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European Journal of Heart Failure 2007 9(1):30-36; doi:10.1016/j.ejheart.2006.04.013
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© 2007 European Society of Cardiology

Post-infarction treatment with simvastatin reduces myocardial no-reflow by opening of the KATP channel

Yue-Jin Yang*,1, Jing-Lin Zhao1, Shi-Jie You, Yong-Jian Wu, Zhi-Cheng Jing, Run-Lin Gao and Zai-Jia Chen

Department of Cardiology, Cardiovascular Institute and Fu-Wai Heart Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Bei Li Shi Road 167, West City District, Beijing, 100037, China

* Corresponding author. Tel.: +86 13501076630. E-mail address: realplayone{at}yahoo.com.cn


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
Simvastatin can prevent cardiac remodelling after myocardial infarction, though the exact mechanisms are uncertain. Myocardial no-reflow is associated with progressive cardiac remodelling. However, it remains unknown whether post-infarction treatment with simvastatin can also reduce myocardial no-reflow for which suppression of adenosine triphosphate-sensitive K+ (KATP) channel opening is an important mechanism.

Methods: Area at risk and the area of no-reflow were determined by myocardial contrast echocardiography (MCE) and by pathology in 45 mini-swine randomised into 5 groups: 10 control, 9 simvastatin, 9 glibenclamide, 9 simvastatin plus glibenclamide and 8 sham-operated. A myocardial infarction and reperfusion model was created by 3-h occlusion of the coronary artery followed by 4 weeks of reperfusion.

Results: Compared with the control group, simvastatin significantly increased coronary blood volume (P<0.01) and decreased the area of no-reflow measured by MCE (78.5±4.5% to 43.7±4.3%) and pathological evaluation (82.3±1.9% to 45.2±3.8%) of area at risk (P<0.01). Simvastatin also increased the levels of KATP channel proteins (SUR2 and Kir6.2) (P<0.05), but had no effect on necrosis area. The combination of simvastatin and glibenclamide had no significant effect on the above parameters.

Conclusions: Post-infarction treatment with simvastatin can reduce myocardial no-reflow. This beneficial effect is due to activation of the KATP channel.

Key Words: Simvastatin • Acute myocardial infarction • No-reflow

Received January 5, 2006; Revised February 27, 2006; Accepted April 27, 2006


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to attenuate post-infarction cardiac remodelling in experimental models [1-3] and to improve survival in humans [4]. Although statins blunt post-infarction cardiac remodelling, the mechanisms involved are incompletely understood. Myocardial no-reflow, a condition of inadequate myocardial perfusion in the absence of epicardial coronary artery obstruction after reperfusion therapy for acute myocardial infarction (MI) [5-7], has been shown to be associated with progressive left ventricular remodelling, heart failure, and poor prognosis [8-10]. We hypothesized that the beneficial effects of statins on post-infarction cardiac remodelling may be due in part to a reduction in myocardial no-reflow. In addition, suppression of adenosine triphosphate-sensitive K+ (KATP) channel opening is an important mechanism for myocardial no-reflow [11]. If post-infarction treatment with statins can reduce myocardial no-reflow, it is possible that this beneficial effect may be partly due to activation of the KATP channel. The K ATP channel is composed of two subunits, namely the ATP-binding cassette protein sulfonylurea receptor (SUR2) and a pore-forming inward rectifier (Kir6.1 or Kir6.2) [12].

In this study, we used a mini-swine model of MI and reperfusion, developed in our laboratory, to assess the effects of post-infarction treatment with simvastatin on myocardial no-reflow and levels of SUR2, Kir6.1 or Kir6.2.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Study limitations
 References
 
The animals and protocols used in the study were approved by the Institutional Animal Care and Use Committee. The mini-swine (30±3 kg) were sedated with 10 mg/kg of azaperone intramuscularly, anesthetized with 10 mg/kg of thiopental intravenously, and given prophylactic antibiotics (cephalothin 50 mg/kg intravenously and gentamicin 5 mg/kg intramuscularly). The swine were intubated and ventilated with a respirator (Siemens elema sv 900). A middle thoracotomy was performed, and the heart was suspended in a pericardial cradle. The middle and distal portion of the left anterior descending coronary artery (LAD) was dissected free from surrounding tissue, and was encircled by a suture. The two ends of the suture were threaded through a length of plastic tubing, forming a snare, which could be tightened to achieve coronary artery occlusion. The right femoral artery and vein were cannulated for haemodynamic monitoring and contrast agent injection respectively. An ultrasonic flow probe was placed proximal to the site of occlusion. The catheters and probe were evacuated after 2 h of reperfusion. The incision was then closed. A single postoperative dose of antibiotics was given after the chest was closed, and an inter-costal nerve block (2% lidocaine) and analgesics (butorphanol 0.025 mg/kg IM) were given postoperatively to alleviate pain. Animals were fully recovered within 24 h and then group housed.

2.1. Experimental protocol
Forty-five animals were randomised into five study groups: 10 controls, 9 simvastatin-pre-treated, 9 glibenclamide (KATP channel blocker [13])-treated, 9 simvastatin and glibenclamide-treated and 8 sham-operated. The former four groups were subjected to 3 h of coronary occlusion followed by 4 weeks of reperfusion. In the sham-operated animals, the LAD was only encircled by a suture, but not occluded. Animals were returned to the laboratory for studies after 4 weeks. The mini-swine were anesthetized, intubated and ventilated as before. A middle thoracotomy was performed. The catheters and probe were again placed in the right femoral artery and vein to monitor parameters.

2.2. Drug administration
In the simvastatin or glibenclamide animals, 1 mg/kg/day of simvastatin (donated by Merck Pharmaceutical Company) or 0.3 mg/kg/day of glibenclamide was given for 4 weeks, beginning immediately after reperfusion based on body surface area [14]. In the combined treatment group animals, both simvastatin and glibenclamide were given for 4 weeks. All drugs were given orally by mixing with fodder once a day.

2.3. Haemodynamics
Fluid-filled multilumen balloon flotation (Swan-Ganz) and 7/8F pigtail catheters were inserted percutaneously under fluoroscopic guidance through the femoral vein and artery for cardiac output (CO) and left ventricular pressure measurements respectively. Cardiac output (CO) was measured using a flow-directed, thermodilution method with Edward's cardiac output computer. Three consecutive readings for CO were used for the final computation. The variability of thermodilution measurements in our laboratory was ±3%. Haemodynamic data measurements were repeated at baseline, the end of 3 h of LAD occlusion, after 2 h of reperfusion, and 4 weeks of reperfusion. Coronary blood flow volume (CBV) was digitally measured by the ultrasonic flow probe connected to a flowmeter (Nikon Kohden Corporation) at baseline, immediately after release of occlusion (3 h), 2 h of reperfusion, and 4 weeks of reperfusion.

2.4. Myocardial contrast echocardiography (MCE)
Echocardiography was performed using an HP 5500 machine (Philips Ultrasound). The transducer was fixed in position to obtain the same short-axis images of the left ventricle at the midpapillary muscle level. A warm-water bath acted as an acoustic interface between the heart and the transducer. A bolus of 0.05 ml/kg of sonovue (Bracco Inc., Geneva, Switzerland) was injected intravenously as a slow bolus over 30 s followed by 5-ml saline flush. Data were collected at baseline, at the end of 3 h of LAD occlusion, after 2 h of reperfusion, and 4 weeks of reperfusion respectively. For each MCE, end-diastolic images were acquired at a pulsing interval of 4 cardiac cycles during contrast injection to allow complete beam replenishment and demarcation between perfused and non-perfused tissue. Area at risk (AR) and the area of no-reflow (ANR) were identified as the region of unopacified myocardium by MCE at 3 h of LAD occlusion, 2 h of reperfusion and 4 weeks of reperfusion respectively. AR, ANR and left ventricular wall area (LVWA) were traced and measured. AR was expressed as a percentage of LVWA, whereas ANR was expressed as a percentage of AR.

2.5. Histopathological evaluation
After completion of the experimental protocol, ANR was delineated by intra-atrial injection of 1 ml/kg of the fluorescent dye thioflavin S (Sigma Chemical Co). Then the LAD was reoccluded, and Evans blue dye was injected into the left atrium to determine AR. The swine was then euthanized and the heart explanted. Five to six LV slices were cut parallel to the atrioventricular groove. Under an ultraviolet light in a dark room, the areas not perfused by thioflavin S were identified. AR was defined as the region unstained by Evans blue, while ANR was defined as the non-fluorescent area within AR. Three slices were incubated in a 1% solution of triphenyltetrazolium chloride (TTC) for 15 min at 37 °C. Regions that failed to demonstrate red staining were considered to represent necrosis area (NA). The outlines of the LVWA, AR, ANR and NA were calculated. AR was expressed as percentage of the LVWA, ANR and NA as percentage of AR. Samples were then taken from the myocardium in the three regions of the other slices, washed thoroughly with saline and snap-frozen in liquid nitrogen.

2.6. Measurement of total cholesterol levels in plasma
Blood samples were collected at two time points: before treatment (at baseline) and after treatment (4 weeks after reperfusion). Total cholesterol levels were measured with enzyme assays based on the formulation of Allain et al. [15] using an AerosetTM System (Abbott Labaratories, Wiesbaden, Germany).

2.7. Western blot analysis for VE-cadherin, SUR2, Kir6.1 and Kir6.2 in myocardial tissue
Myocardial tissue samples were separately suspended in 5 ml of ice-cold lysis buffer containing (mM)—Tris-HCl 20 (pH 7.4), EDTA 1, NaCl 150, DTT 1, 2-mercaptoethanol 10, freshly added proteinase inhibitor and disrupted using a tissue homogeniser. The particulate material was discarded by centrifugation at 100,000xg at 4 °C for 1 h. The clear supernatant of each tissue sample was collected and frozen at –70 °C until use. Protein concentration was determined by the method of Bradford [16]. 50 µg of total protein solubilized for 10 min at 100 °C was loaded per lane onto a 12% SDS-PAGE gel. Electrophoresis was performed for 1 h at 150 mA. Proteins were transferred onto Immobilon-P transfer membrane (Millipore, Bedford, MA, USA) for 1.5 h at 0.8 mA/cm2 in a 20% methanol containing cathodes buffer. The membrane was washed three times for 20 min in PBST (0.1% Tween 20, 100 mM Tris-HCl, 150 mM NaCl, pH 7.5), blocked for 1 h in 5% nonfat milk-TTBS and incubated with the primary antibodies for VE-cadherin, SUR2, Kir6.1 and Kir6.2 (Santa Cruz Biotechnology, Santa Cruz, California). The primary antibodies were used in a 1:1000 dilution in PBST. After washing three times in PBST for 15 min, the membrane was incubated with a 1:10,000 dilution of the secondary antibodies for 30 min at room temperature. To measure protein levels, the Western blots were scanned and digitized on an optical scanner (EPSON GT-8000, Seiko, Tokyo, Japan). Quantification of Western blots was done on a computer using the Gel-Pro image analysis system. All specific values of proteins were standardized to the value of protein in the sham group [17].

2.8. Statistical methods
Data are expressed as mean±S.D. Comparisons of data at all stages were performed with repeated-measures ANOVA followed by Student-Newman-Keuls test for multiple comparisons. Comparisons of AR, ANR and NA among groups were done with one-way ANOVA followed by Student-Newman-Keuls test for multiple comparison. A value of P<0.05 (2-sided) was considered statistically significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Study limitations
 References
 
Five mini-swines (one receiving simvastatin, one receiving glibenclamide, one receiving combination and two controls) died of ventricular fibrillation during the occlusion period and were excluded. Therefore, 8 animals were evaluated in each group.

3.1. Plasma cholesterol
Compared with baseline, plasma cholesterol levels did not change after 4 weeks of reperfusion in the control, glibenclamide, simvastatin and combination groups (P>0.05). There was no significant difference in plasma cholesterol level among the control, glibenclamide, simvastatin and combination groups (P>0.05) (Table 1).


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  		Table 1 Plasma cholesterol (mg/dl) levels at baseline and after 4 weeks of reperfusion

 
3.2. No-reflow and infarct size
There was no significant difference in AR on both MCE and pathological evaluation between the three treated and control groups (P>0.05). In the control group, the area of no-reflow (ANR) was similar, 78.5% and 82.3% respectively for both evaluation methods, with the final necrosis area (NA) reaching 99% of AR. Compared with the control group, ANR in the simvastatin group was significantly decreased to 43.7-45.2% (P<0.01) with the final NA still reaching 99% of AR (P>0.05). There was no significant difference in ANR and NA among the glibenclamide, combination and control groups (P>0.05) (Table 2).


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  		Table 2 Effects of simvastatin on area at risk (AR, %), area of no-reflow (ANR, %) and necrosis area (NA, %)

 
3.3. Coronary blood flow volume
In the control group, CBVs were significantly reduced immediately after release of 3 h occlusion and reperfusion for 2 h and 4 weeks (all P<0.01). In the simvastatin group, CBVs were also significantly reduced immediately after release of 3 h occlusion, and reperfusion for 2 h and 4 weeks (P<0.05). However, CBV values were significantly higher than in the control group at 4 week reperfusion (P<0.01). There was no significant difference in CBVs among the glibenclamide, combination and control groups (P>0.05) (Table 3).


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  		Table 3 The effect of simvastatin on CBV (ml/min)

 
3.4. Haemodynamics
In the control group, left ventricular systolic pressure (LVSP), and cardiac output (CO) were significantly reduced (P<0.05-0.01), while left ventricular end-diastolic pressure (LVEDP) significantly increased at 2 h and 4 week reperfusion (P<0.01). Compared with the control group, CO and LVEDP significantly recovered at 4 week reperfusion in the simvastatin group (all P<0.05) (Figs. 1-3GoGo). There was no significant difference in haemodynamic data among the glibenclamide, combination and control groups (P>0.05).


Figure 01
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  		Fig. 1 Changes in LVSP (expressed as mm Hg). *P<0.05 vs. control. {dagger}P<0.05, {ddagger}P<0.01 vs. baseline. §P<0.05 vs. 3 h ischaemia. Data are expressed as the mean value±S.D.; n=8 per group. LVSP represents left ventricular systolic pressure.

 


Figure 02
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  		Fig. 2 Changes in LVEDP (expressed as mm Hg). *P<0.05 vs. control. {dagger}P<0.05, {ddagger}P<0.01 vs. baseline. §P<0.05 vs. 3 h ischaemia. Data are expressed as the mean value±S.D.; n=8 per group. LVEDP represents left ventricular end-diastolic pressure.

 


Figure 03
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  		Fig. 3 Changes in CO (expressed as l/min). *P<0.05 vs. control. {dagger}P<0.05, {ddagger}P<0.01 vs. baseline. §P<0.05 vs. 3 h ischaemia. Data are expressed as the mean value±S.D.; n=8 per group. CO represents cardiac output.

 
3.5. The effects of simvastatin on SUR2, Kir6.1 and Kir6.2 in the myocardium
In control, as well as the three treated groups, the levels of SUR2, Kir6.1 and Kir6.2 in the reflow myocardium were significantly lower than those in normal myocardium (all P<0.01), while significantly higher than those in no-reflow myocardium (P<0.01). In the simvastatin group, the levels of SUR2 and Kir6.2 were significantly higher than those in the control group (P<0.01). There was no significant difference in the levels of SUR2, Kir6.1 and Kir6.2 among glibenclamide, combination and control groups (P>0.05) (Table 4).


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  		Table 4 Changes in SUR2, Kir6.1 and Kir6.2 levels (expressed as %) in the myocardium

 
3.6. VE-cadherin in the myocardium
In the control as well as the three treated groups, VE-cadherin levels in the reflow myocardium were significantly higher than in no-reflow myocardium, but significantly lower than in normal myocardium (P<0.05-0.01). In the simvastatin group, VE-cadherin level in the reflow myocardium was significantly higher than that in the control group (P<0.01). There was no significant difference in VE-cadherin level among glibenclamide, combination and control groups (P>0.05) (Table 5).


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  		Table 5 Changes in VE-cadherin levels (expressed as %) in the myocardium

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Study limitations
 References
 
Myocardial ischaemia in humans often occurs as a result of the long-term consequences of hypercholesterolemia (endothelial dysfunction, plaque formation, fissures in arterial plaques, etc.) [18]. In this setting, cholesterol-lowering agents have been widely used to reduce cardiovascular risk. The major action of the statins (simvastatin, pravastatin, etc.) is inhibition of cholesterol synthesis in the liver. However, previous studies have shown that these statins also exert effects separate from their cholesterol-lowering actions [19-21]. Although statins have been shown to attenuate post-infarction cardiac remodelling independently of their cholesterol-lowering effect, little is known about the effect and mechanism of statins on myocardial no-reflow.

The present study demonstrated that simvastatin decreased the area of no-reflow and improved CBV. Our data are the first to establish that post-infarction treatment with simvastatin exerts a favourable effect on microvascular perfusion after restoration of flow in epicardial vessels. The mechanism by which simvastatin is beneficial in the reduction of the no-reflow is unclear. Interestingly, the present study demonstrated that the beneficial effect of simvastatin occurred in the absence of significant changes in plasma cholesterol levels in normocholesterolemic animals. These results imply that this beneficial effect of simvastatin could be linked to mechanism beyond its cholesterol lowering action. The proposed mechanism of the no-reflow phenomenon is multifactorial. Animal and post-mortem histological studies have demonstrated varying degrees of small-vessel vasospasm, endothelial gap and bleb formation, neutrophil plugging of capillaries as well as microvascular compression from myocytes, interstitial oedema, and haemorrhage after recanalization [22,23]. Our study provides one possible mechanism for the beneficial effect of simvastatin on myocardial no-reflow. The suppression of KATP channel opening is an important mechanism for myocardial no-reflow. Our findings showed that myocardial tissue levels of SUR2, Kir6.1 and Kir6.2 were significantly decreased in the reflow and no-reflow myocardium compared to those in the non-ischemic myocardium, suggesting that the KATP channel was suppressed to some extent in the reflow and no-reflow myocardium. Simvastatin increased SUR2 and Kir6.2 levels, indicating that it can activate the KATP channel. Furthermore, administration of glibenclamide (KATP channel blocker) after myocardial infarction abrogated the protective effect of simvastatin, also suggesting that simvastatin reduces myocardial no-reflow by the activation of KATP channel. Since activation of the KATP channel is a crucial step in mediating ischemic preconditioning [24,25], simvastatin may mimic the effect of ischemic preconditioning.

Myocardial no-reflow has been classified into two different forms: structural and functional [26]. In structural no-reflow, microvessels confined within necrotic myocardium exhibit irreversible structural disintegrity. In functional no-reflow, patency of anatomically intact microvessels is compromised because of spasm and/or microembolisation. Vascular endothelial (VE)-cadherin, a specific endothelial cadherin, is an important determinant of vascular structural integrity [27,28]. Our findings showed that myocardial tissue levels of VE-cadherin were significantly decreased in the reflow and no-reflow myocardium compared to those in the non-ischemic myocardium, suggesting that microvascular structural integrity was damaged by ischaemia and reperfusion. Our findings also demonstrated that simvastatin increased VE-cadherin level in the reflow myocardium, indicating that simvastatin can preserve endothelial junctions and attenuate structural no-reflow.

The present study demonstrated that simvastatin improved ventricular function after MI, which is consistent with the reports of Nahrendorf et al. [1] and Bauersachs et al. [2]. Our study also showed that simvastatin at a dose which improved ventricular function did not decrease infarct size, implying that this effect of simvastatin on ventricular function is unlikely to be secondary to infarct size lowering. The result that post-infarction treatment with simvastatin did not decrease the infarct size is in agreement with the report of Nahrendorf et al. [1]. No-reflow usually occurs after the myocytes in the area are already dead and the zone of no-reflow is confined to areas of necrotic myocardium [29]. Thus, although post-infarction treatment with simvastatin reduces the area of no-reflow, it may not affect the infarct size.

A significant body of clinical research and experimental study within the past decade has established important prognostic implications of the occurrence and extent of no-reflow for recovery of regional myocardial function, cardiac remodelling, and clinical outcome. There is also evidence that statins have a favourable impact on cardiac remodelling, and improvement in haemodynamics following MI. We believe these beneficial effects of statins on cardiac remodelling are mediated at least in part by the reduction of myocardial no-reflow.


   5. Study limitations
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
References
 
This animal study may not directly represent the patient's situation. However, the mini-swine model of MI and reperfusion closely mimics the clinical condition in patients with MI.

In conclusion, the present study demonstrated that post-infarction treatment with statins markedly attenuated myocardial no-reflow, and also increased the levels of KATP channel proteins after 4 weeks of MI, suggesting this beneficial effect of statins on myocardial no-reflow was in part due to opening of the KATP channel.


   Acknowledgement
 
This study was supported, in part, by a grant-in-aid (90209038) from the National Natural Science Foundation of China.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
1 These authors contributed equally to this work. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 

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Y.-J. Yang, H.-Y. Qian, J. Huang, J.-J. Li, R.-L. Gao, K.-F. Dou, G.-S. Yang, J. T. Willerson, and Y.-J. Geng
Combined Therapy With Simvastatin and Bone Marrow-Derived Mesenchymal Stem Cells Increases Benefits in Infarcted Swine Hearts
Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2076 - 2082.
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