Asian Cardiovasc Thorac Ann 2008;16:124-128
© 2008 Asia Publishing EXchange Ltd
Potential Role of Adipocytokine Leptin in Acute Coronary Syndrome
Laxman Dubey, MD,
He-Song Zeng, PhD,
Hong-Jie Wang, PhD,
Ren-Yan Liu, MD
Department of Cardiology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
For reprint information contact: Laxman Dubey, MD, Tel: 86 27 8369 1225, Fax: 86 27 8369 2560, Email: dubeylax{at}yahoo.com, Department of Cardiology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology (HUST), Wuhan-430030, Hubei, China.
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ABSTRACT
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By activating immune cells or a direct action on the vascular wall, leptin may affect the initiation and progression of atherosclerosis. We investigated whether plasma leptin concentration is associated with coronary artery disease, with particular focus on the relationship between plasma leptin and the development of an acute coronary syndrome. Plasma leptin, interleukin-6 and high-sensitivity C-reactive protein were measured in 34 patients with acute coronary syndrome and 21 with stable angina. Their results were compared with those of 21 normal controls. Plasma leptin levels were significantly higher in the acute coronary syndrome group (13.36 ± 5.02 ng·mL–1) compared to the stable angina group (8.97 ± 4.06 ng·mL–1) or normal controls (5.14 ± 2.75 ng·mL–1). Interleukin-6 and high-sensitivity C-reactive protein were also higher in the acute coronary syndrome group, and leptin correlated positively with interleukin-6 and high-sensitivity C-reactive protein. These findings suggest that plasma leptin levels may be a useful marker of systemic inflammation, and measurement of plasma leptin may be helpful in assessing the risk of developing coronary heart disease.
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INTRODUCTION
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Leptin is an adipocytokine secreted mainly by adipose tissue. Although originally viewed as a mediator in energy homeostasis, several cardiovascular actions of leptin suggest it may also affect the development of coronary artery disease (CAD). Leptin shows angiogenic activity, increases oxidative stress in endothelial cells, promotes vascular smooth muscle cell migration and proliferation, decreases arterial distensibility and contributes to obesity-associated hypertension. These factors correlate negatively with vascular health and are strongly involved in the pathophysiology of atherosclerosis. Leptin has also been reported to be independently associated with increased serum C-reactive protein (CRP) levels. There is growing evidence that leptin can stimulate immune cells and regulate the production of several pro and antiinflammatory cytokines. In-vitro and in-vivo studies have indicated that leptin promotes neutrophil activation and chemotaxis, induces tumor necrosis factor-
and interleukin (IL)-6 from monocytes, promotes monocyte/macrophage activation and phagocytosis, enhances lymphocyte proliferation, and favors a T helper (Th) type 1 cytokine response.1,2 More specifically, leptin modulates Th cells toward a Th1 phenotype, secreting proinflammatory cytokines, such as interferon-
and IL-2, while suppressing the antiinflammatory cytokines IL-4 and IL-10 from Th2 cells in human and animal models.3,4 These mediators play a pivotal role in coronary atherosclerosis as well as plaque rupture. Leptin might adversely affect vascular health by activating immune cells or directly acting on the vascular wall. Thus it may play a role in the initiation and progression of atherosclerosis. However, the relationship of leptin to CAD is still obscure. We examined plasma leptin levels in patients with stable angina pectoris (SAP) or an acute coronary syndrome (ACS) to investigate whether leptin is associated with ACS. To determine the relationship between leptin and other inflammatory markers, the levels were compared with high-sensitivity C-reactive protein (hs-CRP) and proinflammatory cytokine IL-6 levels in these patients.
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PATIENTS AND METHODS
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Seventy-six subjects were included in this study after obtaining their informed consent: 55 had coronary atherosclerosis, defined as 
50% diameter stenosis in 1 coronary artery; and 21 were age, sex and body mass index-matched normal controls. Patient groups consisted of 34 with ACS (27 males) and 21 with SAP (16 males) who were admitted to the Tongji Hospital between March 2006 and February 2007 for initial assessment of CAD by angiography. Acute coronary syndrome included unstable angina and acute myocardial infarction (AMI). Unstable angina was defined as ischemic chest pain at rest within the preceding 48 hours or within the past month (Braunwald class II and III), with transient ST-T segment depression and/or T-wave inversion. Acute myocardial infarction included ST-segment elevation and non-ST-segment elevation infarction with typical chest pain persisting for at least 30 min, ST segment elevation > 0.2 mV in at least 2 contiguous leads, and increased serum troponin I (> 0.3 ng·mL–1). Stable angina pectoris was defined as both typical exertional chest pain relieved by rest, and an electrocardiographically positive exercise stress test. The control group comprised healthy subjects who visited the same hospital for routine physical check-ups; they give no history of chest pain or symptoms suggestive of CAD. They were screened noninvasively through clinical assessment, electrocardiogram, and exercise testing to rule out CAD. They also showed no evidence of ongoing systemic or cardiac inflammatory diseases. The clinical and demographic data of each group are listed in Table 1
. Diabetes mellitus was defined as a history of diabetes, fasting plasma glucose 126 mg·dL–1, or use of hypoglycemic medications. Systemic hypertension was defined as systolic blood pressure 140 mm Hg, and/or diastolic pressure 90 mm Hg, and/or use of antihypertensive medication. Hypercholesterolemia was defined as total cholesterol 200 mg·dL–1, low-density lipoprotein cholesterol 130 mg·dL–1, or treatment with a lipid-lowering agent.
In the patient groups, venous blood samples were drawn immediately before coronary angiography after an overnight fast. The time interval between symptom onset and blood sampling was < 48 hours (median, 25 hours). The samples were collected in tubes containing EDTA, and the plasma obtained after centrifugation at 3,000 rpm was stored at –80°C for subsequent analysis of leptin, hs-CRP and IL-6. Blood samples from the control group were drawn in the morning after an overnight fast. Plasma concentrations of leptin and IL-6 were measured using sandwich ELISA kits (Jingmei Biotech, Shenzhen, China). High sensitivity-CRP was measured using ELISA kits (Chemicon International, Temecula, CA, USA). The lower limits of detection were 2 pg·mL–1 for IL-6, 1 ng·mL–1 for leptin, and 0.02 mg·L–1 for hs-CRP. Laboratory procedures were conducted according to manufacturers’ instructions by an experienced technician who was unaware of the study details.
Results are expressed as mean ± standard deviation. Normality was tested using the Kolmogorov-Smirnov test. Differences among groups were analyzed using one-way analysis of variance. Post-hoc comparisons between different groups were made using the Tukey-Kramer multiple comparisons test because of unequal sample sizes and/or unequal variances. Pearson or Spearman correlation was used as a test of correlation between 2 continuous variables. SPSS 13.0 software (SPSS, Inc., Chicago, IL, USA) was used for analyses. Values of p < 0.05 were considered significant.
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RESULTS
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Plasma Leptin levels in the ACS and SAP groups were significantly higher than in the control group (Table 2). There was a significant difference between leptin levels in the SAP and ACS groups. Compared to the controls, plasma levels of hs-CRP were significantly higher in the ACS group, and IL-6 levels were significantly higher in both ACS and SAP groups. The levels of hs-CRP ( p = 0.02) and IL-6 ( p = 0.01) were higher in the ACS group than the SAP group. The leptin levels correlated positively with those of IL-6 and hs-CRP, and hs-CRP levels showed a positive correlation with IL-6 (Table 3).
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DISCUSSION
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Thrombus formation over vulnerable disrupted atherosclerotic plaques has been implicated as an important mechanism in the development of the acute ischemic syndromes of unstable angina, AMI and sudden death.5 Inflammatory and immunologic mediators may play crucial roles in plaque rupture. Macrophages and T-cells are known to be important components of atherosclerotic lesions, which can generate and release cytokines that play important roles in ACS. Various inflammatory markers and cytokines are associated with atherosclerosis and its progression to clinical syndromes. A number of proinflammatory cytokines, including tumor necrosis factor-, IL-1β, IL-6, IL-12 and interferon- are expressed in human atherosclerotic plaques. These cytokines alone or in combination contribute to the local inflammatory response, and may have great impact on plaque formation and progression.6 On the other hand, antiinflammatory cytokines, such as IL-4 and IL-10, are important in balancing the inflammatory response.
Leptin is a 16-kDa protein composed of 167 amino acid peptides encoded by an obesity gene, and it has an important function in the regulation of body weight. Leptin controls feeding and stimulates thermogenesis by acting on the hypothalamus. Leptin receptors are widely distributed in immune cells, vascular smooth muscle cells, endothelial cells and atherosclerotic plaques. Therefore, leptin has been increasingly implicated as a risk factor for cardiovascular disease. Hyperleptinemia is associated with insulin resistance and has been suggested to play a central role in metabolic syndrome.7 Leptin secretion by adipocytes is stimulated by insulin, and plasma leptin significantly correlates with plasma insulin. It is reported that plasma leptin levels correlate with body mass index and are 3–4 times higher in patients with obesity and diabetes, both of which are major risk factors for atherosclerosis. Recently, Bodary and colleagues8 demonstrated that direct administration of leptin in ApoE-deficient mice increased atherosclerosis. The prospective West of Scotland Coronary Prevention Study also showed that leptin moderately but independently increased the relative risk of CAD.9 The role of leptin in atherosclerosis is supported by findings in ob/ob mice that lack a functioning leptin gene and are resistant to atherosclerosis despite being grossly obese and diabetic; leptin administration resulted in atherosclerotic changes.10 Wolk and colleagues11 demonstrated that plasma leptin is an independent predictor of cardiovascular events in patients with coronary atherosclerosis confirmed by angiography. Nakata and colleagues12 found that the long isoform of the leptin receptor is expressed in human platelets, and concluded that leptin at high concentrations promotes platelet aggregation. Leptin has also been shown to enhance human platelet aggregation in response to thrombin and adenosine diphosphate.
Several studies have demonstrated inflammatory mechanisms of leptin. This adipocytokine polarizes T helper (Th) cells toward a Th1 phenotype, and stimulates the production of proinflammatory cytokines IL-2 and interferon- while suppressing antiinflammatory cytokines IL-4 and IL-10 from Th2 cells in humans and animal models.3,4 Moreover, recombinant methionyl human leptin administration in 2 leptin-deficient children improved CD4+ Th cell counts, T cell proliferation and cytokine release.13 Enhanced leptin levels correlated with IL-6 in septic patients treated in an intensive care unit.14 Stejskal and colleagues15 examined 48 probands who were hospitalized for ACS. They demonstrated that patients with AMI had leptinemia and a higher concentration of IL-6, but no correlation was found between leptinemia and body weight. These cytokines are known to play a role in the immunologic cascade leading to atherosclerosis and its subsequent development into ACS.
Interleukin-6 is a proinflammatory cytokine that can induce the synthesis of CRP and fibrinogen. It has stimulatory effects on T and B lymphocytes. Patients with unstable angina have higher levels of IL-6 than normal controls or SAP patients, with the highest levels predicting the worst prognosis.16 Yamashita and colleagues17 showed that concentrations of IL-6 were significantly higher in unstable angina than in SAP or controls, in agreement with the findings of our study. We also observed that leptin levels correlated positively with those of IL-6. Recently, several studies have focused on plasma markers of inflammation for prognostic evaluation and risk stratification in CAD. One such marker, hs-CRP, has been studied widely and seen to be associated with poor outcome in ACS. C-reactive protein is synthesized by the liver and regulated by cytokines, especially IL-6. C-reactive protein activates the classic complement cascade, mediates phagocytosis and regulates inflammation. In healthy humans, increased leptin is associated with increased CRP, independently of sex, measures of adiposity and other variables. Our findings showed that hs-CRP levels were significantly higher in ACS than SAP patients or controls, which adds weight to the recent recommendations for its use as a marker for risk prediction in ACS.18
Several other studies have suggested that serum leptin may be an independent risk factor for cardiovascular diseases. Wallace and colleagues9 demonstrated that higher plasma leptin levels in hypercholesterolemic men were associated with increased risk of a future coronary event. Soderberg and colleagues19 showed that elevated plasma leptin strongly predicted the first AMI in men. They found that 62 men with a first AMI had higher body mass index, plasma insulin, serum leptin and diastolic blood pressure than controls, but high leptin levels remained a significant risk factor for AMI in a multivariate model.
Increased leptin levels in patients with ACS, and the close association with inflammatory parameters, suggest a significant role of leptin in the development of atherosclerosis. Positive correlation of leptin levels with other inflammatory markers of CAD, such as hs-CRP and IL-6, also supports the hypothesis that leptin is a determinant of CAD, possibly through its proinflammatory action. Thus, plasma leptin may be a useful marker in risk stratification of ACS, and a potential target for treatment of CAD. We believe more approaches aimed at reducing plasma leptin levels or blocking its action on immune cells would be useful in the prevention or inhibition of atherosclerotic lesions. However, this study was limited by the relatively small number of patients studied. Also, our study cannot discern whether elevated leptin is a cause or consequence of CAD. Because of the case-controlled design, our study can show the association with CAD, but it does not allow the conclusion that leptin is a causal factor in CAD. Therefore, a prospective study to determine a cause/effect relationship in a large number of patients is necessary to confirm these results.
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ACKNOWLEDGMENTS
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This study was supported in part by a grant from the National Natural Science Foundation, China (no. 30470713).
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ABSTRACT
INTRODUCTION
