Myocardial autophagy variation during acute myocardial infarction in rats： the effects of carvedilol

Background The loss of cardiac myocytes is one of the mechanisms involved in acute myocardial infarction （AMI）-related heart failure. Autophagy is a common biological process in eukaryote cells. The relationship between cardiac myocyte loss and autophagy after AMI is still unclear. Carvedilol, a non-selective α1-and β-receptor blocker, also suppresses cardiac myocyte necrosis and apoptosis induced by ischemia. However, the association between the therapeutic effects of carvedilol and autophagy is still not well understood. The aim of the present study was to establish a rat model of AMI and observe changes in autophagy in different zones of the myocardium and the effects of carvedilol on autophagy in AMI rats. Methods The animals were randomly assigned to a sham group, an AMI group, a chloroquine intervention group and a carvedilol group. The AMI rat model was established by ligating the left anterior descending coronary artery. The hearts were harvested at 40 minutes, 2 hours, 24 hours and 2 weeks after ligation in the AMI group, at 40 minutes in the chloroquine intervention group and at 2 weeks in other groups. Presence of autophagic vacuoles （AV） in the myocytes was observed by electron microscopy. The expression of autophagy-, anti-apoptotic- and apoptotic-related proteins, MAPLC-3, Beclin-1, Bcl-xl and Bax, were detected by immunohistochemical staining and Western blotting. Results AVs were not observed in necrotic regions of the myocardium 40 minutes after ligation of the coronary artery. A large number of AVs were found in the region bordering the infarction. Compared with the infarction region and the normal region, the formation of AV was significantly increased in the region bordering the infarction （P 〈0.05）. The expression of autophagy- and anti-apoptotic-related proteins was significantly increased in the region bordering the infarction. Meanwhile, the expression of apoptotic-related proteins was significantly increased in the infarction region. In the chloroquine intervention group, a large number of initiated AVs （AVis） were found in the necrotic myocardial region. At 2 weeks after AMI, AVs were frequently observed in myocardial cells in the AMI group, the carvedilol group and the sham group, and the number of AVs was significantly increased in the carvedilol group compared with both the AMI group and the sham group （P 〈0.05）. The expression of autophagy- and anti-apoptotic-related proteins was significantly increased in the carvedilol group compared with that in the AMI group, and the positive expression located in the infarction region and the region bordering the infarction. Conclusions AMI induces the formation of AV in the myocardium. The expression of anti-apoptosis-related proteins increases in response to upregulation of autophagy. Carvedilol increases the formation of AVs and upregulates autophagy and anti-apoptosis of the cardiac myocytes after AMI.

Efficacy and safety of noninvasive positive pressure ventilation in the treatment of acute respiratory failure after cardiac surgery

Background Although noninvasive positive pressure ventilation （NPPV） has been successfully used for various kinds of acute respiratory failure,the data are limited regarding its application in postoperative respiratory failure after cardiac surgery.Therefore,we conducted a prospective randomized control study in a university surgical intensive care unit to evaluate the efficacy and safety of NPPV in the treatment of acute respiratory failure after cardiac surgery,and explore the predicting factors of NPPV failure.Methods From September 2011 to November 2012 patients with acute respiratory failure after cardiac surgery who had indication for the use of NPPV were randomly divided into a NPPV treatment group （NPPV group） and the conventional treatment group （control group）.The between-group differences in the patients＇ baseline characteristics,re-intubation rate,tracheotomy rate,ventilator associated pneumonia （VAP） incidence,in-hospital mortality,mechanical ventilation time after enrollment （MV time）,intensive care unit （ICU） and postoperative hospital stays were compared.The factors that predict NPPV failure were analyzed.Results During the study period,a total of 139 patients who had acute respiratory failure after cardiac surgery were recorded,and 95 of them met the inclusion criteria,which included 59 males and 36 females with a mean age of （61.5±11.2） years.Forty-three patients underwent coronary artery bypass grafting （CABG）,23 underwent valve surgery,13 underwent CABG＋valve surgery,13 underwent major vascular surgery,and three underwent other surgeries.The NPPV group had 48 patients and the control group had 47 patients.In the NPPV group,the re-intubation rate was 18.8％,tracheotomy rate was 12.5％,VAP incidence was 0,and the in-hospital mortality was 18.8％,significantly lower than in the control group 80.9％,29.8％,17.0％ and 38.3％ respectively,P ＜0.05 or P ＜0.01.The MV time and ICU stay （expressed as the median （P25,P75）） were 18.0 （9.2,35.0） hours and 4.0 （2.0,5.0） days,which were significantly shorter than in the control group,96.0 （26.0,240.0） hours and 6.0 （4.0,9.0） days respectively,P ＜0.05 or P ＜0.01.The postoperative hospital stays of the two groups were similar.The univariate analysis showed that the NPPV success subgroup had more patients with acute lung injury （ALl） （17 vs.0,P=0.038）,fewer patients with pneumonia （2 vs.7,P ＜0.001） and lower acute physiology and chronic health evaluation Ⅱ （APACHE Ⅱ） scores （16.1±2.8 vs.21.8±3.2,P ＜0.001）.Multivariate analysis showed that pneumonia （P=-0.027） and a high APACHE Ⅱ score ＞20 （P=-0.002） were the independent risk factors of NPPV failure.Conclusions We conclude that NPPV can be applied in selected patients with acute respiratory failure after cardiac surgery to reduce the need of re-intubation and improve clinical outcome as compared with conventional treatment.Pneumonia and a high APACHE Ⅱ score ＞20 might be the independent risk factors of NPPV failure in this group of patients.

Neuregulin-1 preconditioning protects the heart against ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism

Background Neuregulin-1 （NRG-1）, the ligand of the myocardial ErbB receptor, is a protein mediator with regulatory actions in the heart. This study investigated whether NRG-1 preconditioning has protective effects on myocardial ischemia/reperfusion （I/R） injury and its potential mechanism.Methods We worked with an in vivo rat model with induced myocardial ischemia （45 minutes） followed by reperfusion （3 hours）. NRG-1 message was detected in the heart using RT-PCR and the protein levels of NRG-1 and ErbB4 were detected by Western blotting analysis. Infarct size was assessed using the staining agent triphenyltetrazolium chloride and cardiac function was continuously monitored. The levels of creatine kinase and lactate dehydrogenase in plasma were analyzed to assess the degree of cardiac injury. The extent of cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling （TUNEL） assay and by Western blotting analysis of cleaved caspase-3. We examined the phosphorylation of Akt in the myocardium and the effect of PI3K/Akt inhibition on NRG-1-induced cardioprotection.Results Transcription and expression of NRG-1 and phosphorylation of its ErbB4 receptor were significantly upregulated in the I/R hearts. NRG-1 pretreatment reduced the infarct size following cardiac I/R in a concentration-dependent manner with an optimal concentration of 4 μg/kg in vivo. NRG-1 pretreatment with 4 μg/kg, i.v.markedly reduced the plasma creatine kinase and lactate dehydrogenase levels. Pretreatment with NRG-1 also significantly reduced the percentage of TUNEL positive myocytes and the level of cleaved caspase-3 in the I/R hearts.Pretreatment with NRG-1 significantly increased phosphorylation of Akt following I/R. Furthermore, the cardioprotective effect limiting the infarct size that was induced by NRG-1 was abolished by co-administration of the PI3K inhibitor LY294002.Conclusions The concentration of NRG-1, a new autacoid, was rapidly upregulated after myocardial I/R. NRG-1 preconditioning has cardioprotective effects against I/R injury through a PI3K/Akt-dependent mechanism in vivo.

Matrix metaHoproteinase-8 inhibitors mitigate sepsis-induced myocardial injury in rats

Background Sepsis-induced myocardial injury （SIMI） is caused by a variety of mechanisms. The aim of the study is to investigate the effects of metalloproteinase-8 （MMP-8） on SIMI and its mechanisms in rats. Methods Forty male Sprague Dawley rats were randomly divided into four groups： MMP-8 inhibitor （M81）, dexamethasone （DEX）, sepsis, and sham groups. The sepsis model was established by cecal ligation and puncture （CLP）. Rats in the M81 group immediately received an intraperitoneal injection of M81 （0.1 mg/kg） after CLP. Rats in the DEX group immediately received an intraperitoneal （IP） injection of DEX （2 mg/kg）. Rats in the sepsis and sham groups received intraperitoneal injections of normal saline. Rats were sacrificed 12 hours after CLP. Paraffin sections were stained with hematoxylin and eosin to observe the myocardium. The myocardial ultrastructure was observed with transmission electron microscopy. MMP-8, tumor necrosis factor-Q （TNF-a）, and interleukin-113 （IL-113） were detected by immunohistochemistry. The expression of MMP-8 was measured by Western blotting. TNF-a and IL-113 levels in serum and myocardial tissue were determined by enzyme-linked immunosorbent assay. Results Compared with the sham group, the myocardium in the sepsis group was seriously injured. MMP-8, TNF-α and IL-1β expression was higher in the sepsis group than in the sham group, Treatment with M81 or DEX, however, attenuated sepsis induced histopathological changes in the heart, and was associated with significant reductions in serum and myocardial levels of TNF-a and IL-113 （P 〈0.05）. M81 significantly inhibited MMP-8 expression in myocardial tissue （P 〈0.05）. In addition, treatment with DEX was not associated with a change in myocardial levels of MMP-8 （P 〉0.05）. Conclusion MMP-8 inhibitor attenuated myocardial injury in septic rats, which might be related to reduced expression of TNF-α and IL-1β.