions in the present study. Thus, our finding regarding lower adiponectin levels in patients with complex lesions may support the concept that hypoadiponectinemia could be implicated in the development of coronary plaque instability and may suggest that hypoadiponectinemia could be helpful for the evaluation of coronary plaque instability as well as the presence of CAD. Moreover, therapeutic utility of increasing adiponectin levels remains to be elucidated, and our results may in part suggest that thiazolidinedione, a peroxisome proliferator-activated receptor-gamma agonist known to increase adiponectin (20), could be an agent to stabilize the atheromatous plaques and prevent atherothrombosis. However, further studies are needed to clarify the issue because we did not evaluate the effect of such agents in the present study.

In conclusion, plasma adiponectin levels in men with stable CAD and complex coronary lesions were significantly lower than in those with simple lesions, and ACS patients with multiple complex lesions had significantly lower adiponectin levels than those with single complex lesions. Thus, hypoadiponectinemia is associated with coronary lesion complexity in patients with CAD. Our results suggest that low levels of adiponectin may contribute to coronary plaque vulnerability, and plasma adiponectin levels may provide valuable information regarding coronary plaque vulnerability.


   Acknowledgments
 
The authors thank Sachiyo Tanaka and Megumi Tsukamoto for their excellent technical support.


   Footnotes
 
This study was supported by a Research Grant for Cardiovascular Disease (17C-2) from the Ministry of Health, Labor, and Welfare, Japan; a Grant-in-aid for Scientific Research (B-17390232, C-17590753, and C-18590780) from the Ministry of Education, Science, and Culture, Japan; and the Smoking Research Foundation Grant for Biomedical Research, Japan.


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