Jing-Lin Zhao

Pretreatment with simvastatin reduces myocardial no‐reflow by opening mitochondrial KATP channel

Simvastatin, a cholesterol‐lowering agent, can protect against endothelial dysfunction. However, the effects of simvastatin treatment on the restoration of blood flow to ischemic myocardium are not known. This study sought to assess such effects of simvastatin on an experimental model of myocardial no‐reflow and to explore possible mechanisms.

Different effects of tirofiban and aspirin plus clopidogrel on myocardial no-reflow in a mini-swine model of acute myocardial infarction and reperfusion

Objective: To compare the effects of an aspirin–clopidogrel combination with those of the specific glycoprotein IIb/IIIa inhibitor tirofiban on myocardial no-reflow, nitric oxide concentration and activity of nitric oxide synthase (NOS) isoforms in a mini-swine model of acute myocardial infarction and reperfusion. Methods: Area of no-reflow was determined by both myocardial contrast echocardiography and pathological means in 40 mini-swine randomly assigned to five study groups: eight controls, eight pretreated with aspirin–clopidogrel combination for three days, eight given an intravenous infusion of tirofiban, eight treated with ischaemic preconditioning and eight sham operated. The acute myocardial infarction and reperfusion model was created with 3 h occlusion of the left anterior descending coronary artery followed by 1 h reperfusion. Results: Compared with the control group, tirofiban significantly decreased the area of no-reflow assessed echocardiographically and pathologically, from 78.5% to 22.8% and 82.3% to 23.2%, respectively (both p < 0.01), and increased blood nitric oxide concentration (p < 0.05), enhanced constitutive NOS activity from 0.51 to 0.81 U/mg protein and mRNA expression from 0.47% to 0.66%, but decreased inducible NOS activity from 0.76 to 0.41 U/mg protein and mRNA expression from 0.54% to 0.39% in reflow myocardium (all p < 0.05–0.01). In contrast, the aspirin–clopidogrel combination did not significantly modify the above parameters (all p > 0.05) except for decreasing inducible NOS activity from 0.76 to 0.39 U/mg protein (p < 0.01) and mRNA expression from 0.54% to 0.40% (p < 0.05). Conclusions: Tirofiban is very effective in attenuating myocardial no-reflow; in contrast, aspirin–clopidogrel combination is totally ineffective. These findings also support the concept that endothelial protection, apart from platelet inhibition, contributes to the beneficial effect of tirofiban on myocardial no-reflow.

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+ (KATP) channel opening is an important mechanism.

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

UNLABELLED 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.

Pretreatment with fosinopril or valsartan reduces myocardial no-reflow after acute myocardial infarction and reperfusion.

BackgroundBoth fosinopril and valsartan are effective in protecting endothelial function. We hypothesized that they may also reduce myocardial no-reflow. In addition, suppression of adenosine triphosphate-sensitive K+ (KATP) channel opening is an important mechanism for myocardial no-reflow. Therefore, this study sought to assess the effect of fosinopril and valsartan on myocardial no-reflow and explore the possible mechanism. MethodsCoronary ligation area and the area of no-reflow were determined with both myocardial contrast echocardiography in vivo and pathological means in 56 mini-swine randomized into seven study groups: eight in control, eight in fosinopril-pretreated (1 mg/kg/day) for 3 days, eight in fosinopril and glibenclamide (KATP channel blocker)-pretreated, eight in valsartan-pretreated (2 mg/kg/day) for 3 days, eight in valsartan and glibenclamide-pretreated, eight in glibenclamide-treated and eight in sham-operated. An acute myocardial infarction and reperfusion model was created with a 3-h occlusion of the coronary artery followed by a 2-h reperfusion. The levels of KATP channel proteins (SUR2, Kir6.1, and Kir6.2) in the reflow and no-reflow myocardium were quantified by Western blotting. ResultsCompared with the control group, both fosinopril and valsartan significantly improved ventricular function, decreased area of no-reflow (myocardial contrast echocardiography: from 78.5±4.5 to 24.5±2.7 and 24.3±3.6%, pathological means: from 82.3±1.9 to 25.2±3.2 and 24.9±4.4% of ligation area, respectively; all P<0.01), reduced necrosis size from 98.5±1.3 to 88.9±3.6 and 89.1±3.1% of ligation area, respectively (both P<0.05). They also increased the levels of SUR2 and Kir6.2 (P<0.01), but had no effect on the level of Kir6.1 (P>0.05). A combination of fosinopril or valsartan with glibenclamide significantly increased area of no-reflow (P<0.05) and decreased the levels of SUR2 and Kir6.2 (P<0.01). ConclusionsPretreatment with fosinopril or valsartan can reduce myocardial no-reflow. This beneficial effect is due to activation of the KATP channel.

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

OBJECTIVE To 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 RESULTS In 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 Ser(133) 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 Ser(1179) and Ser(635) 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. CONCLUSION IP attenuates myocardial no-reflow and infarction after ischemia and reperfusion by activating the phosphorylation of eNOS at Ser(1179) and Ser(635) in a partly PKA-dependent manner.

Cardiac Microvascular Barrier Function Mediates the Protection of Tongxinluo against Myocardial Ischemia/Reperfusion Injury

Objective Tongxinluo (TXL) has been shown to decrease myocardial necrosis after ischemia/reperfusion (I/R) by simulating ischemia preconditioning (IPC). However, the core mechanism of TXL remains unclear. This study was designed to investigate the key targets of TXL against I/R injury (IRI) among the cardiac structure-function network. Materials and Methods To evaluate the severity of lethal IRI, a mathematical model was established according to the relationship between myocardial no-reflow size and necrosis size. A total of 168 mini-swine were employed in myocardial I/R experiment. IRI severity among different interventions was compared and IPC and CCB groups were identified as the mildest and severest groups, respectively. Principal component analysis was applied to further determine 9 key targets of IPC in cardioprotection. Then, the key targets of TXL in cardioprotection were confirmed. Results Necrosis size and no-reflow size fit well with the Sigmoid Emax model. Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R2=0.92, R2=0.57, P<0.01, respectively). Functional and structural indices correlate positively with NRS (R2=0.64, R2=0.62, P<0.01, respectively). TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, β-catenin, γ-catenin and P-selectin with a trend toward the sham group. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group. Among the above nine indices, eNOS activity, eNOS, VE-cadherin, β-catenin and γ-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI. Conclusions Our study underlines the lethal IRI as one of the causes of myocardial necrosis. Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC.

The Effect of Statins on the No-Reflow Phenomenon : An Observational Study in Patients with Hyperglycemia before Primary Angioplasty

BACKGROUND An association between admission plasma glucose levels and an increased risk of no-reflow has been well documented. Although HMG-CoA reductase inhibitor (statin) therapy can reduce no-reflow, little is known about its effect on no-reflow in patients with hyperglycemia. In the present study, we investigated whether pretreatment with a statin could reduce no-reflow in patients with hyperglycemia, who underwent primary coronary intervention for acute myocardial infarction (AMI). METHODS A total of 259 consecutive patients who underwent primary angioplasty for a first AMI were studied. Blood glucose and creatinine kinase levels were measured on admission. All patients underwent 2-dimensional echocardiography and electrocardiographic analysis just after admission. No-reflow was defined as a Thrombolysis in Myocardial Infarction (TIMI) flow grade <3. Hyperglycemia was defined as a blood glucose level >or=10 mmol/L. Statin administration prior to admission was determined by detailed interview or information in the medical records. RESULTS Hyperglycemia was diagnosed in 154 patients on admission. The no-reflow phenomenon was found in 31 of the 154 patients with hyperglycemia. The incidence of no-reflow was significantly greater in patients with hyperglycemia compared with no hyperglycemia. A multivariable logistic regression analysis showed that hyperglycemia on admission was an independent predictor of no-reflow. Among the 154 patients with hyperglycemia, there were no significant differences in baseline clinical characteristics between patients who received statin pretreatment and those who did not; however, hyperlipidemia occurred in a greater number of the patients who did not receive statin pretreatment. The 40 patients with hyperglycemia who received statins before admission had a lower incidence of no-reflow than those who did not receive statin pretreatment (5% and 25.4%; p < 0.05). Multivariable logistic regression analysis revealed that absence of statin pretreatment was a significant predictor of no-reflow in patients with hyperglycemia, along with ejection fraction on admission, initial TIMI 0 flow, number of Q waves, and anterior AMI. CONCLUSION The results of our study show that pretreatment with statins could attenuate no-reflow after AMI in patients with acute hyperglycemia.

Chronic pretreatment of metformin is associated with the reduction of the no-reflow phenomenon in patients with diabetes mellitus after primary angioplasty for acute myocardial infarction.

INTRODUCTION Metformin is one of the most commonly prescribed antihyperglycemic agents for the treatment of type 2 diabetes. However, little is known about the effect of metformin on no-reflow in diabetic patients. AIM In this study, we investigated retrospectively whether chronic pretreatment with metformin was associated with no-reflow in diabetic patients who underwent primary coronary intervention for acute myocardial infarction (AMI). RESULTS A total of 154 consecutive diabetic patients who underwent primary angioplasty for a first ST-segment elevation myocardial infarction were studied. No-reflow was defined as a final TIMI flow of ≤2 or final TIMI flow of 3 with a myocardial blush grade of <2. The no-reflow phenomenon was found in 53 of 154 patients. There were no significant differences in clinical characteristics between the patients with and without metformin pretreatment. However, the 65 patients receiving chronic metformin treatment before admission had lower incidence of the no-reflow than those without it (4.2 and 14.6%, P < 0.05). Multivariable logistic regression analysis revealed that absence of metformin pretreatment was a significant predictor of the no-reflow along with high-burden thrombus, ejection fraction on admission and anterior AMI. CONCLUSION These results suggested that chronic pretreatment with metformin may be associated with the reduction of the no-reflow phenomenon in patients with diabetes mellitus after primary angioplasty for AMI.

The Effect of Statins on the No-Reflow Phenomenon

BackgroundAn association between admission plasma glucose levels and an increased risk of no-reflow has been well documented. Although HMG-CoA reductase inhibitor (statin) therapy can reduce no-reflow, little is known about its effect on no-reflow in patients with hyperglycemia. In the present study, we investigated whether pretreatment with a statin could reduce no-reflow in patients with hyperglycemia, who underwent primary coronary intervention for acute myocardial infarction (AMI).MethodsA total of 259 consecutive patients who underwent primary angioplasty for a first AMI were studied. Blood glucose and creatinine kinase levels were measured on admission. All patients underwent 2-dimensional echocardiography and electrocardiographic analysis just after admission. No-reflow was defined as a Thrombolysis in Myocardial Infarction (TIMI) flow grade <3. Hyperglycemia was defined as a blood glucose level ≥10 mmol/L. Statin administration prior to admission was determined by detailed interview or information in the medical records.ResultsHyperglycemia was diagnosed in 154 patients on admission. The no-reflow phenomenon was found in 31 of the 154 patients with hyperglycemia. The incidence of no-reflow was significantly greater in patients with hyperglycemia compared with no hyperglycemia. A multivariable logistic regression analysis showed that hyperglycemia on admission was an independent predictor of no-reflow. Among the 154 patients with hyperglycemia, there were no significant differences in baseline clinical characteristics between patients who received statin pretreatment and those who did not; however, hyperlipidemia occurred in a greater number of the patients who did not receive statin pretreatment. The 40 patients with hyperglycemia who received statins before admission had a lower incidence of no-reflow than those who did not receive statin pretreatment (5% and 25.4%; p < 0.05). Multivariable logistic regression analysis revealed that absence of statin pretreatment was a significant predictor of no-reflow in patients with hyperglycemia, along with ejection fraction on admission, initial TIMI 0 flow, number of Q waves, and anterior AMI.ConclusionThe results of our study show that pretreatment with statins could attenuate no-reflow after AMI in patients with acute hyperglycemia.