Clinical and Population Studies

Simvastatin Reduces Myocardial Injury Undergoing Noncoronary Artery Cardiac Surgery

A Randomized Controlled Trial

Mohammed Ahmed Saad Almansob, Bo Xu, Li Zhou, Xiao-Xia Hu, Wen Chen, Feng-Jun Chang, Hong-Bo Ci, Jian-Ping Yao, Ying-Qi Xu, Feng-Juan Yao, Dong-Hong Liu, Wen-Bo Zhang, Bai-Yun Tang, Zhi-Ping Wang, Jing-Song Ou
https://doi.org/10.1161/ATVBAHA.112.252098
Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:2304-2313
Originally published August 15, 2012

Jump to

Abstract

Objective—Myocardial injury during cardiac surgery is a major cause of perioperative morbidity and mortality. We determined whether perioperative statin therapy is cardioprotective in patients undergoing noncoronary artery cardiac surgery and the potential mechanisms.

Methods and Results—One hundred fifty-one patients undergoing noncoronary artery cardiac surgery were randomly assigned to either a statin group (n=77) or a control group (n=74). Simvastatin (20 mg) was administered preoperatively and postoperatively. Plasma were analyzed for troponin T, isoenzyme of creatine kinase, C-reaction protein, interleukin-6, interleukin-8, creatinine, and blood urea nitrogen. Cardiac echocardiography was performed. Endothelial nitric oxide synthase (eNOS), Akt, p38, heat shock protein 90, caveolin-1, and nitric oxide (NO) in the heart were detected. Simvastatin significantly reduced plasma troponin T, isoenzyme of creatine kinase, C-reaction protein, blood urea nitrogen , creatinine, interleukin-6, interleukin-8, and the requirement of inotropic postoperatively. Simvastatin increased NO production, the expression of eNOS and phosphorylation at serine1177, phosphorylation of Akt, expression of heat shock protein 90, heat shock protein 90 association with eNOS and decreased eNOS phosphorylation at threonine 495, phosphorylation of p38, and expression of caveolin-1. Simvastatin also improved cardiac function postoperatively.

Conclusion—Perioperative statin therapy can improve cardiac function and renal function by reducing myocardial injury and inflammatory response through activating Akt-eNOS and attenuating p38 signaling pathways in patients undergoing noncoronary artery cardiac surgery.

Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01178710.

Introduction

Despite the advances in cardiopulmonary bypass (CPB) technology and myocardial protection techniques, morbidity and mortality remain high in patients with poor preoperative cardiac function, long surgical times, complicated surgical procedures, or incomplete correction of the anatomic malformation. Myocardial injury during cardiac surgery is the primary contributor to these high mortality and morbidity rates. It is, therefore, necessary to search for approaches to reduce myocardial injury during cardiac surgery.

Statins are well known for their ability to decrease hyperlipidemia and are used in the prevention and treatment of coronary artery disease.1,2 In addition to lowering hyperlipidemia, statins also exert other pleiotropic effects, such as improving endothelial dysfunction, increasing nitric oxide (NO) bioavailability, enhancing antioxidant effects and strengthening anti-inflammatory properties.3 These properties of statins suggest that these drugs have the potential ability to attenuate myocardial injury in patients undergoing cardiac surgery with CPB.

Some retrospective studies have shown that perioperative statin therapy reduced myocardial injury, morbidity, and mortality in patients undergoing both coronary artery bypass grafting and valvular heart surgery.4,5 Statin decreased mortality in patients undergoing cardiac surgery even in the face of normal cholesterol levels, suggesting that the cardiac protective effect of statins may be independent of their ability to reduce lipid levels.6 In contrast, another large retrospective study reported that preoperative statin use was not associated with a reduction of in-hospital mortality or major morbidity after cardiac surgery.7 Some small, prospective, randomized studies demonstrated that statins reduced myocardial injury; however, all of those studies were performed in patients undergoing coronary artery bypass grafting.8 Because patients with coronary artery disease may also benefit from statin’s ability to lower hyperlipidemia, it is difficult to confirm that statins really reduce myocardial injury in patients undergoing cardiac surgery with CPB. In addition, although several reports showed that statins decreased the systemic inflammatory response during CPB,9 Florens et al10 reported that acute preoperative statin therapy failed to limit the inflammatory response to CPB in a small randomized trial. Those results prompted the study’s authors to indicate that whether statins protect myocardium during cardiac surgery with CPB remains unclear. The purpose of this single-blinded, randomized, controlled trial was to determine whether statins had cardioprotective effects in patients undergoing cardiac surgery with CPB independent of their ability to reduce lipid levels.

Patients and Methods

Patients, Randomization, and Masking

Patients referred for elective noncoronary artery cardiac surgery between September 2010 and June 2011 were recruited. Patients with coronary artery disease, contraindications to statins treatment, and women who were gestating or lactating were excluded. Patients <10 years of age were also excluded because it is unknown whether statins are safe for these young patients. Patients with noncyanotic congenital heart disease without pulmonary hypertension were also excluded because these patients can be safely treated with current CPB and myocardial protective techniques. One hundred fifty-one patients were eligible and were randomly assigned to either the statin group (n=77) or control group (n=74) by a random number produced by a computer. Simvastatin (20 mg) was administered every day for the 5 to 7 days preoperatively, but not on the day of surgery in the statin group. Then simvastatin was readministered on the second day postoperatively. The control group was administered all of the same routine medications as the statin group, such as digoxin, furosemide, but without statin therapy. The patients, surgeons, anesthetists, perfusionists, ultrasound physicians, the individuals collecting the samples, and people performing data analysis were all blinded. This randomized controlled trial was approved by The First Affiliated Hospital, Sun Yat-sen University Ethics Review Board. Informed consent was obtained from all patients enrolled in this trial and the procedures followed were in accordance with institutional guidelines. The trial profile has been summarized in Figure 1.

Figure 1.
Figure 1.

Trial profile. One hundred fifty-one patients were randomly assigned to either the control or statin group. In total, 132 patients completed the trial. TVP indicates tricuspid valvuloplasty; MVP, mitral valvuloplasty; MVR, mitral valve replacement; CBP, cardiopulmonary bypass; SAM, systolic anterior motion.

Blood Analysis

All patients included in the study underwent routine preoperative examinations. Additionally, plasma troponin-T (TnT) and the isoenzyme of creatine kinase (CKMB) levels were measured preoperatively and at 6, 12, 24, and 72 hours postoperatively via electrochemiluminescence technology (Roche Diagnostics GmbH, Mannheim, Germany). C-reaction protein (CRP), blood urea nitrogen (BUN), and serum creatinine were measured preoperatively and at 24, 48, 72 hours and 7 days postoperatively via turbidimetry technology (Orion Diagnostica, Espoo, Finland), speed enzyme coupling method (Biosino Biotechnology and Science Inc, Beijing, China) and enzymatic method (Sekisui Medical Co Ltd, Tokyo, Japan), respectively. Serum interleukin (IL)-6 and IL-8 were assayed preoperatively and 6 hours postoperatively by commercially available enzyme–linked immunosorbent assay kits (Multisciences, Shanghai, China) and (eBioscience, San Diego, CA), respectively, according to the manufacturer’s instructions.

Surgical Procedures

Operative and anesthetic techniques were standardized in both groups. All surgical procedures were performed by the same group of surgeons. The anesthesia was similar for both groups. Intraoperative myocardial protection techniques were standardized in both groups, using the same cardioplegic solution (hyperkalemic blood cardioplegia). Heart biopsies were taken in the right atrial appendage before cross-clamping the aorta, at 10 minutes after removal of the cross-clamp when finishing the major surgical procedures in the heart. At the end of surgery, patients were transferred to the intensive care unit where a standardized protocol was followed. Patients were then transferred to a ward until discharged from the hospital.

Cardiac Function Measurement

Cardiac echocardiography was performed in patients preoperatively and again 7 days and 1 month postoperatively.

Nitric Oxide Measurement

Frozen right atrial appendages from −80°C were pulverized and homogenized for NO measurement. NO was determined spectrophotometrically by measuring total nitrate plus nitrite (NO3− + NO2−) with a NO detection kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China) according to the manufacturer’s instructions using Griess reagent at an absorbance of 550 nm, as previously described.11 Results were expressed as μmol/g protein.

Western Analysis

Western analysis and protein association in the heart (right atrial appendage) were performed using standard protocol, as previously described.11 Anti-eNOS and anti–heat shock protein 90 (Hsp90) were from Santa Cruz Biotechnology(Santa Cruz, CA). Anti–Ser1177-phospho-eNOS (P-eNOS S1177), anti–Thr495-phospho-eNOS (T495), anti-AKT, anti–Thr308-phopho-AKT (P-Akt), and Anti-P38, and phosphorylation of P38 and anti–caveolin-1 were from Cell Signaling Technology(Danvers, MA). Anti-GAPDH was from Proteintech Group (Chicago, IL). eNOS was immunoprecipitated with H-32 antibody (Enzo Life Sciences, Farmingdale, NY) or with anti-eNOS (BD Biosciences, San Jose, CA). Proteins were visualized using a Western blotting luminol reagent (Santa Cruz Biotechnology).

Statistical Methods

Data were presented as means, SD, and IQR. Comparisons between treatment groups were made with the unpaired Student t test or repeated measures ANOVA where appropriate. Categorical data were expressed as frequency and percentage and compared with the Fisher exact test where appropriate. The total area under the curve was calculated using the trapezoidal method for each patient and compared using the t test. Estimations were presented with 95% CIs. A value of P<0.05 was regarded as significant. All statistical analyses was performed using SPSS for windows, version 17.0 (Chicago, IL) and MedCalc (version 11.0.0.0, Frank Schoonjans, Mariakerke, Belgium).

See the online-only Data Supplement for additional details in the Methods section.

Results

General Preoperative Comparison

One hundred fifty-one patients were randomly assigned to either the statin group (n=77) or control group (n=74). In total, 132 patients (68 in the statin group and 64 in the control group) completed the study. Baseline characteristics have been summarized in Table 1.

View this table:
Table 1.

Baseline Characteristics and Comorbidities

Operative Characteristics and Postoperative Outcomes

There were no significant differences in the operative characteristics between the 2 groups (Table 1). Preoperative atrial fibrillation was identified in 15 patients in the statin group and 13 patients in the control group. There were no differences in cholesterol levels between the 2 groups before administration of simvastatin. There was a tendency for reduction of total cholesterol and low-density lipoprotein levels in 1 week postoperatively. Dyslipidemia (high levels of total cholesterol, low-density lipoprotein, or triglyceride) was diagnosed in 8 patients in the statin group and 7 patients in the control group. Diabetes mellitus was diagnosed in 4 patients in the statin group and 2 patients in the control group. Erythrocyte sedimentation rate, lactate dehydrogenase, and the lipid profiles were the same in both the groups. No statistically significant differences in terms of type and number of surgical procedures were found between the statin and control groups (Table 2). Postoperative development of atrial fibrillation occurred in 1 patient in the control group. One case of preoperative atrial fibrillation disappeared postsurgically in the statin group.

View this table:
Table 2.

Details of Surgical Procedures

Plasma TnT

Preoperatively, plasma TnT concentrations were <0.01 μg/L in both the groups and increased postoperatively—patients administered perioperative simvastatin therapy released less TnT than the patients who did not receive perioperative statins. Specifically, the mean TnT level was 0.88 μg/L (SD, 0.56; IQR, 0.49–1.12) versus 1.35 μg/L (SD, 1.56; IQR, 0.56–1.48) (P=0.020) at 6 hours, 0.81 μg/L (SD, 0.55; IQR, 0.40–1.12) versus 1.22 μg/L (SD, 1.47; IQR, 0.53–1.32) (P=0.037) at 12 hours, 0.59 μg/L (SD, 0.44; IQR, 0.29–0.76) versus 0.91 μg/L (SD, 1.08; IQR, 0.38–0.99) (P=0.031) at 24 hours, and 0.36 μg/L (SD, 0.29; IQR, 0.15–0.42) versus 0.61 μg/L (SD, 0.74; IQR, 0.29–0.69) (P=0.013) at 72 hours in the statin and control groups, respectively (Figure 2A). The total TnT released 72 hours postoperatively was reduced by 36.7%, from 60.33 μg/L (SD, 71.12) in the control group to 38.16 μg/L (SD, 26.58) in the statin group (mean difference was 22.17 [SD, 7.28]; 95% CI, 3.89–40.45; P=0.018). After excluding the 15 patients with dyslipidemia, similar results as those described above were obtained, indicating that statins reduced myocardial injury during CPB independent of their ability to reduce lipid levels (data not shown).

Plasma CKMB

Preoperative plasma CKMB concentrations were not significantly different between the 2 groups (P>0.05). Postoperatively, a significant reduction in plasma CKMB concentrations was identified in patients treated with simvastatin compared with the control group (Figure 2B). The total CKMB released 72 hours postoperatively was reduced by 27.6%, from 1618.68 μg/L (SD, 1232.15) in the control group to 1171.55 μg/L (SD, 776.86) in the statin group. The mean difference was 447.12 μg/L (SD, 31.99; 95% CI, 94.61–799.64; P=0.013). Again, when all patients with dyslipidemia were excluded, similar results were obtained (data not shown).

Figure 2.
Figure 2.

Simvastatin reduced plasma troponin T (TnT), isoenzyme of creatine kinase (CKMB), and C-reaction protein (CRP) concentrations. Plasma TnT, CKMB, and CRP before surgery and different time points after surgery were measured according to the manufacturer’s instructions. Less TnT (A), CKMB (B), and CRP (C) were released in the statin group compared with the control group (P<0.05).

Plasma CRP

There were no significant differences in preoperative plasma concentrations of CRP between both the groups. In contrast, less amounts of CRP release were observed in the statin group in comparison with the control group postoperatively (Figure 2C). After excluding the patients with dyslipidemia, the same significant differences were obtained (data not shown).

Blood Urea Nitrogen, Serum Creatinine, Plasma IL-6, and IL-8

There were no significant differences between the control group and the statin group preoperatively in BUN. BUN was dramatically increased postoperatively both in the control group and the statin group (*,#P<0.05). However, statin reduced BUN concentration in the statin group compared with the control group at 24, 48, and 72 hours postoperatively (P<0.05; Figure 3A). There was no significant difference between the control group and the statin group preoperatively in serum creatinine. However, creatinine was dramatically increased postoperatively in the control group but not in the statin group (*P<0.05). Statin reduced creatinine release compared with the control group at 24, 48, and 72 hours postoperatively (P<0.05). Interestingly, creatinine at 7 days postoperatively is even lower than that of preoperation in the statin group (#P<0.05; Figure 3B). The increase of plasma IL-6 and IL-8 postoperatively was dramatically less in the statin group compared with the control group (Figure 3C and 3D).

Figure 3.
Figure 3.

Simvastatin decreased blood urea nitrogen (BUN), creatinine concentrations, plasma interleukin L (IL)-6, and IL-8 and increased nitric oxide (NO) production in the heart. Plasma BUN, creatinine, IL-6, and IL-8 before surgery and at different time points after surgery were measured according to the manufacturer’s instructions. A, BUN was dramatically increased postoperatively both in the control group and the statin group (*vs control preoperatively (preop); #vs statin preop; P<0.05). Statin reduced BUN postoperatively (&vs control group; P<0.05). B, Creatinine was dramatically increased postoperatively in control group but not in the statin group (*vs control preop; P<0.05). Statin reduced creatinine postoperatively (&vs control group; P<0.05). Creatinine at 7 days postoperatively is lower than that at 7 days preoperatively in statin group (#vs statin preop; P<0.05). C and D, Simvastatin reduced the increase of plasma IL-6 and IL-8 (*P<0.05). E, NO generation was measured by detecting the nitrite+nitrate concentration in the right atrium. Simvastatin increased NO production in the heart both in preoperation and postoperation (*vs control; P<0.05) (mean±SEM).

NO Generation

There was a tendency for reduction in the control group and a tendency of enhancement in the statin group in concentration of NO2−+NO3− postoperatively. Furthermore, the concentration of NO2−+NO3− generation was significantly higher in the statin group than that of the control group both preoperation and postoperation (Figure 3E). Additional experiment showed similar result after using NG-methyl-L-arginine monoacetate to block NO2− release from fresh heart tissues (Figure I in the online-only Data Supplement).

Inotropic Requirement and Left Ventricular Ejection Fraction

There was a significantly greater inotropic requirement in the control group compared with the statin group at both 6 hours (5.5±3.2 µg/kg per minute versus 4.1±2.6 µg/kg per minute, P=0.008) and 12 hours (4.9±3.2 µg/kg per minute versus 3.5±2.5 µg/kg per minute, P=0.005) postoperatively. There was no significant difference in left ventricular ejection fraction between the control group and the statin group preoperatively (Table 1). Ejection fraction was higher in the statin group (60.4±11.0%) than in the control group (56.8±9.3 %) at 7 days postoperation (P=0.029) and 69.5±6.4% in the statin group than 65.3±7.3% in the control group in 1 month postoperation (P=0.002).

Akt-eNOS, p38 MAPK, Caveolin-1, Hsp90 Expression, and the Association eNOS With Hsp90

Both eNOS expression and phosphorylation at serine 1177 in the heart were dramatically increased in the statin group preoperatively and postoperatively. eNOS phosphorylation at serine 1177 was increased even more after than before surgery. eNOS phosphorylation at threonine 495 was increased postoperatively in the control group and decreased both preoperatively and postoperatively in the statin group (Figure 4A). Akt phosphorylation was decreased postoperatively in the control group and increased both preoperatively and postoperatively in the statin group (Figure 4B). Statin inhibited p38 mitogen–activated protein kinase (MAPK) phosphorylation postoperatively (Figure 4C). There was no difference in caveolin-1 expression before and after surgery in the control group and between the control group and the statin group preoperatively. Caveolin-1 expression was decreased postoperatively in the statin group (Figure 4D). There was no difference in Hsp90 expression before and after surgery in the control group and between the control and the statin group preoperatively. However, Hsp90 expression was significantly increased postoperatively in the statin group (Figure 4D). The Hsp90 association with eNOS was reduced postoperatively in the control group. There was no difference in Hsp90 association with eNOS before and after surgery in the statin group and between the control group and the statin group preoperatively. The Hsp90 association with eNOS was higher in the statin group than the control group postoperatively (Figure 4E).

Figure 4.
Figure 4.

Simvastatin activated Akt–enodthelial nitric oxide (eNOS) and attenuated p38 mitogen–activated protein kinase (MAPK) pathway in heart. Proteins expression and association in right atrium were measured. A, Statin increased eNOS phosphorylation at serine 1177 (S1177) site (*vs control; #vs statin preop; P<0.05). eNOS phosphorylation in threonine 495 (T495) site was increased postoperatively and decreased by statin (*vs control; #vs control preoperatively (preop); P<0.05). Statin increased eNOS expression (*vs control; P<0.05). B, Akt phosphorylation was decreased postoperatively and statin increased Akt phosphorylation both preoperatively and postoperatively (*vs control; #vs control preop, P<0.05). C, Statin decreased p38 phosphorylation postoperatively without altering p38 expression (*vs control; #vs statin preop; P<0.05). D, Statin significantly decreased caveolin-1 expression and slightly increased heat shock protein (Hsp90) expression postoperatively (*vs control; #vs statin preop; P<0.05). E, Hsp90 association with eNOS in the heart was reduced postoperatively and was restored by statin (*vs control; #vs control preop; P<0.05) (n=64–68; mean±SEM). p-eNOS indicates phosphorylated eNOS; p-Akt, phosphorylated Akt; postop, postoperatively; IB, immunoblot.

Discussion

This is the first single-blinded, randomized controlled trial exploring the effects of perioperative statin therapy in patients undergoing noncoronary artery cardiac surgery with CPB. In light of the fact that the patients, surgeons, anesthetist, perfusionist, ultrasound physicians, and individuals collecting and analyzing the blood samples and analyzing the data were also all blinded, this randomized controlled study closely approached a double-blind randomized trial in design. Previous studies indicate that elevations in TnT and CKMB after cardiac surgery are associated with poor short- and long-term clinical outcomes.12 The present study found that perioperative simvastatin therapy significantly decreases plasma TnT, CKMB, CRP, IL-6, IL-8, BUN, creatinine, the requirement of inotropic and improves left ventricular ejection fraction, suggesting that perioperative simvastatin therapy can reduce myocardial injury and inflammatory response and improve cardiac and renal function in noncoronary artery cardiac surgery with CPB.

Beneficial effects of statin pretreatment have already been demonstrated in various studies in patients undergoing both coronary artery surgery and cardiac percutaneous interventions.8 However, although these studies indicate that statins reduce myocardial injury during the intervention of coronary artery disease, it is not possible to conclude from those reports whether the reduction in myocardial injury was associated with the decrease in lipid level because statins are designed to treat coronary artery disease. In other words, can statins protect against myocardial injury during CPB? Indeed, 1 large, retrospective study showed that statins had nothing to do with myocardial protection during cardiac surgery. To clarify this controversy, 15 dyslipidemia patients were excluded from the analysis in the current study and similar results were attained. Therefore, although simvastatin decreased cholesterol level, our findings can demonstrate that the myocardial protective effect of statins during cardiac surgery maybe independent of their ability to reduce lipid levels as the patients’ cholesterol levels are normal before administration of simvastatin.

The mechanism by which statins reduce myocardial injury remains unclear. It is known that excessive systemic inflammatory responses unleashed by CPB leads to myocardial injury. Some studies showed that statins decreased the systemic inflammatory response, which, in turn, may contribute to a decrease in myocardial injury.9,13 However, Florens et al10 reported that acute preoperative statin therapy failed to limit the inflammatory response to CPB in a small randomized trial; this study only used a single dose statin. In the present study, we found that perioperative simvastatin therapy reduced concentration of IL-6, IL-8, and CRP, demonstrating that statins can inhibit systemic inflammatory response to reduce myocardial injury.14,15 It is well known that the p38 MAPK pathway participate in the inflammatory response.16,17 Our data showed that simvastatin decreased p38 MAPK phosphorylation, suggesting that one of the mechanisms by which statins reduces myocardial injury is by limiting the inflammatory response by attenuating the p38 MAPK pathway in noncoronary artery cardiac surgery with CPB.

Previous studies showed that statins can improve endothelial dysfunction by protecting tissues from the damage that results from ischemia and reperfusion during cardiac surgery.18 Statin is able to increase vascular endothelial NO production (by modulating NOS expression) and diminish myocardial necrosis after ischemia and reperfusion in mice, contributing to cardioprotective effects.19–21 In the current study, our data showed that eNOS phosphorylation at T495 site was increased and Hsp90 association with eNOS was decreased postoperatively in control, suggesting that not only is the eNOS activation inhibited, but eNOS is also uncoupled during cardiac surgery with CPB.11,22,23 As a result, eNOS may generate superoxide instead of NO, which leads to endothelial dysfunction and myocardial injury. Importantly, simvastatin increased eNOS expression and phosphorylation at serine 1177 site, decreased eNOS phosphorylation at T495 site preoperatively and postoperatively, demonstrating that statin is able to activate eNOS. Meanwhile, we found that Hsp90 association with eNOS was restored by simvastatin postoperatively, suggesting eNOS was maintained in coupling status to maintain NO generation during cardiac surgery.23,24 We further found that Hsp90 expression was increased and caveolin-1 expression was decreased by simvastatin. As Hsp90 is the chaperone of eNOS and positively regulates eNOS and caveolin-1 negatively regulates eNOS, our findings further support the idea of statin’s ability in activating eNOS and maintaining eNOS uncoupled activity to generate NO instead of superoxide.11,24,25 Although NO decreased during surgery in the control group, it did not reach statistical significance and there was a tendency for the reduction of NO production postoperatively (P=0.08). More importantly, simvastatin was able to stimulate NO generation compared with control group. Recent findings from Antoniades et al26 showing that perioperative statin therapy reduced myocardial superoxide generation in cardiac surgery also support our findings. Taken together, our findings demonstrated that statin can stimulate the heart to generate NO and decrease superoxide generation to limit oxidative stress in the heart and avoid injury before and during cardiac surgery. Such findings can explain why statins reduce myocardial injury and improve cardiac and renal function during cardiac surgery.

It is known that Akt phosphorylation is the key step of eNOS activation.27,28 We found that Akt phosphorylation in heart was decreased postoperatively and was increased by simvastatin preoperatively and postoperatively. These data demonstrate that statin can activate Akt-eNOS signaling pathway before and after cardiac surgery.

As simvastatin can improve endothelial function, it is possible that perioperative simvastatin therapy also improves the systemic vascular endothelial function. Our data showing less inotropic requirement postoperatively in the statin group indicate that simvastatin can not only reduce myocardial injury but may improve systemic vascular function.

In summary, our study shows that perioperative simvastatin therapy significantly reduced myocardial injury and inflammatory response and improved cardiac and renal function in patients undergoing noncoronary artery cardiac surgery with CPB by activating Akt-eNOS and attenuating p38 MAPK signaling pathway. Such cardiac protection of simvastatin is independent of its ability to reduce lipid levels. Our findings may provide a novel approach to reduce myocardial injury during cardiac surgery with CPB.

Acknowledgments

We thank the patients and staff at the First Affiliated Hospital, Sun Yat-sen University for their assistance throughout this study.

Sources of Funding

This study was supported by Sun Yat-sen University Clinical Research 5010 Program; the National Natural Science Foundation of China (30971261 and 81170271); Ministry of Education of China (20100171110057); The Science and Technology Research for the Returned Overseas Chinese Scholars from Ministry of Human Resources and Social Security of China (2011); and Bureau of Science and Information Technology of Guangzhou, China (2010GN-E00221).

Disclosures

None.

Footnotes

  • Received April 23, 2012.
  • Accepted June 29, 2012.

References

  1. 1.↵
    1. Mills EJ,
    2. O’Regan C,
    3. Eyawo O,
    4. Wu P,
    5. Mills F,
    6. Berwanger O,
    7. Briel M
    . Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. Eur Heart J. 2011;32:1409–1415.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Baigent C,
    2. Keech A,
    3. Kearney PM,
    4. Blackwell L,
    5. Buck G,
    6. Pollicino C,
    7. Kirby A,
    8. Sourjina T,
    9. Peto R,
    10. Collins R,
    11. Simes R
    ; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Davignon J
    . Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004;109(23 Suppl 1):III39–III43.
    OpenUrlPubMed
  4. 4.↵
    1. Ege E,
    2. Dereli Y,
    3. Kurban S,
    4. Sarigül A
    . Atorvastatin pretreatment diminishes the levels of myocardial ischemia markers early after CABG operation: an observational study. J Cardiothorac Surg. 2010;5:60.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Liakopoulos OJ,
    2. Choi YH,
    3. Haldenwang PL,
    4. Strauch J,
    5. Wittwer T,
    6. Dörge H,
    7. Stamm C,
    8. Wassmer G,
    9. Wahlers T
    . Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30,000 patients. Eur Heart J. 2008;29:1548–1559.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Vaduganathan M,
    2. Stone NJ,
    3. Lee R,
    4. McGee EC Jr.,
    5. Malaisrie SC,
    6. Silverberg RA,
    7. Kansal P,
    8. McCarthy PM
    . Perioperative statin therapy reduces mortality in normolipidemic patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2010;140:1018–1027.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Ali IS,
    2. Buth KJ
    . Preoperative statin use and outcomes following cardiac surgery. Int J Cardiol. 2005;103:12–18.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Patti G,
    2. Chello M,
    3. Candura D,
    4. Pasceri V,
    5. D’Ambrosio A,
    6. Covino E,
    7. Di Sciascio G
    . Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study. Circulation. 2006;114:1455–1461.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Chello M,
    2. Patti G,
    3. Candura D,
    4. Mastrobuoni S,
    5. Di Sciascio G,
    6. Agrò F,
    7. Carassiti M,
    8. Covino E
    . Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery. Crit Care Med. 2006;34:660–667.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Florens E,
    2. Salvi S,
    3. Peynet J,
    4. Elbim C,
    5. Mallat Z,
    6. Bel A,
    7. Nguyen A,
    8. Tedgui A,
    9. Pasquier C,
    10. Menasché P
    . Can statins reduce the inflammatory response to cardiopulmonary bypass? A clinical study. J Card Surg. 2001;16:232–239.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Ou ZJ,
    2. Wei W,
    3. Huang DD,
    4. Luo W,
    5. Luo D,
    6. Wang ZP,
    7. Zhang X,
    8. Ou JS
    . L-arginine restores endothelial nitric oxide synthase-coupled activity and attenuates monocrotaline-induced pulmonary artery hypertension in rats. Am J Physiol Endocrinol Metab. 2010;298:E1131–E1139.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Bignami E,
    2. Landoni G,
    3. Crescenzi G,
    4. Gonfalini M,
    5. Bruno G,
    6. Pappalardo F,
    7. Marino G,
    8. Zangrillo A,
    9. Alfieri O
    . Role of cardiac biomarkers (troponin I and CK-MB) as predictors of quality of life and long-term outcome after cardiac surgery. Ann Card Anaesth. 2009;12:22–26.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Sposito AC,
    2. Santos SN,
    3. de Faria EC,
    4. Abdalla DS,
    5. da Silva LP,
    6. Soares AA,
    7. Japiassú AV,
    8. Quinaglia e Silva JC,
    9. Ramires JA,
    10. Coelho OR
    . Timing and dose of statin therapy define its impact on inflammatory and endothelial responses during myocardial infarction. Arterioscler Thromb Vasc Biol. 2011;31:1240–1246.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Bisoendial RJ,
    2. Boekholdt SM,
    3. Vergeer M,
    4. Stroes ES,
    5. Kastelein JJ
    . C-reactive protein is a mediator of cardiovascular disease. Eur Heart J. 2010;31:2087–2091.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Sever PS,
    2. Poulter NR,
    3. Chang CL,
    4. Hingorani A,
    5. Thom SA,
    6. Hughes AD,
    7. Welsh P,
    8. Sattar N
    ; ASCOT Investigators. Evaluation of C-reactive protein prior to and on-treatment as a predictor of benefit from atorvastatin: observations from the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. 2012;33:486–494.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Cheriyan J,
    2. Webb AJ,
    3. Sarov-Blat L,
    4. Elkhawad M,
    5. Wallace SM,
    6. Mäki-Petäjä KM,
    7. Collier DJ,
    8. Morgan J,
    9. Fang Z,
    10. Willette RN,
    11. Lepore JJ,
    12. Cockcroft JR,
    13. Sprecher DL,
    14. Wilkinson IB
    . Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011;123:515–523.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Sarov-Blat L,
    2. Morgan JM,
    3. Fernandez P,
    4. James R,
    5. Fang Z,
    6. Hurle MR,
    7. Baidoo C,
    8. Willette RN,
    9. Lepore JJ,
    10. Jensen SE,
    11. Sprecher DL
    . Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans. Arterioscler Thromb Vasc Biol. 2010;30:2256–2263.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Liuni A,
    2. Luca MC,
    3. Gori T,
    4. Parker JD
    . The endothelial-protective effects of HMG-CoA reductase inhibition in the setting of ischemia and reperfusion injury. Clin Hemorheol Microcirc. 2010;45:161–167.
    OpenUrlPubMed
  19. 19.↵
    1. Di Napoli P,
    2. Antonio Taccardi A,
    3. Grilli A,
    4. Spina R,
    5. Felaco M,
    6. Barsotti A,
    7. De Caterina R
    . Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts. Cardiovasc Res. 2001;51:283–293.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Mital S,
    2. Zhang X,
    3. Zhao G,
    4. Bernstein RD,
    5. Smith CJ,
    6. Fulton DL,
    7. Sessa WC,
    8. Liao JK,
    9. Hintze TH
    . Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs. Am J Physiol Heart Circ Physiol. 2000;279:H2649–H2657.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Murata T,
    2. Kinoshita K,
    3. Hori M,
    4. Kuwahara M,
    5. Tsubone H,
    6. Karaki H,
    7. Ozaki H
    . Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2005;25:2335–2342.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Herranz B,
    2. Marquez S,
    3. Guijarro B,
    4. Aracil E,
    5. Aicart-Ramos C,
    6. Rodriguez-Crespo I,
    7. Serrano I,
    8. Rodríguez-Puyol M,
    9. Zaragoza C,
    10. Saura M
    . Integrin-linked kinase regulates vasomotor function by preventing endothelial nitric oxide synthase uncoupling: role in atherosclerosis. Circ Res. 2012;110:439–449.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Pritchard KA Jr.,
    2. Ackerman AW,
    3. Gross ER,
    4. Stepp DW,
    5. Shi Y,
    6. Fontana JT,
    7. Baker JE,
    8. Sessa WC
    . Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase. J Biol Chem. 2001;276:17621–17624.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. García-Cardeña G,
    2. Fan R,
    3. Shah V,
    4. Sorrentino R,
    5. Cirino G,
    6. Papapetropoulos A,
    7. Sessa WC
    . Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature. 1998;392:821–824.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Bernatchez P,
    2. Sharma A,
    3. Bauer PM,
    4. Marin E,
    5. Sessa WC
    . A noninhibitory mutant of the caveolin-1 scaffolding domain enhances eNOS-derived NO synthesis and vasodilation in mice. J Clin Invest. 2011;121:3747–3755.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Antoniades C,
    2. Demosthenous M,
    3. Reilly S,
    4. et al.
    Myocardial redox state predicts in-hospital clinical outcome after cardiac surgery effects of short-term pre-operative statin treatment. J Am Coll Cardiol. 2012;59:60–70.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Kureishi Y,
    2. Luo Z,
    3. Shiojima I,
    4. Bialik A,
    5. Fulton D,
    6. Lefer DJ,
    7. Sessa WC,
    8. Walsh K
    . The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000;6:1004–1010.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. Fulton D,
    2. Gratton JP,
    3. McCabe TJ,
    4. Fontana J,
    5. Fujio Y,
    6. Walsh K,
    7. Franke TF,
    8. Papapetropoulos A,
    9. Sessa WC
    . Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999;399:597–601.
    OpenUrlCrossRefPubMed
View Abstract

This Issue

Jump to

Article Tools

Share this Article

  • Email
  • Simvastatin Reduces Myocardial Injury Undergoing Noncoronary Artery Cardiac Surgery
    Mohammed Ahmed Saad Almansob, Bo Xu, Li Zhou, Xiao-Xia Hu, Wen Chen, Feng-Jun Chang, Hong-Bo Ci, Jian-Ping Yao, Ying-Qi Xu, Feng-Juan Yao, Dong-Hong Liu, Wen-Bo Zhang, Bai-Yun Tang, Zhi-Ping Wang and Jing-Song Ou
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:2304-2313, originally published August 15, 2012
    https://doi.org/10.1161/ATVBAHA.112.252098
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects