Efficacy and Mechanism of Preoperative Simvastatin Therapy on Myocardial Protection after Extracorporeal Circulation

Abstract

Background: Cardiopulmonary bypass (CPB) causes systemic inflammatory response and ischemia-reperfusion (IR) injury.

Objective: To investigate the effect and mechanism of simvastatin on myocardial injury in cardiac valve surgery with CPB.

Methods: One hundred thirty patients were randomly assigned to the statin group (n = 65) or control group (n = 65). Simvastatin was administered preoperatively and postoperatively. Duration of intensive care unit stay, duration of assisted ventilation, and left ventricular ejection fraction were recorded. Plasma was analysed for troponin T (cTnT), isoenzyme of creatine kinase (CK-MB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). Ultrastructure of the myocardium and autophagosomes were observed. Beclin-1, LC3-II/I, P62, AMPK, and the phosphorylation of AMPK in cardiomyocytes were detected.

Results: Simvastatin significantly reduced the duration of assisted ventilation (P = 0.030) and ejection fraction was significantly higher in the statin group (P = 0.024). Simvastatin significantly reduced the levels of cTnT, CK-MB, TNF-α, IL-6, and IL-8 (P < 0.05), reduced the expression of LC3-II/LC3-I and Beclin 1, and increased the expression of phosphorylation of AMPK. Simvastatin reduced the generation of autophagosomes and the ultrastructural injuries to myocardium.

Conclusion: Perioperative statin therapy reduced myocardial injury by regulating myocardial autophagy and activating the phosphorylation of AMPK. The registration number of this study is ChiCTR-TRC-14005164.

Figure 1

At all postoperative time points, the indices of cardiac muscle injury, CK-MB and cTnT, were significantly lower in the simvastatin group than in the control group. ^∗P < 0.05 versus control group. Net increases in serum IL-6, IL-8, and TNF-α in the simvastatin group and control group between 6 h before and 6 h after operation.

Figure 2

((a), (b), and (c)) Expression of LC3-II, Beclin-1, P62, and p-AMPK by Western blotting assays in both groups before and after surgery. Data expressed as mean ± SD. n = 62–64. ^∗P < 0.05 versus statin (Pre-OP); ^#P < 0.05 versus statin (Post-OP). ((d) and (e)) Expression of Beclin-1 and P62 by immunohistochemistry in both groups before and after surgery. Magnification 200x. Data expressed as mean ± SD, n = 62–64. ^∗P < 0.05 versus statin (Pre-OP); ^#P < 0.05 versus statin (Post-OP).

Figure 3

Transmission electron microscopy of myocardial ultrastructure (black arrow indicates autophagosome or autolysosome; white arrow indicates mitochondrion. Magnification 2500x).