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Technical Briefs |
1 Department of Cardiology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China;
aaddress correspondence to this author at: Department of Cardiology, the Second Xiangya Hospital, Central South University, Changsha, 410011, China; fax 86-731-4895989, e-mail lij8898{at}medmail.com.cn
Primary and secondary prevention with cholesterol-lowering therapy, especially statins, decreases the morbidity and mortality of coronary heart disease (1). These drugs were designed to be antiatherosclerotic by affecting lipid metabolism. Recently, statins were reported to have other antiatherosclerotic effects, including endothelial function improvement and an antiinflammatory effect (2)(3)(4)(5), that may play a role in determining atherosclerotic plaque stability. Because measured serum lipids changed significantly in these studies, the antiinflammatory effects of statins could have been secondary to changes in plasma lipids. Few studies have addressed this issue with doses of statins that do not affect plasma lipids in a short time in humans. In addition, there is limited evidence on the value of early introduction of statin therapy after acute myocardial infarction. We studied the effect of a low dose of statin on inflammatory markers in patients with acute myocardial infarction in the first 3 days of treatment before changes in serum lipids could be detected. For this study, we selected pravastatin, which is thought to have a strong antiinflammatory action (6).
The present study was designed as an open-label, randomized, parallel-group study in which two treatments, pravastatin (pravastatin group) and conventional (control group) treatment, were compared. Patients randomized for pravastatin received a daily dose of 40 mg and routine treatment of acute myocardial infarction. Conventional treatment consisted of the same routine treatment but without cholesterol-lowering drugs. Routine treatment included nitrates, ß-blockers, calcium antagonists, aspirin, angiotensin-converting enzyme inhibitor, and low-molecular-weight heparin. A total of 48 patients with acute myocardial infarction were recruited from the inpatients of the Department of Cardiology in our hospital. The mean (SD) time from patients’ onset of chest pain to admission was 10.4 (6.8) h, and the time from onset to enrollment was 18.2 (7.1) h. Patients were randomized in a double-blind fashion to pravastatin (40 mg daily; n = 23, 17 men) or control (n = 23; 18 men) for 72 h. Twelve patients in the pravastatin group and 13 in the control group received emergency percutaneous coronary intervention and venous thrombolysis before randomization. We excluded 11 patients [5 in the pravastatin group (3 men) and 6 in the control group (4 men)] because of angiography or percutaneous coronary intervention during the first 3 days after enrollment.
Patients were admitted to the coronary care unit of Xiangya Second Hospital with a diagnosis of acute myocardial infarction. According to the WHO definition, the diagnosis of acute myocardial infarction was based on the presence of at least two of the following three criteria: (a) a clinical history of ischemic type chest discomfort (lasting >30 min) that failed to respond to sublingual nitrates; (b) typical changes on serially obtained electrocardiographic tracings; (c) an increase in serum cardiac markers such as creatine kinase-MB and cardiac-specific troponin T or I. Exclusion criteria were the presence of acute or chronic liver function damage and renal failure with serum creatinine >200 mmol/L, severe infection, fever, malignancy, peripheral obliterated vessel disease, connective disease, and administration of lipid-lowering agents and nonsteroidal antiinflammatory drugs in the preceding 8 weeks. Most of the patients (33 of 35; 91%) were diagnosed with ST-elevation myocardial infarction.
Randomization in the study was done on admission to the critical care unit and was continued for 72 h. We measured serum matrix metalloproteinase-9 (MMP-9), soluble CD 40 (sCD40), and C-reactive protein (CRP) as well as lipid profiles, liver and kidney function, and cardiac enzymes (creatine kinase and creatine kinase-MB), in the fasting state, at randomization and after 72 h of therapy. All venous blood samples were drawn into pyrogen-free blood collection tubes without additive. The serum was collected after centrifugation for 3 min and then stored at –70 °C until analyzed. The study protocol was approved by the Research and Ethics committees of the Xiangya Medical College, and written informed consent was obtained before inclusion in the study.
The sCD40L concentration was determined by enzyme-linked immunosorbent assay (detection limit, 0.095 µg/L; Bender Medsystems) according to the manufacturer’s instructions. MMP-9 concentrations were measured by the quantitative ELISA technique (Human MMP-9 Quantikine ELISA Kit; prod. no. DMP900; R & D System). CRP was measured by turbidimetric immunoassay (Beckman Coulter) on an Array 360 automated system (Beckman Coulter). For sCD40L, MMP-9, and CRP, the intra- and interassay imprecisions (CVs) were <5% and 10%, respectively (7)(8). Total cholesterol (TC) and triglycerides (TGs) were measured on a Hitachi 747 (Boehringer Mannheim). Serum HDL-cholesterol (HDL-C) was determined after fractional precipitation using dextran sulfate–MgCl2. The LDL-cholesterol (LDL-C) concentration was calculated by the Friedewald formula. Serum glucose was measured by the glucose oxidase method.
Data are presented as the mean (SD) unless otherwise stated. Baseline clinical characteristics of the two groups were compared by use of the 
2 test for noncontinuous variables and by two-tailed, unpaired t-test for continuous variables. Variations in serum lipids measured at randomization and after 72 h were evaluated by one-way ANOVA followed by the Bonferroni post hoc test where appropriate. The Mann–Whitey U-test was used for nonnormally distributed data. We used Pearson correlation coefficient. A two-tailed P value <0.05 was considered statistically significant. All statistical analyses were performed with SPSS 10.0 software.
There were no significant differences in baseline characteristics between the two treatment groups (Table 1 in the Data Supplement that accompanies the online version of this Technical Brief at http://www.clinchem.org/content/vol50/issue9/). The measured serum lipids (TGs, TC, LDL-C, and HDL-C) did not change significantly at 72 h in either the control or the pravastatin group (Table 1
).
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At randomization, the concentrations of serum sCD40L, MMP-9, and CRP were similar in both groups (Fig. 1
). In the control group, changes in sCD40L (–19%), MMP-9 (–21%), and CRP (+7.9%) were not statistically significant. In the pravastatin group, sCD40L, MMP-9, and CRP decreased by 38%, 48%, and 33%, respectively, after therapy (P = 0.014, 0.008, and 0.019, respectively, for individual patient results; see Fig. 1
of the online Data Supplement for a statistical summary). No significant correlations were detected between the decreases in sCD40L or MMP-9 and TC [r = 0.09 (P = 0.57) and r = 0.15 (P = 0.38), respectively] or LDL-C [r = 0.08 (P = 0.87) and r = –0.03 (P = 0.83), respectively].
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The present study shows that 3 days of pravastatin therapy rapidly initiated after acute myocardial infarction significantly decreased serum sCD40L, MMP-9, and CRP without significant changes in lipid profiles during the 3 days. Although statin treatment in humans has been reported to decrease serum sCD40L (3)(9), CRP (5)(10)(11), and MMP-9 (2)(12) in as little as 2 weeks, a short-term effect independent of plasma lipid concentrations, such as that in the present study, has not been reported previously.
Soluble CD40L has biological effects on many cell types (13). Increased sCD40L concentrations in patients with acute coronary heart syndrome may reflect important pathogenic aspects in those patients. The interaction of CD40L and CD40 may be involved in the diverse pathogenic processes of acute coronary syndrome (14), which is characterized by plaque rupture and superimposed thrombosis. MMPs can weaken the fibrous skeleton of the plaque, rendering it susceptible to rupture. Interestingly, CD40L colocalized with MMPs at sites of collagenolysis within human atheroma in situ, supporting a role for CD40 signaling in plaque rupture (15).
Early statin therapy may be beneficial for patients with acute myocardial infarctions. Our previous study showed that patients with acute coronary syndrome tended to have higher sCD40L concentrations than patients with stable angina (7). This study shows that short-term pravastatin therapy decreases serum sCD40L and MMP-9 concentrations in patients with acute myocardial infarction, suggesting that early pravastatin therapy decreases the immunologic response. These effects may suppress inflammation and stabilize atherosclerotic plaques. Furthermore, Taku et al. (16) reported that statin improved endothelial function in diabetic patients within 3 days, and Correia et al. (17) also reported that short-term atorvastatin therapy inhibits inflammation in patients with acute coronary syndromes. Moreover, pravastatin significantly decreased CRP concentrations in our study and in others (7)(8)(17), suggesting that short-term statin therapy may inhibit inflammation in patients with acute myocardial infarction.
These studies support the concept that pravastatin has direct antiinflammatory effects independent of changes in lipids. After acute myocardial infarction, changes in lipids may be associated with inhibition of lipoprotein lipase activity by cytokines and acute-phase reactants (18). In the pravastatin group in our study, the changes in the lipid profile were similar to those in the control group, and there were no significant differences between groups at randomization or after 3 days of therapy. Moreover, we found no significant correlations between the decreases in TC and LDL-C and decreases in sCD40L and MMP-9. Antiinflammatory effects of statins maybe caused by blocking of the production of isoprenoid intermediates such as farnesyl or geranylgeranyl pyrophosphates, which are important in modifying small G-proteins, among other biochemical effects (19)(20). The limitations of our study include its small sample size, the inability to perform multivariable analysis to exclude confounders, and the need for confirmation in a larger study.
In conclusion, in patients with acute myocardial infarction, 3 days of early treatment with pravastatin may suppress the inflammatory response without changing the lipid profile. These results suggest that early statin therapy is beneficial for patients with acute myocardial infarction even before changes in serum lipids can be detected.
References
The following articles in journals at HighWire Press have cited this article:
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  C. Antoniades, C. Bakogiannis, D. Tousoulis, A. S. Antonopoulos, and C. Stefanadis The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J. Am. Coll. Cardiol., August 18, 2009; 54(8): 669 - 677. [Abstract] [Full Text] [PDF]
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