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European Heart Journal Advance Access originally published online on September 29, 2006
European Heart Journal 2006 27(24):2945-2955; doi:10.1093/eurheartj/ehl277
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome

Andreas Link1,*, Tarek Ayadhi1, Michael Böhm1 and Georg Nickenig2

1 Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, D-66421Homburg/Saar, Germany
2 Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, D-53105 Bonn, Germany

Received 18 May 2006; revised 18 August 2006; accepted 11 September 2006; online publish-ahead-of-print 29 September 2006.

* Corresponding author. Tel: +49 6841 16 23372; fax: +49 6841 16 23369. E-mail address: link{at}med-in.uni-saarland.de

See page 2916 for the editorial comment on this article (doi:10.1093/eurheartj/ehl376)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Aims HMG-CoA reductase inhibitors (statins) reduce cardiovascular mortality and morbidity in patients with stable coronary artery disease as well as acute coronary syndrome (ACS). It is unclear how rapidly the beneficial effects of statins occur in patients with ACS and whether these drug properties are related to lipid lowering.

Methods and results Patients with troponin-positive ACS (n=35) were randomized to 20 mg/day rosuvastatin therapy or to placebo treatment. Anti-inflammatory effects of rosuvastatin measured by lymphocyte intracellular cytokine production were taken before initiation of treatment and on days 1, 3, and 42. Compared with placebo, rosuvastatin treatment significantly reduced plasma concentrations of pro-inflammatory cytokines TNF-{alpha} and IFN-{gamma} at 72 h. Rosuvastatin also induced a rapid and significant reduction of TNF-{alpha} and IFN-{gamma} production in stimulated T-lymphocytes at 72 h. When compared with placebo, rosuvastatin inhibited the Th-1-immune response measured at 72 h.

Conclusion Rosuvastatin exerts rapid immunomodulatory effects on the level of T-cell activation in patients with ACS.

Key Words: Acute coronary syndromes • Inflammation • Th-1-immune response • Statins


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgement
 References
 
Acute coronary syndromes (ACSs) are associated with high morbidity and mortality.1–3 The pathological features associated with plaque instability and rupture are caused by inflammatory cell infiltration. Key players in this scenario are monocytes/macrophages and T-lymphocytes producing inflammatory cytokines that in turn stimulate macrophages and decrease the production of extracellular matrix by vascular smooth muscle cells.4–6 In ACSs, Th-1 response that resembles the aggressive and deleterious action of T-lymphocytes producing inflammatory cytokines has been shown to be activated.7

The first evidence of anti-inflammatory properties of HMG-CoA reductase inhibitors (statins) came from a retrospective analysis of the CARE study, showing that statins reduced pro-inflammatory markers.8 Two recent clinical trials (MIRACL9 and PROVE IT-TIMI-2210) have shown that high dose statin therapy reduced cardiovascular events in patients with ACS. Experiments in cultured cells and animals demonstrated that statins exert a wide array of immunomodulatory effects, such as reducing pro-inflammatory cytokines, activation and adhesion of monocytes, and activation and cytotoxicity of T-lymphocytes.11–16

Thus, it would be desirable to treat ACSs not only with drugs interfering with platelets and the coagulation cascade but also those with anti-inflammatory effects. We evaluated possible immunomodulatory effects of rosuvastatin in patients with ACSs in a double-blind, placebo-controlled, randomized prospective trial. To this end, cytokine plasma concentrations and specific intracellular cytokine expression in both monocytes and T-lymphocytes were assessed.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgement
 References
 
Patients
Thirty-five patients with troponin-positive ACSs (NSTEMI or STEMI) not on cholesterol lowering drugs (including lipid-lowering drugs, dietary supplements, or food additives within the last 2 weeks) were randomized in a double-blind, placebo-controlled, monocentric trial for 6 weeks testing rosuvastatin 20 mg or placebo once daily in oral tablet form. Randomization was done according to a defined unknown scheme. The randomization treatment codes were provided in sealed individual subject envelopes. The treatment code must not be broken except during medical emergencies. Primary endpoints were changes of the immune responses such as monocyte and lymphocyte intracellular cytokine expression. Four time points were investigated. After enrolment and randomization before initiating therapy, blood samples were taken for analysis of full clinical chemistry, haematology, and immunological markers (discussed subsequently). After 24 h, 72 h, and 6 weeks, further blood samples for the analysis of clinical chemistry, haematology, and immunological markers were taken. The exclusion criteria comprised any kind of inflammation. A patient flow chart was given (Figure 1).


Figure 2771
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  		Figure 1 Study flow chart for registered and randomized patients with ACS.

 
The study was performed in accordance with the ethical principles in the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained from all patients and the study protocol was approved by the Ethics Committee of the University of Saarland, Germany.

Blood sampling
At each visit, 20 mL of heparinized and 10 mL of EDTA-buffered blood were drawn from a venous canula.

Intracellular cytokine measurement by flow cytometry
Heparinized whole blood samples were stimulated with lipopolysaccharide (LPS) (100 ng/mL LPS, Sigma, Germany) for monocyte cytokine expression, with Staphylococcus aureus enterotoxin B (2.5 µg/mL SEB) in the presence of CD28 (clone Leu-28, BD Pharmingen, Germany) and CD49d (clone 9F10, BD Pharmingen) for CD3-T-lymphocyte cytokine expression, or with phorbol-2-myristate-13-acetate (PMA, Sigma) and ionomycin (Sigma) for CD4-T-cell cytokine expression. Cells were incubated in polypropylene tubes at 37°C for a total of 6 h. During the last 4 h, 10 µg/mL Brefeldin A (Sigma) was added to block extracellular secretion of cytokines. Cell fixation was done with 2 mM EDTA for 15 min for planned measurement of monocyte or lymphocyte cytokine expression or with paraformaldehyde 4% for 5 min for planned measurement of CD4-T-cell cytokine expression. Erythrocytes were lysed for 10 min by using lysing solution (BD Pharmingen), according to the manufacturer's instructions. Cell membranes were reversibly permeabilized with saponine 0.1% (Sigma) in PBS containing 5% milk powder and 0.1% bovine serum albumin (Sigma). Cell surface markers and intracellular cytokines were labelled with mouse anti-human antibodies conjugated to fluorescent dyes at saturating concentrations in permeabilization buffer. For staining the cell surface markers, we used PE-Cy5-labelled anti-CD14 (clone RMO52, Beckmann/Coulter, Germany) for monocytes; PerCP-labelled anti-CD3 (clone SK7, BD Pharmingen) for lymphocytes; and PerCP-labelled anti-CD4 (clone SK3, BD Pharmingen) for the T-helper-cells (Th-cells). For staining the intracellular cytokines, we used for monocyte intracellular cytokines FITC-labelled anti-TNF-{alpha} (clone MAb11, BD Pharmingen) and PE-labelled anti-IL-6 (clone MQ2-13A5, BD Pharmingen); for lymphocyte intracellular cytokines FITC-labelled anti-TNF-{alpha} (clone MAb11, BD Pharmingen) and PE-labelled anti- IFN-{gamma} (clone 4s.B3, BD Pharmingen); and for Th-cells FITC-labelled anti-IFN-{gamma} (clone 4S.B3, BD Pharmingen) and PE-labelled anti-IL4 (clone 8D4-8, BD Pharmingen). After 45 min of incubation at 4°C, cells were washed three times in permeabilization buffer and twice in FACS buffer. Subsequently, stained antigens were fixed with 1% paraformaldehyde. Measurements were performed on a Becton Dickinson FACScan flow cytometer and the Cellquest software system. Normal ranges of the per cent of cytokine positive producing T-cells and monocytes are given in Table 1.


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  		Table 1 Measured parameters were presented as absolute amounts (described as median and value of the 25th and 75th percentiles) and per cent changes from baseline

 
Intraplasmatic cytokine measurement by cytometric bead array
To measure intraplasmatic cytokines, serum samples were separated from EDTA whole blood. According to the manufacturer's instructions, we used the Cytometric Bead Array System (CBA, Becton Dickinson, Heidelberg, Germany) for quantitative measurement of the following cytokines by flow cytometry: IL-6; TNF-{alpha}; IFN-{gamma}; IL-4; and IL-10. Measurements were performed on a Becton Dickinson FACScan flow cytometer and the BD-CBA software system. The detection limits of the cytokine assays were measured by 0.5 pg/mL. Normal ranges of the levels of intraplasmatic cytokines are given in Table 1.

Statistical methods
The size of the trial population has been calculated to the null hypothesis that rosuvastatin and placebo therapy were not different for the primary endpoints (immunological markers). A sample size of 17 patients in each group had a power of 80% to detect an effect size of 1.00 SD using a two-group t-test with a 0.05 two-sided significant level.

For all immunological markers and lipid data, the following statistical parameters were calculated: median, the value of the 25th and 75th percentile, and the percentage of change from baseline to 24 h, 72 h, or 42 days. All immunological parameters and lipid data were normally distributed, tested by the analysis of variance. The type I error rate was fixed as {alpha}=0.05 (two-sided; 95% confidence limit). Differences were considered significant if P<0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgement
 References
 
Patient baseline characteristics
Thirty-five patients with troponin-positive ACS (NSTEMI or STEMI) and angiographically documented coronary artery disease were randomized to receive rosuvastatin 20 mg/day (n=18) or placebo (n=17). The groups were well matched with respect to age [rosuvastatin group 55.5 (48.0–69.0) vs. placebo group 60.0 (51.0–69.5) years], gender, infarction size measured by the maximum of creatine kinase 872 (180.8–2837.5) vs. 787 (320.8–1478.0) U/L, and the use of additional standard infarction therapy (Table 2).


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  		Table 2 Baseline characteristics of both treatment groups: age, gender, lipid profile, infarction size, and concomitant therapy

 
Lipid profile
The baseline lipid levels in both groups were equivalent for total cholesterol 201 (178.0–235.0) vs. 208 (190.0–219.0) mg/L, LDL cholesterol 134 (103.9–143.8) vs. 134 (115.3–144.4) mg/L, HDL cholesterol 43 (38.9–46.9) vs. 39 (33.7–47.3) mg/L, and triglycerides 118 (90.0–177.0) vs. 143 (121.2–211.8) mg/L. Rosuvastatin decreased total cholesterol significantly more than placebo at 72 h (rosuvastatin: –16% vs. placebo: +8%, P=0.0008) and after 6 weeks (rosuvastatin: –26% vs. placebo: +15%, P=0.0001). LDL cholesterol was reduced by 16% at 72 h and by 49% after 6 weeks of statin treatment (both P<0.0002 vs. placebo). There was no significant treatment effect at 24 h for any of the lipids (Table 1).

Cytokine plasma concentrations and C-reactive protein
In all patients, the baseline levels of the pro-inflammatory cytokines IFN-{gamma}, TNF-{alpha}, and IL-6 were above the normal ranges. Although there were no differences in baseline characteristics and severity of the ACSs between the treatment groups, by chance the median baseline levels of the pro-inflammatory cytokines IFN-{gamma}, TNF-{alpha}, and IL-6 were greater in the rosuvastatin group than in the placebo group at baseline: IFN-{gamma} (rosuvastatin: 124 pg/L vs. placebo: 67 pg/L), TNF-{alpha} (rosuvastatin: 4 pg/L vs. placebo: 2 pg/L), and IL-6 (rosuvastatin: 36 pg/L vs. placebo: 19 pg/L). Rosuvastatin reduced IFN-{gamma} (Figure 1; Table 1), TNF-{alpha} (Figure 2; Table 1), and IL-6 (Table 1) significantly more than placebo at 72 h. These reductions were sustained for up to 6 weeks. We found no rapid effect of rosuvastatin on C-reactive protein. Plasma concentrations of the anti-inflammatory cytokines IL-4 and IL-10 remained unaltered (Table 1).


Figure 2772
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  		Figure 2 Relative changes to baseline of the pro-inflammatory cytokine interferon-{gamma} (IFN-{gamma}) during a therapy with rosuvastatin or placebo over 42 days. In order to examine the values of significance, individual patient data separated in a placebo or rosuvastatin group are shown before therapy and at days 1, 3, and 42.

 
Changes in the inducible intracellular monocyte cytokine expression
Monocyte activity was measured after LPS stimulation in vitro. The inducible intracellular cytokine expression of IL-6 and TNF-{alpha} in monocytes was measured by immunofluorescent staining and flow cytometry. Baseline data showed no differences in median values of the inducible production of IL-6 or TNF-{alpha} in monocytes in the rosuvastatin group or in the placebo group. Furthermore, no significant modulation during the experimental time course by placebo or rosuvastatin was observed (Table 1).

Changes in the inducible intracellular T-lymphocyte cytokine expression
T-lymphocyte cytokine expression was induced by two different methods of activation: first, activation of T-cells by superantigen (S. enterotoxin B, SEB) mediated cross-linking of T-cell receptor and major histocompatibility complex-II-receptor and secondly, activation of T-cells by PMA/ionomycin inducing different intracellular transcription factors. Baseline SEB stimulation induced IFN-{gamma} production in 5% (2.6–11.7) of CD3-T-cells in the rosuvastatin group and 3% (2.5–5.4) in the placebo group. During rosuvastatin treatment, there was a significant and rapid decrease of lymphocytes able to produce IFN-{gamma} –33% at 72 h (P=0.0079 vs. placebo) (Figure 4; Table 1). We found similar data with a significant decrease of the SEB-induced TNF-{alpha} production in CD3-T-cells in the rosuvastatin group (rosuvastatin: –38% and placebo: +7%; P=0.0008) (Figure 5, Table 1).


Figure 2774
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  		Figure 4 Relative changes to baseline of the inducible intracellular lymphocyte cytokine expression during therapy with rosuvastatin or placebo over 42 days. After superantigen (S. enterotoxin B, SEB) stimulation, the inducible intracellular cytokine expression of interferon-{gamma} (IFN-{gamma}) was measured in lymphoyctes. In order to examine the values of significance, individual patient data separated in a placebo or rosuvastatin group are shown before therapy and at days 1, 3, and 42.

 

Figure 2775
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  		Figure 5 Relative changes to baseline of the inducible intracellular lymphocyte cytokine expression during therapy with rosuvastatin or placebo over 42 days. After superantigen (S. enterotoxin B, SEB) stimulation, the inducible intracellular cytokine expression of tumour necrosis factor-{alpha} (TNF-{alpha}) was measured in lymphoyctes. In order to examine the values of significance, individual patient data separated in a placebo or rosuvastatin group are shown before therapy and at days 1, 3, and 42.

 
Baseline frequency of IFN-{gamma} production in CD4-T-cells was of no significant difference: 34% (23.9–48.6) in the rosuvastatin group and 24% (20.9–37.3) in the placebo group. In the statin group, there was also a significant decrease of lymphocytes able to produce IFN-{gamma} at 72 h (rosuvastatin: –44% vs. placebo: –2%; P=0.0318) (Th-1 immune response) (Figure 6; Table 1). This effect was sustained for up to 42 days. PMA/ionomycin induced IL-4 production in 3–4% of CD4-positive T-cells (Th-2 immune response) before treatment (Figure 7). Within the statin group, the Th2-immune response declined significant at 72 h (rosuvastatin: –77% vs. placebo: +6%; P=0.0397) (Th-2 immune response) (Figure 7; Table 1).


Figure 2776
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  		Figure 6 Relative changes to baseline of the inducible intracellular cytokine expression in T-helper-cells (Th-cells) during therapy with rosuvastatin or placebo over 42 days. After PMA/ionomycin stimulation, the inducible intracellular cytokine expression of interferon-{gamma} (IFN-{gamma}) and Th-1 immune response was measured. In order to examine the values of significance, individual patient data separated in a placebo or rosuvastatin group are shown before therapy and at days 1, 3, and 42.

 

Figure 2777
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  		Figure 7 Relative changes to baseline of the inducible intracellular cytokine expression in T-helper-cells (Th-cells) during therapy with rosuvastatin or placebo over 42 days. After PMA/ionomycin stimulation, the inducible intracellular cytokine expression of interleukin-4 (IL-4) and Th-2 immune response was measured. In order to examine the values of significance, individual patient data separated in a placebo or rosuvastatin group are shown before therapy and at days 1, 3, and 42.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgement
 References
 
The lipid-lowering properties of statins have been suggested as the main reason for the reduction of morbidity and mortality rates.17–20 However, in addition, multiple investigations have indicated the possibility that statins may evoke beneficial effects via LDL cholesterol-independent mechanisms. By blocking the HMG-CoA reductase, not only cholesterol biosynthesis but also numerous additional intermediates are diminished. These factors, such as geranylgeranylpyrophosphate, are involved in a wide array of cellular events which makes it conceivable that statins exert additional effects beyond cholesterol reduction.21 Many of these investigations concentrated on the effect of statins on vascular cells, as atherosclerosis predominately takes place in the vessel wall.22–24 In addition, it is well established that atherosclerosis resembles a systemic inflammatory disease.1 Therefore, findings of diverse immunomodulatory effects of statins on circulating monocytes and lymphocytes have been of special interest.12,13 These drugs exert versatile changes in inflammatory cells such as reduction of cytokines and adhesion molecules.25 Most of these results were derived from studies on isolated cells and animal models.

In agreement with this, statins were found to suppress global inflammatory markers such as high sensitive C-reactive protein and cytokines in various types of patients.26,27 In contrast to these larger studies, our patients have no significant difference in C-reactive protein values between placebo and rosuvastatin groups. This might be due to the observation that in our patients, only mild elevations in C-reactive protein could be detected. Nevertheless, these studies were not able to distinguish anti-inflammatory effects on the basis of the vascular healing from direct impact of statins on circulating white blood cells. More mechanistic insight came from studies demonstrating that statins alter the immunity by reducing the Th-1 response in animals with experimental autoimmune myocarditis,28 in patients with chronic graft vs. host disease,29 and in patients with ACSs.30 However, these small-scale studies were not able to differentiate putative acute effects and were, therefore, not designed to point at potentially lipid independent effects.

Patients with ACS are at very high risk of immediate cardiovascular complications. Pathophysiologically, this is based on an inflammatory distress which causes plaque rupture and ultimately vessel occlusion, indicating that these individuals are candidates for an instant immunomodulatory treatment.

The data presented herein suggest that rosuvastatin treatment is accompanied by a rapid anti-inflammatory effect at 72 h in patients with ACS. This is evidenced by the reduction of the circulating pro-inflammatory cytokines IL-6, TNF-{alpha}, and IFN-{gamma}. Most inflammatory cytokines are derived from either vascular cells, monocytes, or lymphocytes. In order to provide more mechanistic insight, inducible cytokine expression was assessed in monocytes and lymphocytes. Whereas rosuvastatin showed no significant effect on monocytes, TNF-{alpha} and IFN-{gamma} expression was profoundly reduced in lymphocytes, indicating that statins predominately target the adaptive immune response in patients with ACS. In agreement with these data, Th-1 response evidenced as IFN-{gamma} expression in T-helper cells was reduced, whereas there was no effect on anti-inflammatory cytokines such as IL-4 or IL-10, shifting the immune system to a less aggressive state.

In most patients, the inflammatory markers (TNF-{alpha} and IFN-{gamma} as well as inducible TNF-{alpha} and IFN-{gamma} expression in lymphocytes) showed a rapid suppression 24 h after initiation of rosuvastatin therapy. However, different kinetics of inflammatory suppression could be observed in individual patients at that point of time, making it difficult to interpret the 24 h data. However at 72 h, all patients showed a similar depression of inflammatory parameters in contrast to the placebo-treated patients. Therefore, the interval of 72 h was considered to be the time when inflammatory depression was clearly evident.

It is reasonable to suggest that these anti-inflammatory properties confer clinical benefit. Interventional trials such as MIRACL and PROVE-IT-TIMI-22 demonstrated that patients with ACS benefit from statin treatment.9,10 However, it is not known whether this is due to lipid lowering or the so-called pleiotropic, lipid-independent effects of HMG-CoA reductase inhibitors. Of note, the anti-inflammatory effects of rosuvastatin appeared at 72 h and the magnitude of anti-inflammation was not appreciably increased over the 6 weeks observation period.

The present study shows for the first time in patients with ACS that statins inhibit T-cell immune response by downregulation of pro-inflammatory intracellular cytokines and suppressing Th-1-immune response, thereby targeting adaptive immunity of T-lymphocytes rather than monocytes. These effects appear rapidly at 72 h. Function and cytokine expression of circulatory monocytes were not depressed by rosuvastatin. This part of the innate immunity was not modulated by our rosuvastatin patients. This defence mechanism is always present, ready to recognize, and eliminates microbes. In contrast, activated marcophages are able to be modulated by statins. Statins diminish the pro-inflammatory activity of activated macrophage, their endothelial adhesion, and ability to bind to the vessel wall but not of monocytes.

These data suggest that in patients with ACSs, statins rapidly inhibit the activity of Th-1 response independently of the present plasma lipid levels. Thus, clinical studies are necessary to evaluate the cardiovascular outcome by rapidly suppressing the Th-1-immune response in patients with ACS by statins.


Figure 2773
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  		Figure 3 Relative changes to baseline of the pro-inflammatory cytokine tumour necrosis factor-{alpha} (TNF-{alpha}) during therapy with rosuvastatin or placebo over 42 days. In order to examine the values of significance, individual patient data separated in a placebo or rosuvastatin group are shown before therapy and at days 1, 3, and 42.

 


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
References
 
The study was supported by the Deutsche Forschungsgemeinschaft and an unrestricted grant of AstraZeneca.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 

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