Myocardial protection by volatile anesthetics

Myocardial ischaemia/reperfusion situations may occur during the perioperative period. The cardioprotective effects of anaesthetics have been known for a long time: volatile anaesthetics reduce the ischaemic cell damage and infarct development. Besides ischaemia, reperfusion itself can also lead to cellular damage, thereby further increasing the ischaemic injury (reperfusion injury). Inhalational anaesthetics offer specific protective effects against reperfusion injury in isolated hearts as well as in rabbit hearts in vivo. This protection does not depend on haemodynamic side-effects of the substances and is even present after protecting the heart against ischaemic damage using a cardioplegic solution. Short periods of ischaemia render the myocardium resistant to subsequent longer periods of ischaemia. This strongest endogenous protective mechanism against the consequences of an ischaemia is known as ischaemic preconditioning. The protective effect can also be produced by stimulation of different types of receptors: the respective agonists produce pharmacological (chemical) preconditioning. The common pathway of the signal transduction cascade of both ischaemic and chemical preconditioning includes the sarcolemnal and/or mitochondrial ATP-sensitive potassium channel. Volatile anaesthetics can imitate the protective effects of a short ischaemia, thereby producing chemical preconditioning. This effect depends, at least in part, on anaesthetic-induced opening of ATP-sensitive potassium channels.     

The endothelin-1 receptor antagonist bosentan protects against ischaemia/reperfusion-induced endothelial dysfunction in humans

Endothelial dysfunction may contribute to the extent of ischaemia/reperfusion injury. ET (endothelin)-1 receptor antagonism protects against myocardial ischaemia/reperfusion injury in animal models. The present study investigated whether oral administration of an ET(A)/ET(B) receptor antagonist protects against ischaemia/reperfusion-induced endothelial dysfunction in humans. FBF (forearm blood flow) was measured with venous occlusion plethysmography in 13 healthy male subjects. Forearm ischaemia was induced for 20 min followed by 60 min of reperfusion. Using a cross-over protocol, the subjects were randomized to oral administration of 500 mg of bosentan or placebo 2 h before ischaemia. Endothelium-dependent and -independent vasodilatation were determined by intra-brachial infusion of acetylcholine (1-10 microg/min) and nitroprusside (0.3-3 microg/min) respectively, before and after ischaemia. Compared with pre-ischaemia, the endothelium-dependent increase in FBF was significantly impaired at 15 and 30 min of reperfusion when the subjects received placebo (P<0.01). When the subjects received bosentan, the endothelium-dependent increase in FBF was not affected by ischaemia/reperfusion. Endothelium-independent vasodilatation was not affected during reperfusion compared with pre-ischaemia. The vaso-constrictor response induced by intra-arterial infusion of ET-1 was attenuated significantly by bosentan (P<0.001). The results suggest that the dual ET(A)/ET(B) receptor antagonist bosentan attenuates ischaemia/reperfusion-induced endothelial dysfunction in humans in vivo. Bosentan may thus be a feasible therapeutic agent in the treatment of ischaemia/reperfusion injury in humans.     

Volatile anaesthetics and cardioprotection – lessons from animal studies

Volatile anaesthetics emerged as important cardioprotective agents in both animal models of ischaemia/reperfusion injury and humans with coronary artery disease. Their administration before a prolonged ischaemic episode is known as anaesthetic preconditioning, whereas when given at the very onset of reperfusion, the strategy is termed anaesthetic postconditioning. Both types of anaesthetic conditioning reduce, albeit not to the same degree, the extent of myocardial injury. They share similar, albeit not identical, intracellular signal transduction pathways with their widely investigated counterparts, ischaemic pre‐ and postconditioning. Despite a wealth of preclinical evidence for cardioprotection for anaesthetic conditioning strategies, their translation into clinical therapy has been rather disappointing. This review highlights the major findings on the cardioprotective effects of volatile anaesthetics in experimental settings. It explores hypotheses that may explain the lack of efficacy observed in several past clinical studies paving the way for future preclinical and translational studies.     

Does method of anesthesia modify postoperative ischemia incidence? A study of patients after aortocoronary bypass operations

In the postoperative period after coronary artery bypass graft surgery, the physician's enhanced attention should be focused on the incidence of myocardial ischaemia. The increased stress in the awakening patient as well as the return of autonomous reflexes can be the cause of imbalances in myocardial oxygen supply and uptake. Therefore, a probable influence of the pharmacologic profile of the intraoperatively applied anaesthetics on the incidence of postoperative myocardial ischaemia is of importance for adapting therapy on ICU to minimize any ischaemic risk. After approval by the ethics committee, a prospective randomized study was performed in 40 male patients who underwent coronary artery bypass graft surgery. The aim of the study was to compare balanced anaesthetic techniques performed with fentanyl and halothane, isoflurane and enflurane, respectively, with total intravenous anaesthesia performed with fentanyl and midazolam. An index to classify detection of ischaemia into three categories (ischaemia, probable ischaemia, no ischaemia) was established, based on measurements of myocardial lactate extraction and ST-segment analysis. Simultaneously, measurements of haemodynamic parameters and serum concentrations of catecholamines and intraoperatively applied anaesthetics were taken. In 8% of all measurements (30% of all patients) ischaemia was detected in the observation period and in 37% of all measurements (72.5% of all patients) probable ischaemia was detected. No significant difference was found concerning the incidence of myocardial ischaemia between all groups. The results of this investigation indicate that the application of inhalational anaesthetics for maintaining anaesthesia in coronary artery bypass graft surgery does not increase the risk of postoperative myocardial ischaemia.     

双羟基黄酮醇对心肌再灌注损伤中局部心肌血流量影响的实验研究

目的:评价双羟基黄酮醇对缺血后冠脉内皮功能的作用以及评价其对致死性心肌缺血再灌注损伤的防治效果。方法:测定意识清醒、无应激状态下绵羊的冠状血管对不同浓度静脉输注的乙酰胆碱的反应,闭塞冠状动脉1 h然后进行7 d的连续再灌注,再灌注的同时进行双羟基黄酮醇或vehicle的治疗,测定缺血状态下和再灌注开始后的血液动力学指数和局部心肌收缩力,评估冠脉血管对乙酰胆碱的反应,并心脏测量梗死面积。结果:(1)双羟基黄酮醇处理后可预防心率上升,显著降低左室舒张末压在再灌注过程中的升高幅度;(2)乙酰胆碱引起的浓度依赖性心率、心搏出量和外周血管传导力的上升并不受到双羟基黄酮醇的处理和心肌缺血/再灌注的影响;(3)双羟基黄酮醇处理后梗死面积显著缩小;(4)双羟基黄酮醇处理可以显著改善危险心肌边缘区域的局部心肌血流。结论:双羟基黄酮醇可显著缩小心肌梗死面积,延长缺血后心肌再灌注中可显著改善内皮功能,可显著减弱危险心肌边缘区局部血流量的进行性损伤。     

Myocardial stunning following no flow ischaemia is diminished by levosimendan or cariporide, without benefits of combined administration

AIM OF THE STUDY: Levosimendan, a calcium sensitiser, and cariporide, a blocker of the Na+/H+ exchanger, decrease necrosis and improve function following myocardial ischaemia. However, their role in myocardial stunning is unclear. We tested the hypothesis that levosimendan, cariporide, or their combination reduce stunning after global myocardial ischaemia. METHODS: In a prospective, controlled, randomised laboratory study isolated guinea pig hearts (n=48) were perfused in a Langendorff apparatus. Stunning was induced by 20 min of global no-flow ischaemia. Levosimendan (0.1 micromol/l) or cariporide (1 micromol/l) were given either before or after ischaemia, and effects of both drugs combined were also assessed. Left ventricular developed pressure (LVdp) was assessed continuously before ischaemia and for 45 min after reperfusion. RESULTS: Levosimendan (24+/-7%) and the combination of levosimendan and cariporide (38.7+/-4%) increased LVdp from baseline values before ischaemia, without differences between groups. In contrast, cariporide alone decreased LVdp (-11+/-2%) from baseline. Ischaemia/reperfusion decreased LVdp by about 70% in vehicle treated hearts compared to baseline. Treatment with cariporide, levosimendan, or their combination both before and after ischaemia, and treatment with cariporide after ischaemia caused a 25% greater recovery of LVdp than in control hearts. There were no differences between these groups and no enhanced effect with levosimendan/cariporide combined. In contrast, levosimendan only given after ischaemia did not improve LVdp. CONCLUSIONS: Cariporide diminished stunning when given before or after ischaemia, while levosimendan was only effective if given before ischaemia. Thus, levosimendan or cariporide may be useful in settings where ischaemia/reperfusion is to be expected.     

多普勒组织成像技术定量评价缺血再灌注局部心室壁运动

目的探讨多普勒组织成像(DTI)技术定量判断急性缺血再灌注局部室壁运动异常的可行性。方法应用Acuson Sequoia     

多普勒组织成像定量评价心室壁运动的价值

目的　探讨多普勒组织成像 (DTI)技术与传统二维超声判断心脏局部室壁运动异常的准确性与敏感性。方法　采用二维超声及DTI速度模式观察 8条犬冠脉结扎前后的局部室壁运动 ,所用仪器为AcusonSequoiaC 2 5 6彩色超声成像系统。 结果　缺血导致局部心室壁运动明显减弱 ,脉冲频谱DTI技术于冠脉闭塞后5s可检出这种异常 ,而传统超声指标在闭塞 1min后才出现显著性差异。血流再灌注 1min时 ,局部室壁运动明显增强。结论　DTI技术可定量评价急性缺血早期和再灌注局部室壁运动异常 ,方法较传统二维超声敏感准确。     

Intracoronary magnesium is not protective against acute reperfusion injury in the regional ischaemic-reperfused dog heart

Abstract. Intravenous magnesium lowers mortality in patients with suspected myocardial infarction. We tested the hypothesis that the protective effect may be due to a direct, local influence of magnesium on myocardial reperfusion injury in a dog model of ischaemia/reperfusion. Ten anaesthetized open chest dogs underwent 1 h of left anterior descending artery (LAD) occlusion and 6 h of reperfusion. The animals received intracoronary (i.c.) magnesium aspartate (Mg, n = 5) or vehicle infusion ( n = 5) for the first hour of reperfusion. Mg infusion was adapted to actual LAD flow (ultrasonic flow probe) to increase regional plasma concentration by 4 mmol L^-1. Regional myocardial function was measured as percent systolic wall thickening (sWTh, sonomicrometry). Intracoronary Mg increased LAD flow during application (at 15min reperfusion; Mg, 194±44 (mean±SD); control, 116±41 mLmin^-1 100g^-1, P < 0.01). sWTh decreased during coronary occlusion from 14.3 ± 7.1 % to - 4.7 ± 2.7% in the control group and from 14.8±2.5% to -4.1 ±3.1% in the Mg group. Throughout the reperfusion period wall function remained depressed in both groups to a similar degree (control, - 3.5 ± 1.8%; Mg, - 3.0 ± 1.9% at 6 h reperfusion). Global haemodynamics were not different. Infarct size after 6h reperfusion (TTC staining) was similar in both groups (Mg, 20.6±5.0; control, 24.4±8.7% of area at risk). Regional magnesium application (i.e.) to post-ischaemic reperfused myocardium had no influence on infarct size or post-ischaemic regional wall function in this model. The beneficial action of systemic Mg in patients with myocardial infarction is probably not due to an early direct protective effect on ischaemic-reperfused myocardium.     

Amiodarone offsets the cardioprotective effects of ischaemic preconditioning against ischaemia/reperfusion injury

Both ischaemic preconditioning (IPC) and amiodarone protect against myocardial ischaemia. We examined whether a combination of IPC and amiodarone demonstrated an additive protective effect in isolated rat hearts (n = 40). The controls (group I) were subjected to ischaemia/ reperfusion injury; group II was subjected to cycles of IPC prior to ischaemia/ reperfusion injury; group III was subjected to ischaemia in the presence of amiodarone (10(-10) mol/1); and group IV was subjected to IPC followed by ischaemia in the presence of amiodarone (10(-10) mol/l). Amiodarone produced the best preserved left ventricular end-systolic pressure and dP/dtmax, less developed ventricular stiffness, the shortest arrhythmia duration, and the smallest infarct size among the groups. All of the myocardial protective effects against ischaemia/reperfusion injury were diminished or abolished when IPC and amiodarone were applied sequentially.     

Characterization of an in vitro model for the study of the short and prolonged effects of myocardial ischaemia and reperfusion in man

The mechanisms underlying myocardial ischaemia and reperfusion-induced injury have been investigated, mainly by using animal experimental preparations in vitro and in vivo, but little is known of the process in human myocardium. The present studies characterize an in vitro model using human myocardium for the study of early and delayed effects of ischaemia and reperfusion. The right atrial appendage was manually sliced and incubated in buffer through which was bubbled O(2)/CO(2) (19:1, v/v) for various time periods. Lactate dehydrogenase (LDH) leakage, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl-2H-tetrazolium bromide (MTT) reduction, oxygen consumption, nucleotide levels and tissue morphology were all investigated as markers of myocardial injury. The specimens remained stable and viable up to 24 h, but had significantly deteriorated by 48 h. The preparation responded to ischaemia in a time-related manner. Tissue viability was reduced by 25% after 30 min ischaemia, declined to 60% after 60 min ischaemia and to 75% after 120 min ischaemia. Interestingly, the tissue was more susceptible when ischaemia was induced after 24 h of aerobic incubation. The effects of the duration of reperfusion were investigated after a fixed 60 min ischaemic insult. The results of LDH leakage suggest that reperfusion injury is mainly sustained within the first 2 h of reperfusion. However, the results of MTT reduction show that there is a progressive decrease in tissue viability over the 24 h reperfusion period, possibly reflecting the occurrence of tissue necrosis and apoptosis at different reperfusion times. In conclusion, the data provide evidence that the incubation of human atrial tissue in vitro is stable, and slices are viable for at least 24 h, which permits the study of early and delayed consequences of ischaemia and reperfusion in the human myocardium.     

Myocardial ischaemic preconditioning in the pig has no effect on the ventricular fibrillation and defibrillation thresholds

INTRODUCTION: The effects of myocardial ischaemia preconditioning in pigs on the vulnerability to ventricular fibrillation during subsequent ischaemic events are controversial. This study examined the time course of changes in ventricular fibrillation (VFT) and defibrillation (DFT) thresholds during transient myocardial ischaemia after a 45 min preconditioning period. METHODS AND RESULTS: In five open-chest pigs, VFT was measured after 3 min of regional myocardial ischaemia, at time 0, 2, 15, 30, 60 and 90 min (Control group). In seven other pigs (Test group), VFT was measured before (time 0) and 2, 15, 30, 60 and 90 min after ischaemic preconditioning by three consecutive 5 min periods of regional coronary occlusion, followed by 10 min of reperfusion. DFT was measured by increasing the stored energy systematically until successful defibrillation. Ischaemic preconditioning caused no significant change in the effective refractory period (ERP), VFT or DFT over the 90 min of the experiments. In the Control group, ERP remained stable for 30 min, though was significantly lower at 90 min (178 +/- 28 ms) than at baseline (204 +/- 32 ms, P = 0.007). VFT and DFT remained unchanged throughout the experiments, and no difference was observed in ERP, VFT and DFT between the two groups at any time during the experiment. CONCLUSION: No changes were observed in the refractory duration, ventricular vulnerability or defibrillation energy requirements up to 90 min after ventricular ischaemic preconditioning in the pig.     

The effects of adenocaine (adenosine and lidocaine) on early post-resuscitation cardiac and neurological dysfunction in a porcine model of cardiac arrest

Aim

Return of spontaneous circulation (ROSC) elicits ischaemia/reperfusion injury and myocardial dysfunction. The combination of adenosine and lidocaine (AL, adenocaine) has been shown to (1) inhibit neutrophil inflammatory activation and (2) improve left ventricular function after ischaemia. We hypothesized that resuscitation with adenocaine during early moments of cardiopulmonary resuscitation (CPR) attenuates leucocyte oxidant generation and myocardial dysfunction.

Methods

Pigs were randomized to: (1) sham (n = 7), (2) cardiac arrest (CA; n = 16), or 3) cardiac arrest + adenocaine (CA + AL; n = 12). After 7 min of electrically induced ventricular fibrillation, start of CPR was followed by infusion of saline (CA) or adenocaine (CA + AL) for 6 min. Haemodynamics, cardiodynamics (pressure–volume loops) and leucocyte superoxide anion generation were assessed. Neurological function was evaluated after 24 h by histology and neurological deficit score (0 = normal; 500 = brain dead).

Results

Rate of ROSC was comparable between groups: CA group 11/16 and CA + AL group 7/12 p = 0.57). Cardiac index transiently increased after ROSC in both groups. Left ventricular dysfunction demonstrated by a rightward shift of the intercept of end-systolic pressure–volume relations in CA was avoided in the CA + AL group. Leucocyte superoxide anion generation 2 h after ROSC was significantly attenuated in the CA + AL group compared to the CA group. Neurological deficit scores [CA: median: 17.5(IQR:0–75) and CA + AL: 35(IQR:15–150)] and histopathological damage were comparable in both groups (p = 0.37).

Conclusion

Infusion of adenocaine during early resuscitation from CA significantly improved early post-resuscitation cardiac function and attenuated leucocyte superoxide anion generation, without a change in post-ROSC neurological function. (IACUC protocol number 023-2009).     

Taurine at early reperfusion significantly reduces myocardial damage and preserves cardiac function in the isolated rat heart

OBJECTIVE: The Myocardial protective effects of taurine (TA) are well known. We investigated the optimal phase of giving taurine to reduce myocardial ischaemia-reperfusion injury in isolated rat hearts. METHODS: Isolated rat hearts were subjected to 20 min of global ischaemia followed by 60 min of reperfusion under three different conditions: global ischaemia alone (control group; n=8); pre-ischaemic administration of taurine (pre-TA group; n=8), perfusion with 10 mmol/L taurine for 10 min just before ischaemia; post-ischaemic administration of taurine (post-TA group; n=8), perfusion with 10 mmol/L taurine for the first 10 min of reperfusion. Ventricular functional and biochemical variables, the area at risk (AAR), and infarct size (IS) after reperfusion were compared between groups. RESULTS: Recovery of ventricular function in the post-TA group was significantly greater than that in the control and pre-TA groups in terms of left ventricular pressure and rate-pressure product. Lipid peroxide product as a marker of oxidant stress in the post-TA group was significantly less than that in the control and pre-TA groups. AAR relative to left ventricular area in the post-TA group was significantly less than that in the control and pre-TA groups. IS relative to AAR in the post-TA group was significantly less than that in the control group. CONCLUSION: Taurine administered before or after ischaemia prevents infarction; being a potent free radical scavenging antioxidant, it reduced myocardial injury and provided significantly better functional recovery when given immediately after reperfusion.     

Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines

We have recently demonstrated the benefits of glucagon-like peptide-1 (GLP-1) in enhancing regional and global myocardial function after reperfusion in the clinical setting of acute myocardial infarction. We hypothesized that GLP-1 facilitates recovery from myocardial stunning after an ischemic event. To investigate this, we administered GLP-1 (1.5 pmol/kg/min) to six dogs undergoing 10-min occlusion of the left circumflex coronary artery, followed by 24-h reperfusion. We compared the responses of coronary blood flow and regional thickening of the posterior wall with a group of eight vehicle-treated dogs undergoing the same occlusion-reperfusion protocol. Although recovery of coronary blood flow was identical, regional wall motion recovery occurred significantly ((*)p < 0.05) earlier (92 +/- 4 versus 57 +/- 5%(*) at 15 min) and was complete in the GLP-1-treated dogs, whereas residual contractile dysfunction persisted in the control group (99 +/- 4 versus 78 +/- 3%(*) at 24 h). This phenomenon was independent of changes in systemic hemodynamics or global systolic function. However, isovolumic left ventricular relaxation improved significantly in GLP-1-treated dogs. GLP-1 caused an insulinotropic effect, but no hypoglycemia. We conclude that GLP-1 enhances recovery from ischemic myocardial stunning after successful reperfusion.     

Microcirculatory and therapeutic effects of whole body periodic acceleration (pGz) applied after cardiac arrest in pigs

Aims

Cardiac arrest (CA) and resuscitation are models of whole body ischemia reperfusion injury. Interventions performed prior to (pre-treatment) or after (post-treatment) can result in cardioprotection. Myocardial stunning, characterized by microcirculatory and contractile dysfunction after CA, is an important component of the post-cardiac arrest syndrome. Periodic acceleration (pGz), produced by the cyclical motion of the supine body headward to footward, increases microcirculatory blood flow to vital organs and elicits production of endothelial derived cytoprotective factors in normal animals. We tested the hypothesis that application of pGz 30 min after return of circulation from CA, as a delayed post-treatment strategy, would improve regional microcirculatory blood flow to vital organs and functional indices of myocardial stunning in pigs.

Methods

8 min of unsupported VF followed by cardiopulmonary resuscitation and defibrillation was carried out in twenty anesthetized and paralyzed male swine who were randomized to delayed post-treatment with pGz (dPost) or none (CONT). pGz was begun 30 min after return of circulation along with conventional mechanical ventilation. Hemodynamics, echocardiogram, and regional blood flows were measured as well as biochemical index of cardiac tissue injury.

Results

All animals had spontaneous return of circulation after cardiopulmonary resuscitation (CPR) and defibrillation. dPost animals had less myocardial stunning and greater regional blood flows to the heart, brain, kidneys, ileum and stomach than CONT. Post-treatment with pGz blunted the increase in Troponin I produced by CA and resuscitation, and, induced a greater rise in endothelial derived nitric oxide synthase (eNOS) and its phosphorylation (p-eNOS).

Conclusions

Delayed post-treatment with pGz as a therapeutic strategy, protects against early myocardial stunning in VF cardiac arrest by improving microcirculatory blood flow to the heart and also protects other vital organs by this mechanism.     

Ischaemia or reperfusion: which is a main trigger for changes in nitric oxide mRNA synthases expression?

OBJECTIVE: To investigate alterations in endothelial nitric oxide synthase and inducible nitric oxide synthase mRNA expressions and nitric oxide release in the myocardium during ischaemia/reperfusion and determine whether these changes are ischaemic and/or reperfusion dependent. MATERIALS AND METHODS: Isolated rat hearts were perfused by a modified Langendorff system. Following 1 h of global cardioplegic ischaemia, left ventricle haemodynamic parameters were recorded at baseline and during 30 min of reperfusion. Levels of endothelial, inducible nitric oxide synthases mRNA expression and nitric oxide release were measured at baseline, after ischaemia and at 30 min of reperfusion. RESULTS: Global cardioplegic ischaemia caused a significant depression of left ventricular function and a decrease of coronary flow. Postischaemic intensities of the endothelial nitric oxide synthase mRNA bands were significantly lower than at baseline (P < 0.01). There were no significant differences in endothelial nitric oxide synthase mRNA band intensities immediately after ischaemia compared to the end of reperfusion, nor between the intensities of inducible nitric oxide synthase mRNA bands at baseline, at end of ischaemia and at end of reperfusion. Nitric oxide in the myocardial effluent was below detectable levels at all measured points. CONCLUSION: Ischaemic injury causes down-regulation of endothelial nitric oxide synthase mRNA expression, which is then associated with reduction of coronary flow during reperfusion, representing one possible mechanism of ischaemia/reperfusion injury. We did not find expected elevations of inducible nitric oxide synthase mRNA expression during ischaemia or reperfusion and we suggest that ischaemia/reperfusion injury is not associated with nitric oxide overproduction.     

Serum levels of endostatin, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in patients with acute myocardial infarction undergoing early reperfusion therapy

Angiogenesis is controlled by anti-angiogenic factors as well as by angiogenic factors, such as VEGF (vascular endothelial growth factor) and HGF (hepatocyte growth factor). Endostatin, a potent endogenous angiogenesis inhibitor, is known to inhibit endothelial proliferation and suppress tumour growth. However, to date, little is known about the pathophysiology of endostatin in ischaemia/reperfusion. To investigate the mechanisms of angiogenesis induced by myocardial ischaemia/reperfusion in more detail, we studied the circulating levels of endostatin, VEGF and HGF in 17 patients with acute myocardial infarction, who underwent early reperfusion therapy. In all patients, serum endostatin, VEGF and HGF levels before reperfusion were increased significantly compared with those in 17 control subjects (endostatin, 49.2+/-11.7 ng/ml, but not detectable in controls; VEGF, 685.6+/-150.3 pg/ml compared with 173.7+/-33.6 pg/ml; HGF, 3638+/-1285 pg/ml compared with 59+/-13 pg/ml; values are means+/-S.E.M.). After reperfusion, the serum endostatin and VEGF levels decreased significantly, but still remained higher than those in control subjects (endostatin, 19.6+/-7.0 ng/ml; VEGF, 284.2+/-90.2 pg/ml). In contrast, serum HGF levels increased significantly (15 146+/-2230 pg/ml) after reperfusion. These data indicated that serum levels of endostatin changed in parallel with those of VEGF in response to myocardial ischaemia/reperfusion, and the marked increase in serum HGF levels after reperfusion seemed to be, at least in part, due to heparin administration. Our data offer a possible anti-endostatin therapy in patients with acute myocardial infarction to facilitate collateral vessel formation.     

Leucocyte depletion in cardiopulmonary bypass: a comparison of four strategies

Leucocytes have been shown to play a fundamental role in the pathophysiology of inflammation. This prospective, randomized, controlled study was designed to identify the most advantageous leucocyte depletion technique in terms of reduction in systemic inflammatory response syndrome and myocardial ischaemia reperfusion injury associated with cardiopulmonary bypass (CPB). Forty consecutive patients undergoing elective coronary artery bypass graft (CABG) surgery were randomly allocated to one of four groups. The four groups consisted of a control group, a systemic leucocyte depletion (SLD) group, a cardioplegic leucocyte depletion (CLD) group and a total leucocyte depletion (TLD) group. There were 10 patients in each group. Lactoferrin (marker of neutrophil activation) and troponin-I (marker of myocardial ischaemia reperfusion injury) were measured at six time points: post induction, 5 min on CPB, 5 min before releasing the aortic crossclamp, 15 min after releasing the clamp and 1 and 24 hours after the discontinuation of CPB. Plasma lactoferrin levels increased rapidly in every group after the commencement of CPB, subsequently reached a peak after releasing the aortic crossclamp and gradually declined after the discontinuation of CPB. The lowest lactoferrin concentration was observed in the TLD (range 2.15-141.9 ng/mL) and CLD groups (7.469-114.6 ng/mL). Regarding myocardial injury, plasma cardiac troponin-I levels did not differ significantly between groups; but troponin-I concentrations rose dramatically after releasing the aortic crossclamp in all groups. Nevertheless, the CLD group had the lowest troponin-I level (1.37-5.55 ng/mL). In conclusion, it is believed that myocardial ischaemia is probably a major contributor to the inflammatory response. Although there is no clear statistical significance shown in this pilot study, the data tend to support the cardioplegic leucocyte depletion strategy as the optimal method for attenuating neutrophil activation and myocardial ischaemia reperfusion injury.     

Protection against myocardial dysfunction after a brief ischemic period in transgenic mice expressing inducible heat shock protein 70.

Brief ischemic periods lead to myocardial dysfunction without myocardial infarction. It has been shown that expression of inducible HSP70 in hearts of transgenic mice leads to decreased infarct size, but it remains unclear if HSP70 can also protect against myocardial dysfunction after brief ischemia. To investigate this question, we developed a mouse model in which regional myocardial function can be measured before and after a temporary ischemic event in vivo. In addition, myocardial function was determined after brief episodes of global ischemia in an isolated Langendorff heart. HSP70-positive mice and transgene negative littermates underwent 8 min of regional myocardial ischemia created by occlusion of the left descending coronary artery, followed by 60 min of reperfusion. This procedure did not result in a myocardial infarction. Regional epicardial strain was used as a sensitive indicator for changes in myocardial function after cardiac ischemia. Maximum principal strain was significantly greater in HSP70-positive mice with 88+/-6% of preischemic values vs. 58+/-6% in transgene-negative mice (P < 0.05). Similarly, in isolated Langendorff perfused hearts of HSP70-positive and transgene-negative littermates exposed to 10 min of global ischemia and 90 min of reperfusion, HSP70 transgenic hearts showed a better-preserved ventricular peak systolic pressure. Thus, we conclude that expression of HSP70 protects against postischemic myocardial dysfunction as shown by better preserved myocardial function.