Myocardial No-reflow Research Articles

Myocardial ‘No-Reflow’ Prevention

Despite achievement of optimal epicardial coronary flow in the majority of patients treated for ST-segment elevation myocardial infarction (STEMI) by primary percutaneous coronary intervention (PPCI), myocardial no-reflow is a common phenomenon occurring in 5 to 50% of patients. The no-reflow phenomenon is a predictor of infarct size and an independent predictor of mortality both in the short and long term. Prevention of no-reflow is therefore a crucial step in improving prognosis of patients with STEMI. Several strategies including pharmacological and mechanical ones have been developed to improve microvascular perfusion in the setting of a myocardial infarction. Prevention starts by conservation of the microvascular reserve especially in patients at high risk of acute coronary syndromes such as diabetes patients. Optimal glycaemic control and the use of statins have been shown to reduce no-reflow in this context. Reducing ischaemic time by shortening door to balloon times, administration of intracoronary GP IIb/IIIa antagonists during PPCI and the use of manual aspiration thrombectomy have been shown to result in better myocardial perfusion and improved clinical outcome in major trials. In this review we discuss some of these major trials and studies of other therapeutic options that aim to prevent the no-reflow phenomenon.

Suppression of NF-κB Reduces Myocardial No-Reflow

No-reflow phenomenon is a risk factor which severely compromises the benefits of coronary revascularization in patients with acute myocardial infarction. Inflammatory response, as an essential component of cardiac ischemia/reperfusion (I/R) injury, has been suggested to contribute to the myocardial no-reflow. Since nuclear factor kappa B (NF-κB) is a key mediator of inflammation, we reasoned that inhibition of NF-κB might reduce the extent of no-reflow. To test this hypothesis, the left circumflex coronary arteries of New Zealand white male rabbits were ligated for 1.5 h, followed by reperfusion for 1 h to induce I/R injury. Pretreatment of the rabbits with a specific NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), significantly attenuated neutrophil infiltration in the no-reflow area as well as the expansion of no-reflow. These beneficial effects were associated with a marked reduction in the serum levels of myocardial induced I/R tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and CXCL16. Consistently, simulative I/R culture of human umbilical vein endothelial cells (HUVECs) resulted in an increase of TNF-α, ICAM-1 and CXCL16, and all of these changes were significantly suppressed by pretreatment of the cells with PDTC or with siRNA-mediated p65 knockdown. Our data thus suggest that inhibition of NF-κB may reduce I/R-associated myocardial no-reflow through reduction of myocardial inflammation.

The cardioprotection of simvastatin in reperfused swine hearts relates to the inhibition of myocardial edema by modulating aquaporins via the PKA pathway

Background and objectiveMyocardial edema plays a role in myocardial no-reflow and infarction during ischemia and reperfusion. The effects of statins against no-reflow and infarction may relate to the inhibition of myocardial edema. The current study investigated the role of protein kinase A (PKA) in statin-reduced myocardial edema in reperfused swine hearts. Methods and resultsMinipigs were treated with simvastatin (SIM, 2mg/kg), SIM+H-89 (a PKA inhibitor, 1.0μg/kg/min), or H-89 alone 1h before 90-min ischemia and 3-h reperfusion or sham operation. Ischemia or ischemia–reperfusion induced severe myocardial edema, PKA activation, and up-regulation of aquaporin-1, -4, -8, and ‐9 in the reflow and no-reflow myocardium. SIM pretreatment reduced the sizes of no-reflow and infarct areas by 18.5% and 11.1% (P<0.01), decreased water content in the left ventricle, reflow and no-reflow myocardium by 1.4%, 5.3%, and 4.3% (P<0.05), inhibited cardiomyocytes swelling in the reflow and no-reflow areas by 19.8% and 13.1% (P<0.01), suppressed mitochondrial water accumulation in the reflow and no-reflow areas by 49.0% and 35.9% (P<0.01), increased PKA activity (P<0.01), and blocked the up-regulation of aquaporin-1, -4, -8, and ‐9 in the reflow and no-reflow myocardium. However, these beneficial effects of SIM were partially abolished by inhibiting PKA with H-89. ConclusionsThe cardioprotective effects of acute SIM therapy against myocardial no-reflow and infarction relate to the reduction of myocardial edema by suppressing the expression of aquaporin-1, -4, -8, and ‐9 in a partially PKA-dependent manner.

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statin-mediated eNOS phosphorylation and cardioprotection. 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser(133) p-CREB protein, Ser(1179) p-eNOS, and Ser(635) p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 μg·kg(-1)·min(-1)) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg(-1)) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser(1179) and Ser(635) that was partially mediated via the PKA signaling pathway.

The preventive effect of garlicin on a porcine model of myocardial infarction reperfusion no-reflow

To evaluate whether garlicin can prevent reperfusion no-reflow in a catheter-based porcine model of acute myocardial infarction (AMI). Twenty-two male Chinese mini swines were randomized into 3 groups: sham-operation group (n=6), control group (n=8), and garlicin group (n=8). The distal part of left anterior descending coronary artery (LAD) in swines of the latter two groups was completely occluded by dilated balloon for 2 h and a successful AMI model was confirmed by coronary angiography (CAG) and electrocardiograph (ECG), which was then reperfused for 3 h. In the sham-operation group, balloon was placed in LAD without dilatation. Garlicin at a dosage of 1.88 mg/kg was injected 10 min before LAD occlusion until reperfusion for 1 h in the garlicin group. To assess serial cardiac function, hemodynamic data were examined by catheter method before AMI, 2 h after occlusion and 1, 2, and 3 h after reperfusion. Myocardial contrast echocardiography (MCE) and double staining with Evans blue and thioflavin-S were performed to evaluate myocardial no-reflow area (NRA) and risk area (RA). Left ventricular systolic pressure and left ventricular end-diastolic pressure significantly improved in the garlicin group after reperfusion compared with the control group P<0.05) and 2 h after AMI (P<0.05). MCE showed garlicin decreased reperfusion NRA after AMI compared with the control group (P <0.05). In double staining, NRA/RA in the garlicin group was 18.78%, significantly lower than that of the control group (49.84%, P<0.01). Garlicin has a preventive effect on the porcine model of myocardial infarction reperfusion no-reflow by improving hemodynamics and decreasing NRA.

PKA-mediated eNOS phosphorylation in the protection of ischemic preconditioning against no-reflow

ObjectiveTo investigate whether ischemic preconditioning (IP) can reduce myocardial no-reflow by activating endothelial (e-) nitric oxide synthase (NOS) via the protein kinase A (PKA) pathway. Methods and ResultsIn a 90-min ischemia and 3-h reperfusion model, minipigs were assigned into sham, ischemia–reperfusion (IR), IR+IP, IR+IP+L-NNA (an eNOS inhibitor, 10mg·kg−1), IR+IP+H-89 (a PKA inhibitor, 1.0μg·kg−1·min−1), IR+L-NNA, and IR+H-89 groups. IP pretreatment improved cardiac function and coronary blood flow, decreased the activities of creatine kinase by 36.6% after 90 min of ischemia and by 32.8% after 3 h of reperfusion (P<0.05), reduced the no-reflow areas from 49.9% to 11.0% (P<0.01), and attenuated the infarct size from 78.2% to 35.4% (P<0.01). IP stimulated myocardial PKA activities and the expression of PKA and Ser133 phosphorylated (p-) cAMP response element-binding protein (CREB) in the reflow and no-reflow myocardium, and enhanced the activities of constitutive NOS and the phosphorylation of eNOS at Ser1179 and Ser635 in the no-reflow myocardium. IP suppressed the expression of tumor necrosis factor-α and P-selectin, and attenuated cardiomyocytes apoptosis by regulating the expression of Bcl-2 and caspase-3 in the reflow and no-reflow myocardium. The eNOS inhibitor L-NNA completely canceled these beneficial effects of IP without any influence on PKA activity, whereas the PKA inhibitor H-89 partially blocked the IP cardioprotective effects and eNOS phosphorylation at the same time. ConclusionIP attenuates myocardial no-reflow and infarction after ischemia and reperfusion by activating the phosphorylation of eNOS at Ser1179 and Ser635 in a partly PKA-dependent manner.

Usefulness of the SYNTAX Score to Predict “No Reflow” in Patients Treated With Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction

The no-reflow phenomenon has been shown to have a significant effect on clinical outcomes in patients with acute ST-segment elevation myocardial infarction. Angiographic features incorporated in the SYNTAX Score (SXScore) obtained on diagnostic angiography during primary percutaneous coronary intervention (PPCI) may be associated with the occurrence of myocardial no-reflow. The aim of this study was to assess the ability of the SXScore to predict no-reflow during PPCI. The SXScore was applied to 669 consecutive patients presenting with acute ST-segment elevation myocardial infarction from November 2006 to February 2008. Angiographic analysis of the PPCI procedure was used to determine no-reflow. The median SXScore was 16 (range 9.5 to 23). No-reflow occurred in 77 patients (12%). On univariate logistic regression analysis, the SXScore showed a strong association (for each 10-unit increase in SXScore, odds ratio 1.42, 95% confidence interval 1.16 to 1.76, p <0.001). On multivariate logistic regression in a model including clinical variables, SXScore was an independent predictor of no-reflow (odds ratio 1.29, 95% confidence interval 1.02 to 1.63, p <0.001). Classification and regression tree analysis identified SXScore >21 as the best cutoff, with patients having double the risk for no-reflow compared to those with SXScore ≤21 (events 9% vs 18%, p = 0.006). In conclusion, the SXScore obtained in the diagnostic phase of PPCI for acute ST-segment elevation myocardial infarction can identify patients at risk for developing no-reflow.

No-reflow: again prevention is better than treatment

Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for treating acute ST-segment elevation myocardial infarction (STEMI). The main goals are to restore epicardial infarct-related artery patency and achieve microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured (necrotic) myocardium.1 Angiographic assessment of myocardial blood flow is reported as thrombolysis in myocardial infarction (TIMI) flow, and although TIMI flow grade relates to outcome, even in the presence of TIMI-3 flow tissue level perfusion can still be disturbed as measured by other indexes such as corrected TIMI frame count (cTFC) or more invasive measures of coronary blood flow. Thus, depending on how it is measured, inadequate tissue level reperfusion can occur in up to 50% of cases. No-reflow is the term used to describe inadequate myocardial perfusion of a given coronary segment without angiographic evidence of mechanical vessel obstruction.2 Despite optimal evidence-based PPCI, myocardial no-reflow can still occur, negating many of the benefits of restoring culprit vessel patency, and is associated with a worse in-hospital and long-term prognosis.2 It is important to outline that no-reflow is only one of the four types of cardiac dysfunction (myocardial stunning, no-reflow, reperfusion arrhythmias, and lethal reperfusion injury) caused by myocardial reperfusion as recently summarized by Yellon and Hausenloy,3 and it refers to the high impedance of microvascular blood flow encountered during opening of the infarct-related coronary artery. In this manuscript, we concentrate on the processes of no-reflow while recognizing the relationships with reperfusion injury and the complexity of each of the interactions involved. The multifactorial nature of no-reflow has been summarized recently into four interacting processes: ischaemic injury, reperfusion injury, distal embolization, and susceptibility of microcirculation to injury ( Figure 1 ).4 Ischaemia–reperfusion (IR) injury is central to the pathophysiology of no-reflow and is associated …

TCT-185: Pretreatment with Single Low Loading Dose of Simvastatin Reduces Myocardial Ischemia-Reperfusion Injury and No-Reflow via PKA Pathway

TCT-185: Pretreatment with Single Low Loading Dose of Simvastatin Reduces Myocardial Ischemia-Reperfusion Injury and No-Reflow via PKA Pathway

Evaluation of the effects of tirofiban on myocardial infarction-reperfusion injury by delayed enhancement multi-slice spiral CT

Objective To evaluate the effcets of tirofihan on myocardial no-reflow after acute myocardial infarction and reperfusion by delayed enhancement-multi-slice CT(DE-MSCT).Methods Chinese mini pigs were randomized into control group and firofiban treatment group. Acute myocardial infarction was induced by balloon occlusion of the medium segment of the left anterior descending artery for 90 minutes. Repeffusion was created by withdrawing the balloon during angiography. All successful models received DE-MSCT examinatons at 1 h, 24 h, 48 h, and 72 h after reperfusion to observe the myocardial noreflow area. Data were analyzed with Spearman rank correlation and Wilcoxon Rank Sum test. Results Six pigs were successfully induced as acute reperfusion myocardial infarction in each group. Furthermore,4 pigs in control group and 3 pigs in firofiban treatment group had no-reflow phenomenon. The no-reflow volume percent increased from 1 h to 72 h in both groups. The no-reflow volume percent was significantly reduced in tirofiban treatment group compared with control group after reperfusion at 1 h, 24 h, 48 h and 72 h respectively[(4.78±0.66)% and (9.62±3.05)%, t =6.000, P＜0.05; (5.84 ± 1.19)% and (13.44±3.33)% ,t=6.000,P＜0. 05;(6.41± 1.24)% and (15.10±3.76)%,t =6.000,P ＜0.05;(6.63 ±0. 82)% and (15.94 ±4.62)% ,t =6.000,P ＜0.05] ,as well as the infarct myocardium volume percent was significantly reduced in tirofiban treatment group compared with control group at 24 h, 48 h and 72 h after reperfusion [ (19.74± 2. 94) % and ( 25.08 ± 4.68) %, t = 25.000, P ＜ 0.05;(20.34±2.46) % and (27.07 ±5.44)%, t =26. 000,P ＜0.05; (20.72 ±2.10)% and (26.17 ±5.19)% ,t = 24.000,P ＜0.05]. Conclusions DE-MSCT can be used to detect the extent of no-reflow phenomenon. Tirofiban can reduce the volume of myocardial infarct and no-reflow area after reperfusion. Key words: Myocardial infarction; Cardiovascular drugs; Tomography, X-ray computed; Animal model, experiment

Effect of Chronic Aspirin Therapy on Angiographic Thrombotic Burden in Patients Admitted for a First ST-Elevation Myocardial Infarction

Myocardial no-reflow may negate the benefit of urgent coronary revascularization in patients with acute ST-elevation myocardial infarction (STEMI). Among its pathogenetic mechanisms, distal embolization is of prominent importance and several studies have shown that a high coronary thrombotic burden is associated with distal embolization. We aimed at assessing predictors of angiographic thrombus grade in patients undergoing primary percutaneous coronary intervention. Ninety-one patients (62 +/- 12 years old, 79% men) presenting for a first STEMI and undergoing urgent coronary angiography within 12 hours from onset of symptoms were consecutively included in the study. Thrombus grade was evaluated by angiography according to the Gibson score and patients were allocated to the high thrombus grade (HTG; score 4 to 5) group or to the low thrombus grade (score 0 to 3) group. Variables predicting angiographic thrombus grade were assessed among clinical, angiographic, procedural, and laboratory data. Sixty-four patients (61 +/- 12 years old, 78% men) presented with HTG, whereas 27 patients (63 +/- 10 years old, 80% men) presented with low thrombus grade. Patients an HTG showed a significantly higher white blood cell count (12.5 +/- 4.8 vs 10.5 +/- 2.9, p = 0.015). Aspirin and beta-blocker therapy before admission were less frequently taken in the HTG group (5% vs 26% and 7% vs 23%, respectively, p = 0.01 and p = 0.03). At multivariate analysis, lack of previous therapy with aspirin was the only independent predictor of an HTG (odds ratio 6.14, 95% confidence interval 1.09 to 34.67, p = 0.04). In conclusion, previous aspirin therapy is associated with a decrease in angiographic thrombus grade in patients with STEMI treated with primary percutaneous coronary intervention, thus further priming efforts for appropriate use of aspirin in primary prevention of a first STEMI.

Effects of tongxinluo on mini-swine vascular endothelial integrity and myocardial no-reflow in early reperfusion of acute myocardial infarction

To assess the effects of tongxinluo on vascular endothelial integrity and myocardial no-reflow in early reperfusion of acute myocardial infarction. Forty mini-swines were divided into five groups randomly, sham group, control group, low dose (0.1 g/kg), medium dose (0.2 g/kg) and high dose (0.4 g/kg) groups of Tongxinluo. It was administered at 2 hours pre-reperfusion. Animals except in sham group were subjected to 1.5 hour of coronary occlusion followed by 3 hours of reperfusion. Content of VE-cadherin, beta-catenin, matrix metalloproteinase (MMP)-2 and 9 in myocardium were evaluated; no-reflow area was examined with myocardial contrast echocardiography (MCE) at 1.5 hour of AMI and 3 hours of reperfusion. (1) Compared with that of normal myocardium, content of VE-cadherin and beta-catenin decreased in reperfusion and no-reflow myocardium while MMP-2 and 9 increased significantly (all P < 0.05); (2) Compared with that of control group, a high dose of Tongxinluo could increase significantly the content of VE-cadherin in both reperfusion and no-reflow myocardium, (22.2 +/- 3.2)% vs (32.0 +/- 3.9)% and (14.5 +/- 2.8)% vs (28.3 +/- 2.2)% respectively, beta-catenin, (20.5 +/- 3.5)% vs (27.3 +/- 2.9)% and (13.3 +/- 2.1)% vs (20.6 +/- 2.4)%, while reduce MMP-2, (48.3 +/- 4.1)% vs (29.4 +/- 3.5)% and (57.3 +/- 4.3)% vs (38.2 +/- 4.0)% respectively, MMP-9, (55.6 +/- 4.0)% vs (34.3 +/- 3.5)% and (62.4 +/- 4.8)% vs (44.4 +/- 4.1)%, all P < 0.05; (3) Compared with that of control group, a high dose of Tongxinluo could reduce significantly both no-reflow area, (6.6 +/- 1.7) cm2 vs (4.7 +/- 1.5) cm2, P < 0.05, and percentage (90.8 +/- 3.8)% vs (71.4 +/- 4.1)%, P < 0.05, at 3 hours of reperfusion. A high dose of tongxinluo could effectively maintain the integrity of vascular endothelium and attenuate no-reflow area in early reperfusion of acute myocardial infarction.

Interventional therapy of coronary artery disease in China: retrospective and perspective

Interventional therapy of coronary artery disease in China: retrospective and perspective

Intravenous adenosine reduces myocardial no-reflow by decreasing endothelin-1 via activation of the ATP-sensitive KM+ channel

It has been verified that adenosine can attenuate myocardial no-reflow. However, the effects of adenosine on adenosine triphosphate-sensitive K+ (KATP) channel and endothelin-1 (ET-1) are unknown.Methods — Forty mini-swines were randomized into 5 study groups: 8 in the control group, 8 in the adenosine pretreatment group, 8 in the glibenclamide (KATP channel blocker)-treated group, 8 in the adenosine and glibenclamide-pretreated group and 8 in the sham-operated group. An acute myocardial infarction and reperfusion model was created with three-hour occlusion of the left anterior descending coronary artery followed by a one-hour reperfusion.Results — Compared with the control group, adenosine significantly decreased the area of no-reflow (myocardial contrast echocardiography: from 78.5 ± 4.5% to 20.7 ± 4.1%, pathological means: from 82.3 ± 1.9% to 21.5 ± 4.3% of ligation area, respectively; all P < 0.01), reduced necrosis size from 98.5 ± 1.3% to 75 ± 4.7% of ligation area, P < 0.05). It also decreased plasma ET-1 and myocardial tissue ET-1. However, glibenclamide abrogated the protective effect of adenosine.Conclusion — The beneficial effect of adenosine on myocardial no-reflow could be due to its effect on ET-1 via the activation of KATP channel.

Carvedilol reduces myocardial no-reflow by decreasing endothelin-1 via activation of the ATP-sensitive K+ channel

It has been verified that carvedilol can attenuate myocardial no-reflow. However, the effects of carvedilol on adenosine triphosphate-sensitive K(+) (K(ATP)) channel and endothelin-1 (ET-1) are unknown. Forty mini-swines were randomized into 5 study groups: 8 control, 8 carvedilol pretreatment, 8 glibenclamide (K(ATP) channel blocker)-treated, 8 carvedilol and glibenclamide-pre-treated and 8 sham-operated. An acute myocardial infarction(AMI) and reperfusion model was created with a three-hour occlusion of the left anterior descending coronary artery followed by one-hour reperfusion. Compared with the control group, carvedilol significantly decreased the area of no-reflow (myocardial contrast echocardiography: from 78.5+/-4.5% to 24.9+/-4.1%, pathological means: from 82.3+/-1.9% to 25.8+/-4.3% of ligation area, respectively; all p < 0.01) and reduced necrosis size from 98.5+/-1.3% to 74.4+/-4.7% of ligation area, p < 0.05). It also decreased plasma ET-1 and myocardial tissue ET-1. However, glibenclamide abrogated the protective effect of carvedilol. The beneficial effect of carvedilol on myocardial no-reflow could be due to its effect on ET-1 via the activation of the K(ATP) channel.

Remote periconditioning reduces myocardial no-reflow by the activation of K ATP channel via inhibition of Rho-kinase

Remote periconditioning is induced by brief cycles of ischemia and reperfusion of a remote organ applied during sustained myocardial ischemia. It remains unknown whether the remote periconditioning reduces myocardial no-reflow. The adenosine triphosphate-sensitive potassium (K ATP) channel opening and inhibition of Rho-kinase may be the important mechanism of protection against myocardial no-reflow. Therefore, this study was sought to assess the effect of remote periconditioning on myocardial no-reflow and explore the possible mechanism. Methods Coronary ligation area and area of no-reflow were determined with pathological means in 58 mini-swines randomized into 7 study groups: 9 controls, 8 in remote periconditioning, 8 in hydroxyfasudil (a specific inhibitor of Rho-kinase)-treated, 9 in glibenclamide (K ATP channel blocker)-treated, 8 in remote periconditioning and glibenclamide, 8 in hydroxyfasudil and glibenclamide and 8 sham-operated. The ischemia and reperfusion model was created with 3 h of left anterior descending artery occlusion followed by 2 h of reperfusion. Results Compared with the control group, remote periconditioning decreased Rho-kinase activity ( P < 0.01), increased coronary blood volume ( P < 0.05), decreased area of no-reflow (from 82.3 ± 3.9% to 45.5 ± 5.7% of ligation area, P < 0.01) and reduced necrosis size (from 98.5 ± 1.3% to 74.7 ± 6.3% of ligation area, P < 0.05). Hydroxyfasudil had the same effect on the above parameters as remote periconditioning. Glibenclamide abrogated the effect of remote periconditioning or hydroxyfasudil on area of no-reflow and necrosis area, but not Rho-kinase activity. Conclusion Remote periconditioning can reduce myocardial no-reflow after ischemia and reperfusion. This beneficial effect could be due to its activation of K ATP channel via inhibition of Rho-kinase.

Tirofiban Preserves Endothelial Junctions and Decreases Endothelin-1

It has been verified that glycoprotein IIb/IIIa inhibitor tirofiban can attenuate myocardial no-reflow. Myocardial no-reflow has been associated with alterations in endothelial junctions. In addition, ET-1 is an important mechanism for myocardial no-reflow. However, the effect of tirofiban on endothelial junctions and Endothelin-1 (ET-1) is unknown. Methods: Twenty-eight mini-swines were randomized into 3 study groups: 10 in control, 10 given an intravenous infusion of tirofiban and 8 in sham-operated. Acute myocardial infarction and reperfusion model was created with three-hour occlusion of the left anterior descending coronary artery followed by one-hour reperfusion. Results: In control group, plasma ET-1 significantly increased, ET-1 or VE-cadherin level in the reflow and no-reflow myocardium was significantly higher or lower than that in normal myocardium. Compared with the control group, tirofiban significantly decreased plasma ET-1 and myocardial tissue ET-1, maintained VE-cadherin level. Conclusions: Tirofiban is effective in preserving endothelial junction. This beneficial effect of tirofiban could be partly due to its reduction of ET-1.

Intravenous nicorandil preserves endothelial junctions by decreasing endothelin-1 via activation of ATP-sensitive K+ channel

It has been verified that nicorandil can attenuate myocardial no-reflow. However; the effects of nicorandil on endothelial junctions and Endothelin-1 (ET-1) are unknown. 40 mini-swines randomized into 5 study groups: 8 in control, 8 nicorandil pretreatment, 8 in glibenclamide (KATP channel blocker)-treated, 8 in nicorandil and glibenclamide-pretreated and 8 in sham-operated. Acute myocardial infarction and reperfusion model was created with three-hour occlusion of the left anterior descending coronary artery followed by one-hour reperfusion. In control group, plasma ET-1 significantly increased, ET-1 or VE-cadherin level in the reflow and no-reflow myocardium was significantly higher or lower than that in normal myocardium. Compared with the control group, nicorandil significantly decreased plasma ET-1 and myocardial tissue ET-1, maintained VE-cadherin level. However, glibenclamide abrogated the protective effect of nicorandil. The beneficial effect of nicorandil on endothelial junctions could be due to its effect on ET-1 via the activation of KATp channel.

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

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+ (K(ATP)) channel opening is an important mechanism. 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. 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 K(ATP) 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. Post-infarction treatment with simvastatin can reduce myocardial no-reflow. This beneficial effect is due to activation of the K(ATP) channel.

Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic mini-swines

Background: Postconditioning with multiple very short coronary occlusions immediately after prolonged ischemia has been found to reduce infarction size. However, it remains unknown whether postconditioning under the normal or hypercholesterolemic condition can also reduce myocardial no-reflow for which endothelial dysfunction is an important mechanism. Methods: Twenty-four normal mini-swines were randomized into 3 study groups: 8 in control, 8 in postconditioning, 8 in sham-operated group. Twenty-four hypercholesterolemic mini-swines were also randomized into 3 study groups: 8 in control, 8 in postconditioning, 8 in sham-operated group. Acute myocardial infarction and reperfusion model was created with 3 h occlusion of the left anterior descending coronary artery followed by two-hour reperfusion. Coronary ligation area (LA) and area of no-reflow were determined with pathological means (Path). Results: Compared with the normal control group, postconditioning under the normal condition significantly improved endothelial function, decreased area of no-reflow (Path: from 81.3 ± 3.9% to 54.3 ± 3.69% of LA, P < 0.01) and reduced necrosis area from 98.5 ± 2.35% to 76.1 ± 5.6% of LA ( P < 0.05–0.01). However, compared with the normal control group, postconditioning under the hypercholesterolemic condition did not significantly modify endothelial function, area of no-reflow and necrosis area ( P > 0.05). Conclusion: These findings support the concept that postconditioning under the normal condition can reduce the area of no-reflow and necrosis area, while postconditioning under the hypercholesterolemic condition cannot. The beneficial effect of postconditioning on myocardial no-reflow could be due to its protection of endothelial function.