ABSTRACT
Background
Statins reduce the incidence of cardiovascular events after percutaneous coronary intervention (PCI), but no clinical studies have investigated the role of statins in ischemia‐reperfusion injury after PCI.
Hypothesis
Rosuvastatin could reduce ischemia‐reperfusion injury in patients with acute coronary syndrome treated with PCI.
Objectives
We investigated the effects of rosuvastatin on ischemia‐reperfusion injury in patients with acute coronary syndrome after PCI and evaluated short‐term prognosis.
Methods
Patients scheduled for emergent PCI were given either rosuvastatin for ≥6 months (10 mg/d, every night; n = 55) or no statins (control group; n = 65). Serum superoxide dismutase activity, malondialdehyde, brain natriuretic peptide (BNP), and high‐sensitivity C‐reactive protein (hs‐CRP) were determined before and after PCI, as well as left ventricular ejection fraction and left ventricular end‐diastolic volume. Major adverse cardiac events were observed at follow‐ups for 6 months.
Results
Superoxide dismutase activity in the rosuvastatin‐treated group was higher than that of the control group; serum levels of malondialdehyde were lower. BNP and hs‐CRP levels in the rosuvastatin‐treated group were lower than that of the control group. Four weeks after PCI, the left ventricular ejection fraction in the treatment group was higher than that of the control group, and the left ventricular end‐diastolic volume was lower. At the 6‐month follow‐up, there was no difference in major adverse cardiac events between the 2 groups.
Conclusions
Rosuvastatin before PCI reduced ischemia‐reperfusion injury in patients with acute coronary syndrome, which suggests the importance of application of rosuvastatin before PCI for early intervention.
Introduction
Acute coronary syndrome (ACS), or obstruction of the coronary arteries, is a common cardiovascular emergency. The standard treatment for ACS is percutaneous coronary intervention (PCI), the technology for which has become increasingly proficient in recent years.1, 2 However, coronary ischemia‐reperfusion injury and increased inflammatory responses associated with PCI may lead to conditions that inhibit myocardial function, such as myocardial stunning, reperfusion arrhythmias, myocardial necrosis,3 decreasing left ventricular contractility, and falling ventricular pressure,4, 5 resulting in cardiovascular events that put patients' lives in jeopardy.6 To reduce mortality due to PCI and improve patient prognosis, reperfusion injury must be prevented.
Ischemia‐reperfusion injury activates peripheral blood mononuclear cells and T lymphocytes, which gather and infiltrate into endothelial cells and release a large number of inflammatory mediators, including high‐sensitivity C‐reactive protein (hs‐CRP). Recent studies have shown that PCI treatment exacerbates an inflammatory response, which can promote vascular intimal hyperplasia, thrombosis, and vascular remodeling, triggering a variety of serious cardiovascular events.7
Increasingly, more attention has been focused on the role of B‐type natriuretic peptide (also known as brain natriuretic peptide [BNP]) in ischemia‐reperfusion injury, as BNP levels are correlated with the success rate of PCI surgery, and BNP testing helps guide treatment and assess prognosis. Ischemia and hypoxia‐induced regional myocardial dysfunction is the most important stimulatory factor for BNP secretion.8 In addition, superoxide dismutase (SOD) and malondialdehyde (MDA) are 2 important factors involved in ischemia‐reperfusion injury of the cardio‐cerebrovascular system,9, 10 Therefore, monitoring C‐reactive protein (CRP), BNP, SOD activity, and MDA levels has great value in assessing inflammatory responses and ischemia‐reperfusion injury in ACS patients after PCI.
Studies have shown that statins to treat high cholesterol could reduce the incidence of cardiovascular events after PCI.11, 12, 13 In previous studies, we demonstrated that Xuezhikang (an extract of Chinese red yeast rice whose main ingredient is lovastatin), especially large‐dose Xuezhikang, decreased serum levels of hs‐CRP, matrix metallopeptidase 9, and low‐density lipoprotein cholestero.14 Recent studies have shown that rosuvastatin lowered CRP significantly compared with placebo,15 and atorvastatin could increase SOD activity levels and reduce reactive oxygen species levels, with a protective effect on myocardial cells during ischemia‐reperfusion injury. 16 However, these studies did not investigate changes in SOD, MDA, or hs‐CRP after PCI, nor did they study the levels of BNP, which is an important factor for predicting prognosis after PCI. Moreover, these studies did not analyze the short‐term prognosis of these patients (ie, observing cardiac function with cardiac ultrasound). Therefore, in the current clinical study, we investigated whether rosuvastatin prior to PCI is able to decrease the ischemic‐reperfusion injury and inflammatory response induced by PCI.
Methods
Patients
One hundred twenty consecutive patients (58.5 ± 4.5 years old) who met the diagnostic criteria for ACS17 and who had undergone emergent PCI were recruited for the study. Among these patients, 55 were prescribed rosuvastatin (10 mg every night) for at least 6 months rosuvastatin‐treated group), and 65 patients who never took any statins or other lipid control drugs (control group) before recruitment. Patients with severe infection, trauma, or liver or kidney dysfunction were excluded. Patients with histories of chronic obstructive pulmonary disease, asthma, or other inflammatory diseases were also excluded.
The patients consisted of 58 cases of ST‐segment elevation myocardial infarction, 22 cases of non–ST‐segment elevation myocardial infarction, and 40 cases of unstable angina. The ethics committee of Liuzhou People's Hospital approved the study, and all the patients provided informed written consent.
Study Procedure
All of the patients were enrolled in this study before hospitalization. After hospitalization, all of the patients received at least 300 mg of clopidogrel and 300 mg of aspirin before PCI, and other interventions were performed in accordance with standard treatment guidelines. Physicians who performed the procedure decided the types of balloons and stents implanted during the surgery. After PCI, patients received 75 mg of clopidogrel, 100 mg of aspirin, and statins daily unless there were adverse effects or allergies. There were no significant differences in other interventions, such as calcium antagonists or nitrate esters, between the 2 groups.
Measurement of SOD and MDA
Peripheral blood samples were collected before PCI and at 2 hours, 1 week, and 4 weeks after the surgery. A colorimetric assay kit (Genmed Scientifics. Inc, Arlington, MA, USA) was used to quantitatively determine the MDA levels, and an SOD kit (Dojindo Molecular Technologies, Inc., Kumamoto, Japan) were used to detect the SOD activity levels.
Measurement of CRP and BNP
Peripheral blood samples were collected before PCI and at 2 hours, 1 day, and 3 days after the surgery to determine serum levels of CRP and BNP. Automatic chemistry analyzer system (model: Dimension EXL with LM, Siemens Healthcare Diagnostics, Tokyo, Japan) was used to detect CRP levels, and a chemiluminescence immunoassay was used to determine the BNP concentrations.
Measurement of LVEDV and LVEF
Each patient underwent echocardiography to determine the left ventricular end‐diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) before PCI, and 2 hours, 1 week, and 4 weeks after the surgery.
Incidence of Major Adverse Cardiac Events
After PCI, the 120 patients were followed‐up through telephone or outpatient service for 6 months. The incidence of major adverse cardiac events (MACEs) such as cardiac death, malignant arrhythmias, angina pectoris, or acute myocardial infarction were noted.
Statistical Analyses
Statistical analyses were conducted using SPSS software version 17.0 (IBM, Armonk, NY). Quantitative data are expressed as mean ± standard deviation. The data of the time points before and after PCI in each group were analyzed using a paired sample t test. For comparisons between the 2 groups, an independent samples t test was used. The comparison of the 2 groups was analyzed using 1‐way analysis of variance and then the Wilcoxon signed rank test. P values <0.05 were considered significant.
Results
Basic Characteristics of Patients in the 2 Groups
From January 2012 to February 2013, 120 patients were enrolled in the study and divided into either a rosuvastatin treatment group (10 mg every night for at least 6 months) or a control group (without statin therapy). There were no differences in demographics or clinicopathological features between the 2 groups (P > 0.05; Table 1).
Table 1.
Demographic and Clinicopathological Features of Patients
| Treatment Groups | ||
|---|---|---|
| Rosuvastatin, n = 55 | Control, n = 65 | |
| Male gender | 38 (69.1%) | 45 (69.2%) |
| Age, y | 57.8 ± 6.3 | 59.1 ± 3.2 |
| Smoking | 40 (72.7%) | 46 (70.8%) |
| STEMI | 26 (47.3%) | 32 (49.2%) |
| NSTEMI | 12 (21.8%) | 15 (23.1%) |
| Unstable angina | 16 (29.1%) | 19 (29.2%) |
| Hypertension | 45 (81.8%) | 56 (83.1%) |
| Dyslipidemia | 55 (100.0%) | 65 (100.0%) |
| Chronic obstructive pulmonary disease | 2 (3.6%) | 3 (4.6%) |
| Asthma | 3 (5.5%) | 4 (6.2%) |
| Diabetes | 8 (14.5%) | 11 (16.9%) |
| LVEF | 53.1 ± 3.8% | 56.2 ± 2.9% |
| Previous MI | 1 (1.8%) | 1 (1.5%) |
| Previous PCI | 2 (3.6%) | 2 (3.1%) |
| Angiographic and procedural characteristics | ||
| No. of intervened vessels | ||
| 1 | 33 (60.0%) | 41 (36.1%) |
| 2 | 19 (34.5%) | 21 (32.3%) |
| 3 | 3 (5.5%) | 3 (4.6%) |
| Total stent length, mm | 27.6 ± 3.4 | 28.2 ± 1.8 |
| Total procedure time, min | 75.5 ± 7.5 | 74.0 ± 9.5 |
Abbreviations: LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non–ST‐segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST‐segment elevation myocardial infarction.
Data are presented as number of cases (%) unless stated otherwise.
Serum SOD and MDA Before and After PCI
Blood samples were centrifuged at 300g for 10 minutes, and supernatants were stored at −80°C. SOD activity and MDA levels in blood sera were measured with an SOD kit and colorimetric assay kit, respectively. The SOD activity in the rosuvastatin‐treated group was significantly higher than that of the control group (P < 0.05), whereas the level of serum MDA was lower (P < 0.05; Figure 1).
Figure 1.
Effects of rosuvastatin on serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels after percutaneous coronary intervention (PCI). (A) Effects of rosuvastatin on serum SOD after PCI. There was no significant difference between the 2 groups in SOD activity before PCI. After PCI, SOD activity in the treatment group was significantly higher than that of control group (P < 0.05). (B) Effects of rosuvastatin on serum MDA after PCI. MDA levels were similar between the 2 groups before PCI. After PCI, MDA levels in the treatment group were significantly lower than those of the control group (P < 0.05).
Levels of hs‐CRP and BNP Before and After PCI
Blood samples were treated similarly as mentioned above. Hs‐CRP and BNP levels were measured with the Dimension EXL with LM integrated chemistry system (Siemens Healthcare Diagnostics) and chemiluminescence immunoassay, respectively. The levels of serum BNP and hs‐CRP were lower in the rosuvastatin‐treated group compared with the control group at 2 hours and 3 days after PCI (P < 0.05). However, no difference was found between the 2 groups at 1 week after PCI (P > 0.05; Figure 2).
Figure 2.
Effects of rosuvastatin on serum brain natriuretic peptide (BNP) and high‐sensitivity C‐reactive protein (hs‐CRP) after percutaneous coronary intervention (PCI). Before PCI, there was no difference between the 2 groups with regard to hs‐CRP or BNP. After PCI, BNP and hs‐CRP levels were lower in the rosuvastatin‐treated group compared with the control group at 2 hours and 3 days after PCI (P < 0.05). However, no differences were found between the 2 groups at 1 week after PCI.
LVEDV and LVEF Before and After PCI
Echocardiography was used to detect LVEDV and LVEF values before and after PCI at 2 hours, 1 week, and 4 weeks. No difference was found between the groups at 2 hour and 1 week after PCI. However, LVEF in the rosuvastatin‐treated group at 4 weeks after PCI was significantly higher than that of the control group (P < 0.05). LVEDV of the rosuvastatin‐treated group at 4 weeks after PCI was significantly lower than that of the control group (P < 0.05; Figure 3).
Figure 3.
Effects of rosuvastatin on left ventricular end‐diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) after percutaneous coronary intervention (PCI). (A) Effects of rosuvastatin on LVEDV after PCI. No difference was found between the 2 groups before or after PCI at 2 hours and 1 week. LVEDV of the rosuvastatin‐treated group at 4 weeks after PCI was significantly lower than that of the control group (P < 0.05). (B) Effects of rosuvastatin on LVEF after PCI. No difference was found between the 2 groups before or after PCI at 2 hours and 1 week (P > 0.05). LVEF levels in the treatment group at 4 weeks after PCI were significantly higher than those of the control group (P < 0.05).
Incidence of MACEs During Follow‐Ups
During the 6‐month follow‐up, there was no difference in the rate of MACEs between the rosuvastatin‐treated group (9.1%) and the control group (9.2%; P > 0.05). Specifically, there were no incidences of cardiac death, malignant arrhythmias, or acute myocardial infarction in either group, and the incidence of angina pectoris was similar (rosuvastatin‐treated group: 5 cases, 9.1%; the control group: 6 cases, 9.2%).
Discussion
In this study, by observing serum SOD, MDA, hs‐CRP, and BNP levels before and after PCI, we found that rosuvastatin therapy could reduce ischemia‐reperfusion injury and inflammatory response caused by PCI in ACS patients,. We also found that rosuvastatin improved short‐term prognosis, as shown by a decrease in LVEDV and an increase in LVEF.
Today there is increasing concern regarding coronary ischemia‐reperfusion injury caused by PCI, and an effective drug to decrease ischemia‐reperfusion injury and inhibit inflammatory responses in ACS patients before PCI is needed. Statins not only lower blood lipids, such low‐density lipoproteins, but also decrease levels of inflammatory factors and improve endothelial function.18, 19, 20 A recent clinical study showed, by measurements of the serum levels of SOD activity and MDA, that atorvastatin could reduce free radical levels of oxygen developed during reperfusion.21 Therefore, statins effectively reduce cardiovascular events such as heart failure and malignant arrhythmia.22
The main aim of our study was to investigate the effects of rosuvastatin on ischemia‐reperfusion injury in ACS patients undergoing PCI, and evaluate their short‐term prognosis. SOD is a well‐known scavenger enzyme that protects cells from oxidative stress, and MDA is a marker of lipid peroxidation, which is detrimental to cellular function.4, 23 Our results showed that serum SOD activity was significantly higher, and the level of serum MDA was lower, in patients treated with rosuvastatin. This suggests that rosuvastatin could reduce oxidative stress. In addition, the levels of serum BNP and hs‐CRP were lower in the rosuvastatin‐treated group, indicating that rosuvastatin could inhibit inflammatory responses induced by ischemia‐reperfusion injury.
Ischemia‐reperfusion injury activates the peripheral blood mononuclear cells, accompanied by release of a large amount of inflammatory mediators, which in turn aggravate the local inflammatory response. CRP is a commonly used biomarker of inflammation.24 Previous studies have shown that CRP levels are high in the smooth muscle cells of patients with atherosclerosis, a condition that leads to atherosclerotic plaque formation and rupture, and subsequent ischemia‐reperfusion injury.7 Studies also have shown that PCI treatment exacerbates inflammatory responses, thus facilitating intimal hyperplasia, thrombosis, and vascular remodeling, and eventually a variety of serious cardiovascular events.25 In addition, the most important factor leading to increased secretion of BNP is regional myocardial dysfunction induced by ischemia and hypoxia, myocardial apoptosis and necrosis after myocardial infarction.26, 27 BNP levels have also been shown to not only help physicians evaluate the patient's condition, but also reflect coronary recanalization in the early stage.28, 29, 30 Therefore, BNP is an important factor predicting the success rate of PCI. Preoperative and postoperative BNP assays can guide treatment and assess prognosis of patients undergoing PCI.
Our present study showed that serum levels of BNP and hs‐CRP in patients treated with rosuvastatin were lower than those of patients in the control group at 2 hours and 3 days after PCI, whereas no difference was found 1 week after PCI. Therefore, BNP and hs‐CRP may be short‐term prognostic factors for PCI surgery. We also found that LVEF was significantly higher and LVEDV was significantly lower 4 weeks after PCI in patients taking rosuvastatin for more than 6 months, whereas there was no difference between the 2 groups 2 hours and 1 week after PCI. These results indicate that rosuvastatin therapy before PCI improved the short‐term prognosis of the surgery, which might be assessed by LVEF and LVEDV measurements. Finally, at the 6‐month follow‐up, no differences were found between the 2 groups with regard to the incidences of cardiac death, malignant arrhythmias, angina pectoris, or acute myocardial infarction. A recent study showed that simvastatin and rosuvastatin significantly reduced markers of inflammation and oxidative stress (8‐epiPGF2a, oxLDL, and Lp‐PLA2 activity) in subjects with hypercholesterolemia.30 However, that study did not discuss the effects of statins on SOD and MDA, 2 important markers of oxidative stress.
Conclusion
We found that rosuvastatin could reduce ischemia‐reperfusion injury and inhibit the inflammatory response and elevated BNP levels in ACS patients undergoing PCI. This study provides important support for early intervention before PCI to decrease ischemia‐reperfusion injury after PCI. Future studies with a larger sample size and longer follow‐up will be required to confirm the effects of rosuvastatin in ACS patients undergoing PCI.
The authors have no funding, financial relationships, or conflicts of interest to disclose.
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