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European Journal of Heart Failure 2005 7(7):1099-1104; doi:10.1016/j.ejheart.2005.01.020
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© 2005 European Society of Cardiology

Effects of Atorvastatin on Th polarization in patients with acute myocardial infarction*

Xiang Chenga, Yu-Hua Liaoa,*, Jinying Zhanga, Bin Lia, Hongxia Gea, Jing Yuana, Min Wanga, Baojun Lua, Ying Liua and Yan Chengb

a The Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology Wuhan 430022, China
b The Center for Experimental Therapeutics, University of Pennsylvania School of Medicine 816 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA

* Corresponding author. Tel.: +86 27 85726376; fax: +86 27 85727140. E-mail address: liaoyh27{at}hotmail.com


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: The development of heart failure after acute myocardial infarction (AMI) has been shown to be associated with inflammation, which is positively and negatively regulated by T helper (Th) 1 and Th2 lymphocytes, respectively. Several studies have indicated that statins can improve heart function after AMI.

Aims: To study the effects of atorvastatin on Th polarization in patients with AMI.

Methods: Peripheral blood mononuclear cells were collected from 20 patients with AMI treated with oral atorvastatin (10 mg/d, group AMI-A) and 18 patients with AMI (group AMI-C) who did not receive treatment with statins. Cytokine-producing Th lymphocytes were quantified by 3-color flow cytometry. After in vitro culturing in the presence or absence of atorvastatin (0, 0.3, 1 and 3 µmol/L) for 6 days, cytokine-producing Th lymphocytes were quantified again in AMI-C group.

Results: The ratio of IFN-{gamma}-producing T cells was significantly higher in AMI-C group (17.8%±6.4%) than in the AMI patients treated with oral atorvastatin (AMI-A, 13.1%±4.6%). In vitro culturing with atorvastatin significantly reduced Th1 development in the AMI-C group. There was no significant difference on the frequencies of interleukin (IL)-4-producing T cells between each group.

Conclusions: Atorvastatin can reduce Th1 development but has no effect on Th2 cell-functions in AMI patients. Our findings suggest that atorvastatin can regulate the polarization of Th1/Th2, this may be one of the mechanisms through which atorvastatin improves heart function after AMI.

Key Words: HMG-CoA reductase inhibitor • Acute myocardial infarction • T lymphocyte • helper • Heart failure

Received August 28, 2004; Revised November 14, 2004; Accepted January 27, 2005


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
It is well known that local and global inflammation plays an important role in the development of left ventricular dysfunction and heart failure after acute myocardial infarction (AMI) [1,2]. Maisel et al. [3] adoptively transferred splenocytes of post-MI rats into syngeneic rats and observed organ specific autoimmune myocarditis in recipient rats. In a previous study we reported that transferred splenocytes could not only lead to organ specific autoimmune myocarditis in recipient rats, but also slightly impair left ventricular systolic function [4]. This proved the pathological significance of autoimmune inflammation in the process of heart failure after myocardial infarction.

T lymphocytes play an important role in autoimmune diseases. When they encounter antigen on antigen-presenting cells (APCs), CD4+ T cells develop into at least two distinct T helper (Th) cells: Th1 cells and Th2 cells. In general, Th1 cells secrete proinflammatory cytokines [e.g., interferon (IFN)-{gamma} and interleukin (IL)-2] that promote cellular immunity, while Th2 cells produce anti-inflammatory cytokines (e.g., IL-4 and IL-10) that promote humoral immunity. Th2 cytokines can down-regulate Th1 development and may confer protection from Th1-mediated autoimmune diseases. Athanassopoulos et al. reported that a possible Th1 response in end-stage heart failure [5], indicated that Th imbalance was associated with heart function. In our previous study, we found up-regulation of Th1 cell functions in AMI patients but not in unstable angina (UA) or stable angina (SA) patients at 1 week and 1 month after the onset of symptoms, suggesting that the imbalance of Th1/Th2 cell functions participated in the development of heart failure after AMI [6].

The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have been shown to improve left ventricular remodeling and function after AMI [7–9], but the mechanism is still largely unknown. Many studies have shown that atorvastatin possesses anti-inflammatory properties [10–12]. The aim of this study was therefore to assess the effects of atorvastatin on Th polarization in patients with AMI.


   2. Materials and methods
Top
 Notes
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Reagents
Atorvastatin (Pfizer) was first solubilized in dimethylsulfoxide (DMSO, Sigma) at 600 µM concentration in RPMI 1640 medium (Sigma) with 10% fetal calf serum (FCS, Gibco) and was further diluted to achieve the final concentrations just before use. DSMO never exceeded the toxic concentration of 0.05%. To test the reversibility of the atorvastatin effect, mevalonate (Sigma) was used at a concentration of 100 µM.

2.2. Clinical population
We studied 38 patients with AMI (inclusion criteria: myocardial infarction confirmed by significant rise in creatine kinase MB and troponin I levels and electrocardiograph abnormalities) who underwent diagnostic catheterization (27 men and 11 women, mean age±S.D. 60±9 years). Before AMI, none of the patients were treated with statins. Blood samples were obtained within 24 h after the onset of symptoms, and patients were randomly classified into 2 groups: (1) AMI-A group [14 men and 6 women, mean age 61±8 years, treated with oral atorvastatin (10 mg/d) for 1 week] and (2) AMI-C group (13 men and 5 women, mean age 60±10 years, without statin treatment).

None of the patients were treated with anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs, steroids, etc. None had collagen disease, thromboembolism, disseminated intravascular coagulation, advanced liver disease, renal failure, malignant disease, other inflammatory disease (such as septicemia, pneumonia, etc.), valvular heart disease, atrial fibrillation or was using a pacemaker. The investigation conformed with the principles outlined in the Declaration of Helsinki" (Br Med J 1964;ii:177) and to the approved institutional guidelines. Informed consent was obtained from each patient.

2.3. Cell culture
Blood samples were obtained from AMI-A and AMI-C groups within 24 h (AMI-AB and AMI-CB) and at 1 week after the onset of symptom (AMI-A1 and AMI-C1). In the AMI-C1 group, 10 mL of blood was collected into an evacuated tube containing 0.2 mL of sodium heparin; in the other three groups, 2 mL of blood was collected. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation on Ficoll-Hypaque (Sigma) [13] and used for intracellular cytokine staining. Cells derived from patients in AMI-C1 group were stimulated with plate-bound anti-CD3 Ab (0.2 µg/mL; BD PharMingen) and anti-CD28 Ab (0.5 µg/mL; BD PharMingen) in the presence or absence of atorvastatin (0, 0.3, 1 and 3 µmol/L) and atorvastatin (3 µmol/L)+mevalonate (100 µmol/L). Cultures were maintained in RPMI, with 2 mM L-glutamine, 100 IU/mL penicillin, 100 µg/mL streptomycin, and 10% FCS.

2.4. Intracellular cytokine staining
PBMCs were stimulated at 1x106 cells/mL with 50 ng/mL phorbol myristate acetate (PMA) and 5 µg/mL ionomycin (BD Pharmingen) and with or without 4 µL/mL GolgiStop (BD Pharmingen) for 5 h. Cells were centrifuged after being washed with PBS and adjusted to 5x105 cells per test, then stained with PE-Cy5-labeled anti-human CD4 monoclonal antibody (BD Pharmingen). The fixation and permeabilization of cells were performed with FACSTM Perm 2 (BD) according to the manufacturer's instructions. Intracellular cytokines were stained with FITC-labeled anti-human IFN-{gamma} and PE-labeled anti-human IL-4 monoclonal antibodies (BD Pharmingen). The IFN-{gamma}- and IL-4-producing CD4+ T cells were analyzed with FACSCalibur (BD). Nonspecific staining with the isotype-matched control monoclonal antibody was <1%. After culture for 6 days, cells from group AMI-C1 were recovered by centrifugation, cytokine-producing Th lymphocytes were quantified again.

2.5. Statistical analysis
All data are given as mean±S.D.. The comparisons between 2 groups were made using Student's t test. Probability values <0.05 were considered statistically significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Clinical characteristics of patients with AMI
The baseline clinical characteristics of the AMI-A and AMI-C groups are shown in Table 1. The 2 groups were matched for age, gender, frequency of coronary risk factors, Killip class, location, number of coronary arteries narrowed and medication at baseline.


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  		Table 1 Clinical data of patients with AMI

 
3.2. Assessment of frequencies of IFN-{gamma}-producing and IL-4-producing T cells in the 4 patient groups
Within 24 h after the onset of symptoms, the ratios of IFN-{gamma}-producing T cells were similar between AMI-AB and AMI-CB groups. But 1 week after AMI, the frequency of IFN-{gamma}-producing T cells was significantly lower in AMI-A1 group (13.1%±4.6%) than in AMI-C1 group (17.8%±6.4%, P<0.05). There was no significant difference in the frequencies of IL-4-producing peripheral T cells between each group (Figs. 1 and 2). These data indicate that atorvastatin could effectively suppress Th1 response but had no effect on Th2 response in vivo.


Figure 1
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  		Fig. 1 Representative flow diagrams of experiments. Cytokine-producing T cells of AMI patient within 24 h after the onset of symptoms (A), in AMI-A1 (B) and AMI-C1 (C) group at 1 week after the onset of symptoms.

 


Figure 2
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  		Fig. 2 Cytokine production profiles of CD4+ cells in 4 groups. Proportions of IFN-{gamma}-producing T cells (A) and IL-4-producing T cells (B) in AMI-AB, AMI-CB, AMI-A1 and AMI-C1 groups obtained from flow diagrams. *P<0.05 vs. AMI-C1 group.

 
3.3. Atorvastatin inhibits Th1 response in vitro
To further investigate the therapeutic potential of atorvastatin, we performed parallel studies in which the ability of atorvastatin to regulate the polarization of Th1/Th2 from AMI patients in vitro was evaluated. We found the frequencies of IFN-{gamma}-producing T cells markedly lower in mononuclear cells cultured with atorvastatin (0.3, 1 and 3 µmol/L, 15.2%±2.4%, 14.7%±2.8% and 12.4±3.1%, respectively) than in mononuclear cells cultured without atorvastatin (18.1%±3.7%), while there was no difference on the frequencies of IL-4-producing T cells (Figs. 3 and 4). These data showed that atorvastatin could down-regulate Th1 response in vitro and were consistent with our prior observations in vivo. In atorvastatin (3 µmol/L)+mevalonate (100 µmol/L) group, the frequencies of IFN-{gamma}-producing T cells were significantly higher (17.4%±4.1%) than in the atorvastatin (3 µmol/L) group, indicating that the reduction of Th1 development by atorvastatin could be reversed by mevalonate.


Figure 3
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  		Fig. 3 Changes in frequencies of IFN-{gamma}-producing (A) and IL-4-producing (B) CD4+ T cells from AMI-C1 group after in vitro culture with atorvastain (0, 0.3, 1 and 3 µmol/L).

 


Figure 4
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  		Fig. 4 Effects of atorvastain on cytokine production profiles of CD4+ T cells in vitro. Flow cytometric analysis of intracellular IFN-{gamma} (A) and IL-4 (B) staining of CD4+ T cells cultured with plate-bound anti-CD3 Ab, anti-CD28 Ab, atorvastatin (0, 0.3, 1 and 3 µmol/L) and atorvastatin (3 µmol/L)+mevalonate (100 µmol/L; A+M). *P<0.05 vs. cultured without atorvastatin group; #P<0.05 vs. cultured with atorvastatin (3 µmol/L) group.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
Inflammation is regarded as an important mechanism in the development of heart failure after AMI [1,2]. Following AMI, myocardial necrosis releases or exposes normally sequestered antigenic constituents (such as myosin, actin, etc.) that may cause proliferation of antigen-recognizing T cells. Given the opportunity, these stimulated T lymphocytes might target the heart in an autoimmune response, assisting the development of heart failure. Varda-Bloom et al. [14] co-cultured lymphocytes from AMI rats and neonatal cardiomyocytes, and observed that cytotoxic T lymphocytes (CD8+) were activated following MI and could recognize and kill normal cardiomyocytes in vitro. Maisel et al. [3] and our previous study [4] showed that adoptively transferred splenocytes of post-MI rats could induce organ specific autoimmune myocarditis in recipient rats, suggesting the pathological significance of autoimmune inflammation after myocardial infarction. Another previous study demonstrated that up-regulation of Th1 cell-functions could promote the development of organ specific autoimmune disease such as experimental autoimmune encephalomyelitis [15] while up-regulation of Th2 cell-functions could promote the development of systemic autoimmune disease such as systemic lupus erythematosus [16]. Our previous study showed that the up-regulation of Th1 cell-functions existed in patients with AMI but not in patients with UA or SA 1 week and 1 month after the onset of symptoms, suggesting that imbalance of Th1/Th2 might participate in heart failure process after AMI [6].

It is well known that statins have anti-inflammatory properties [10–12,17,18]. Recently Youssef et al. [19] reported that atorvastatin could reverse paralysis in central nervous system autoimmune disease by promoting a Th2 bias. Aktas et al. [20] showed that atorvastatin could ameliorate relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells. Two other Th1-bias diseases: inflammatory arthritis and glomerular sclerosis have also been improved by statins [21,22]. It has been shown that statins can suppress production of IL-12, which plays a central role in Th1 development [19,20,23]. Atorvastatin has been shown to induce STAT6 phosphorylation and inhibit STAT4 phosphorylation in T cells, and have pleiotropic immunomodulatory effects involving both APC and T-cell compartments [19]. Ortego et al. [24] reported that atorvastatin reduced NF-{kappa}B activity in relation to IP-10 and MCP-1, and Aronica et al. [25] showed that NF-{kappa}B activation was required for type 1 T cell-dependent response in transgenic mice.

It has been shown that statins could improve heart function after AMI [7–9], but the mechanism is still largely unknown. Athanassopoulos et al. reported that the up-regulation of Th1 response was associated with bad heart function [5]. In the present study, we demonstrated that atorvastatin markedly suppressed Th1 response of AMI patients in vivo and in vitro, suggesting that atorvastatin could improve heart function in part through modulation of the imbalance of Th1/Th2 functions after AMI.

HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid during cholesterol synthesis. Atorvastatin can confer its anti-inflammatory effects both dependent on [26] and independent of [27] inhibition of HMG-CoA reductase. In order to clarify whether the reduction of Th1 development here is mediated by the HMG-CoA reductase pathway, we used mevalonate and found that mevalonate could reverse the reduction of Th1 by atorvastatin, providing direct evidence that the anti-inflammatory effects of atorvastatin are mediated by the HMG-CoA reductase pathway.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
* This study was supported by grants from National Natural Science Foundation of China (No. 30370574). Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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