缺血预处理减轻在体家兔心肌细胞凋亡

对麻醉家兔心肌缺血－再灌注（ｉｓｃｈｅｍｉａ－ｒｅｐｅｒｆｕｓｉｏｎ,ＩＲ）模型上,观察ＩＲ和缺血预处理（ｉｓｃｈｅｍｉｃ ｐｒｅｃｏｎｄｉｔｉｏｎｉｇｎ,ＩＰ）对血流动力学、心外膜电图、心肌梗塞范围、心肌细胞调亡和调亡相关调控基因蛋白（Ｆａｓ、Ｂｃｌ－２、Ｂａｘ等）的影响。所得结果如下：⑴在ＩＲ过程中,动脉血压、心率和心肌耗氧量进行性降低;心外膜电图ＳＴ段在缺血期明显抬高（Ｐ＜０．００１）,再灌     

Neovascularization of ischemic myocardium by newly isolated tannins prevents cardiomyocyte apoptosis and improves cardiac function

During remodeling progress post myocardial infarction, the contribution of neoangiogenesis to the infarct-bed capillary is insufficient to support the greater demands of the hypertrophied but viable myocardium resulting in further ischemic injury to the viable cardiomyocytes at risk. Here we reported the bio-assay-guided identification and isolation of angiogenic tannins (angio-T) from Geum japonicum that induced rapid revascularization of infarcted myocardium and promoted survival potential of the viable cardiomyocytes at risk after myocardial infarction. Our results demonstrated that angio-T displayed potent dual effects on up-regulating expression of angiogenic factors, which would contribute to the early revascularization and protection of the cardiomyocytes against further ischemic injury, and inducing antiapoptotic protein expression, which inhibited apoptotic death of cardiomyocytes in the infarcted hearts and limited infarct size. Echocardiographic studies demonstrated that angio-T-induced therapeutic effects on acute infarcted myocardium were accompanied by significant functional improvement by 2 days after infarction. This improvement was sustained for 14 days. These therapeutic properties of angio-T to induce early reconstitution of a blood supply network, prevent apoptotic death of cardiomyocytes at risk, and improve heart function post infarction appear entirely novel and may provide a new dimension for therapeutic angiogenesis medicine for the treatment of ischemic heart diseases.     

Therapeutic potential of vitamin E against myocardial ischemic-reperfusion injury.

Myocardial ischemia is a disease process characterized by reduced coronary flow such that the supply of nutritive blood to heart muscle (myocardium) is insufficient for normal myocardial aerobic metabolism. Prompt reestablishment of coronary flow by invasive and noninvasive clinical procedures is the most direct and effective means of limiting myocardial damage in ischemic heart disease patients, although reperfusion carries with it an injury component which may reflect, at least to some degree, the toxic effects of partially reduced oxygen species and their participation in degenerative cellular processes such as membrane lipid peroxidation. Vitamin E, a lipophilic, chain-breaking antioxidant, is a prominent membrane constituent in heart muscle, where it modulates/regulates various aspects of heart muscle-cell metabolism and function. Vitamin E's beneficial effects against experimentally induced oxidative damage to the heart, along with inverse epidemiological correlations between plasma vitamin E level and either anginal pain or mortality due to ischemic heart disease, suggest that vitamin E might have protective and therapeutic roles against myocardial ischemic-reperfusion injury. Laboratory investigations aimed at addressing this possibility have demonstrated that vitamin E supplementation protects isolated hearts against ischemic-reperfusion injury, and relatively more inconsistent and limited data document cardioprotective effects of vitamin E in some animal models of myocardial ischemia-reperfusion, especially when administered prior to the ischemic period. Clinical attempts to establish whether vitamin E has therapeutic benefit in ischemic heart disease patients remain inconclusive, having relied upon a variety of nonuniformly controlled protocols and a single, rather subjective endpoint (anginal pain). Consequently, although laboratory data constitute a conceptual context for and indirect support of the idea that vitamin E could be a cardioprotectant against ischemic-reperfusion injury, compelling clinical evidence regarding vitamin E's therapeutic potential in the ischemic heart-disease patient is lacking. Elective coronary revascularization would appear to provide an attractive clinical setting for evaluating the therapeutic efficacy of vitamin E in the context of cardiac ischemia-reperfusion. Further biochemical work would still be required to define how vitamin E exerts any cardioprotective effect observed in these patients.     

Effect of superoxide dismutase and catalase on myocardial energy metabolism during ischemia and reperfusion

Survival of cardiac patients undergoing heart surgery depends critically upon the recovery of myocardial energy metabolism during reperfusion of ischemic myocardium. The present study compares various parameters of myocardial energy metabolism using an isolated in situ pig heart. The left anterior descending (LAD) coronary artery was occluded for 60 min, followed by 60 min of global hypothermic cardioplegic arrest and 60 min of reperfusion. Free radical scavengers [superoxide dismutase SOD and catalase] were used to protect the ischemic heart from reperfusion injury. In both control and SOD plus catalase-treated groups, ATP, creatine phosphate (CP), ATP/ADP ratio, energy charge and phosphorylation potential dropped significantly during ischemic insult. After reperfusion, CP, ATP/ADP ratio and phosphorylation potential improved significantly, but they were restored to control level only in treated animals. In either case, free energy of ATP hydrolysis (delta G) lowered only by 5% during ischemia, but recovered promptly upon reperfusion. SOD and catalase also improved coronary blood flow and reduced creatine kinase release compared to those of untreated animals, suggesting improved myocardial recovery upon reperfusion. Our results suggest that SOD and catalase significantly improve the myocardial recovery during reperfusion by enhancing rephosphorylation steps, and the value of delta G is more critical compared to those of ATP and CP for myocardial recovery.     

Treatment of chronical myocardial ischemia by adenovirus-mediated hepatocyte growth factor gene transfer in minipigs

Growth factor gene transfer-induced therapeutic angiogenesis has become a novel approach for the treatment of myocardial ischemia. In order to provide a basis for the clinical application of an adeno- virus with hepatocyte growth factor gene (Ad-HGF) in the treatment of myocardial ischemia, we estab- lished a minipig model of chronically ischemic myocardium in which an Ameroid constrictor was placed around the left circumflex branch of the coronary artery (LCX). A total of 18 minipigs were ran- domly divided into 3 groups: a surgery control group, a model group and an Ad-HGF treatment group implanted with Ameroid constrictor. Ad-HGF or the control agent was injected directly into the ischemic myocardium, and an improvement in heart function and blood supply were evaluated. The results showed that myocardial perfusion remarkably improved in the Ad-HGF group compared with that in both the control and model groups. Four weeks after the treatment, the density of newly formed blood vessels was higher and the number of collateral blood vessels was greater in the Ad-HGF group than in the model group. The area of myocardial ischemia reduced evidently and the left ventricular ejection fraction improved significantly in the Ad-HGF group. These results suggest that HGF gene therapy may become a novel approach in the treatment of chronically ischemic myocardium.     

Statins enhance clonal growth of late outgrowth endothelial progenitors and increase myocardial capillary density in the chronically ischemic heart

Background

Coronary artery disease and ischemic heart disease are leading causes of heart failure and death. Reduced blood flow to heart tissue leads to decreased heart function and symptoms of heart failure. Therapies to improve heart function in chronic coronary artery disease are important to identify. HMG-CoA reductase inhibitors (statins) are an important therapy for prevention of coronary artery disease, but also have non-cholesterol lowering effects. Our prior work showed that pravastatin improves contractile function in the chronically ischemic heart in pigs. Endothelial progenitor cells are a potential source of new blood vessels in ischemic tissues. While statins are known to increase the number of early outgrowth endothelial progenitor cells, their effects on late outgrowth endothelial progenitor cells (LOEPCs) and capillary density in ischemic heart tissue are not known. We hypothesized that statins exert positive effects on the mobilization and growth of late outgrowth EPCs, and capillary density in ischemic heart tissue.

Methodology/Principal Findings

We determined the effects of statins on the mobilization and growth of late outgrowth endothelial progenitor cells from pigs. We also determined the density of capillaries in myocardial tissue in pigs with chronic myocardial ischemia with or without treatment with pravastatin. Pravastatin therapy resulted in greater than two-fold increase in CD31+ LOEPCs versus untreated animals. Addition of pravastatin or simvastatin to blood mononuclear cells increased the number of LOEPCs greater than three fold in culture. Finally, in animals with chronic myocardial ischemia, pravastatin increased capillary density 46%.

Conclusions

Statins promote the derivation, mobilization, and clonal growth of LOEPCs. Pravastatin therapy in vivo increases myocardial capillary density in chronically ischemic myocardium, providing an in vivo correlate for the effects of statins on LOEPC growth in vitro. Our findings provide evidence that statin therapy can increase the density of capillaries in the chronically ischemic heart.     

Scanning electron microscopy of the heart of the climbing perch

The air-breathing climbing perch Anabas testudineus has two ventral aortas, one directs blood through well developed anterior gill arches into the suprabranchial chambers and back to the heart and the other sends blood through rudimentary shunt-like posterior arches and onto the systemic circulation. The sinus venosus is a thin-walled structure and lacks myocardial trabeculae. The atrium is similar to that of other teleosts and it is traversed by numerous myocardial trabeculae. There are no sinoatrial valves, whereas the atrioventricular aperture is guarded by one pair of large wing-shaped and two small cap-shaped valves. The ventricle is composed only of spongy myocardium and has numerous branching lacunae extending to the epicardium. The thick-walled bulbus arteriosus is lined with longitudinal ridges and this and the ventricular trabeculae may minimize mixing of respiratory and systemic flow while blood is passing through the heart. However, with the exception of the absence of sinoatrial valves and the ridged bulbar lumen, the heart of the climbing perch is essentially similar to that of most other non air-breathing teleosts.     

Correction of contractile function and metabolism in canine ischemic myocardium due to exogenous glutamic acid

The effect of intravenous glutamic acid infusion (3 mg/kg/min) was studied during myocardial ischemia and reperfusion in anesthetized dogs. Left ventricular ischemia was induced by underperfusion of the anterior descending and circumflex coronary arteries. Glutamic acid reduced the ischemic contractile depression 2 min after a 60%-reduction of the coronary blood flow. The left ventricular systolic pressure was decreased by 9% versus 22%, dP/dt by 16% versus 29%, left ventricular systolic pressure heart rate product by 16% versus 31%. Reperfusion with glutamic acid improved the recovery of cardiac performance without any increase in myocardial oxygen consumption. Glutamic acid infusion resulted in a 2-fold augmentation of glutamate uptake by the ischemic myocardium. It led to cessation of ammonia release by the heart due to activation of glutamine synthesis, enhancement of alanine formation coupled with pyruvate utilization and did not change lactate production. The mechanisms of the protective action of glutamic acid are discussed.     

External transport of beta-adrenergic binding sites in ischemic myocardium

The properties of beta-adrenergic receptors were studied in normal and in flow restricted regions of the dog heart. Purified cardiac membrane preparations and papillary muscle preparations were isolated from control and ischemic areas and tested a) following chronic beta-receptor blockade with metipranolol or exaprolol, and b) after acute regional myocardial ischemia. A significant reduction in the sensitivity of the heart muscle preparations from compromised heart for isoprenaline resulting in a reduced affinity of beta-adrenergic receptors to exaprolol was observed. Quantitative ligand binding data showed higher numbers of (3H) dihydroalprenolol/(3H) DHA/binding sites in the membrane fraction obtained from compromised compared to control myocardium. The ratio of intra- to extracellular beta-adrenergic receptors decreased from 1.35 to 0.55 in the membrane fractions obtained from the compromised hearts. Pretreatment of experimental animals with metipranolol or propranolol attenuated the observed increase in the total number of beta-adrenergic receptor sites in myocardial membrane fractions from ischemic hearts. These data suggest preferential distribution of beta-adrenergic binding sites from intracellular to membrane fractions in flow restricted regions of the dog heart after coronary occlusion.     

Echocardiographic and cardiac single photon emission computed tomography predictors of left ventricle reverse remodeling after surgical revascularization in patients with ischemic cardiomyopathy and left ventricle systolic dysfunction

Background: The extent of scar or viable hypocontractile myocardial tissue determines postinfarction left ventricle remodeling. The aim of this pilot study was to evaluate the revascularization effect in a group of patients with ischemic cardiomyopathy and LV systolic dysfunction indicated for surgical revascularization, based on evidence for multivessel disease on coronarography and viable myocardium (CMR, SPECT). Aims: To evaluate the revascularization effect in patients with ischemic LV systolic dysfunction and to find preoperative predictors of revascularization effect. Methods: 33 patients (64+/-11 years) with baseline LVEF 34.9+/-9.3 % were included in the study. After a follow-up of 10.7+/-1.2 months, ECHO and SPECT were performed again. The whole group of patients was divided according to revascularization effect (postoperative increase LVEF > 5 % and postoperative decrease LVESV > 5 % compared with baseline) into revascularization responders (R, n = 22) and nonresponders (NR, n = 11). Results: At baseline there was no difference between the subgroups in LVEF (R = 35.7+/-11.0 % vs. NR = 34.3+/-8.2 %), EDV (R = 183.6+/-43.2 vs. NR = 180.2+/-80.5 ml), ESV (R = 118.5+/-40.4 vs. NR = 119.7+/-55.2 ml). The responders showed in a revascularization effect subanalysis differences in the values of LVEF (+9.8+/-8.1 %, p < 0.009), reduction of EDV (-39.9+/-50.9 ml, p = 0.05) and ESV (-35.4+/-42.6 ml, p = 0,002) compared with baseline. The only preoperative parameters predicting LV reverse remodeling were the T(E-Em) (R = -10.6+/-44.1 vs. NR = 29.7+/-43.7 ms, p = 0.037) and the size of fixed perfusion defect (FPD) (R = 11.9+/-13.5 vs. NR = 22.9+/-15.3 % of LV, p = 0.044). Conclusions: Patients with ischemic LV systolic dysfunction with a preoperatively determined myocardial viability develop LV reverse remodeling. The only preoperative parameters predicting LV reverse remodeling were echocardiographic T(E-Em) and FPD on SPECT.     

自体内皮前体细胞移植对急性心肌梗死大鼠微血管新生及心功能的影响

目的探讨外周血来源的内皮前体细胞自体移植,对大鼠急性心肌梗死后微血管新生与心功能的影响。方法抽取SD大鼠外周动脉血,应用Ficoll密度梯度离心法获取单个核细胞。应用含有VEGF和bFGF的特定培养基体外培养,得到内皮前体细胞;结扎SD大鼠冠状动脉左前降支,建立急性心肌梗死模型;然后将得到的自体内皮前体细胞植入缺血心肌局部区域。对照组动物注入细胞培养液。结果与对照组比较,细胞移植组大鼠心功能明显改善,心肌收缩力显著优于对照组;梗死心肌微血管新生更为明显。结论急性心肌梗死心肌局部移植外周血来源的自体内皮前体细胞,能够促进血管新生;对局部梗死心肌组织结构有一定的保护作用,并可在不同时点不同程度恢复心肌收缩力,显著改善心功能。     

Preconditioning the hyperlipidemic myocardium: fact or fantasy?

Ischemic heart disease is a leading cause of death worldwide. Myocardial ischemia results in reduced coronary flow, followed by diminished oxygen and nutrient supply to the heart. Reperfusion to an ischemic myocardium often augments the ischemic damage, known as ischemia-reperfusion (I/R) injury. Number of studies demonstrated that the hyperlipidemic myocardium is rather sensitive and more vulnerable to I/R-induced myocardial injury. Repeated brief ischemia and reperfusion cycles, termed as ischemic preconditioning, given before a sustained ischemia is known to reduce myocardial damage occur as a result of I/R. A plethora of evidence supports the fact that preconditioning is one of the promising interventional strategies having an ability to limit I/R-induced myocardial injury. Despite this fact, the preconditioning-mediated cardioprotection is blunted in chronic hyperlipidemic condition. This suggests that preconditioning is moderately a ‘healthy heart protective phenomenon’. The mechanisms by which chronic hyperlipidemia abrogates cardioprotective effects of preconditioning are uncertain and are not completely understood. The impaired opening of mitochondrial-K_ATP channels, eNOS uncoupling and excessive generation of superoxides in the hyperlipidemic myocardium could play a role in attenuating preconditioning-mediated myocardial protection against I/R injury. Moreover, hyperlipidemia-induced loss of cardioprotective effect of preconditioning is associated with redistribution of both sarcolemmal and mitochondrial Connexin 43. We addressed, in this review, the potential mechanisms involved in hyperlipidemia-induced impairment of myocardial preconditioning. Additionally, novel pharmacologic interventions to attenuate hyperlipidemia-associated exaggerated I/R-induced myocardial injury have been discussed.     

Changes in the myocardial area at risk, infarct size, and collateral flow following nicardipine infusion in dogs.

The area at risk of infarction after an acute occlusion of the left anterior descending coronary artery was defined in anesthetized dogs using the distribution of 99mTc-labelled albumin microaggregates and Monastral blue dye. In thirteen dogs, it was determined that these two particulate labels identified identical areas of unperfused myocardium. In a second group of dogs (n = 12), the risk areas determined at 10 (99mTc-labelled macroaggregates) and at 180 min (Monastral blue dye) were found to be identical, with no change in collateral blood flow, indicating the absence of a spontaneous change in underperfused myocardium over this time. In a third group of dogs (n = 17) nicardipine was infused (10 micrograms.kg-1.min-1 for 5 min, followed by 8 micrograms.kg-1.min-1 for 165 min). This resulted in a significant and sustained fall (32 +/- 4 mmHg; 1 mmHg = 133.32 Pa) in mean arterial blood pressure but no significant change in collateral blood flow was found, except for a marginal increase in the center of the ischemic zone. Area at risk and infarct sizes were also not significantly different between the latter two groups (18.2 +/- 4.1 vs. 21.6 +/- 4.0% of left ventricle). In this model, the magnitude of the area at risk appears to be determined early after a coronary occlusion and appears to be unmodified by treatment with nicardipine begun after the occlusion.     

COMMD1 upregulation is involved in copper efflux from ischemic hearts

Copper depletion is associated with myocardial ischemic infarction, in which copper metabolism MURR domain 1 (COMMD1) is increased. The present study was undertaken to test the hypothesis that the elevated COMMD1 is responsible for copper loss from the ischemic myocardium, thus worsening myocardial ischemic injury. Mice (C57BL/6J) were subjected to left anterior descending coronary artery permanent ligation to induce myocardial ischemic infarction. In the ischemic myocardium, copper reduction was associated with a significant increase in the protein level of COMMD1. A tamoxifen-inducible, cardiomyocyte -specific Commd1 knockout mouse (C57BL/6J) model (COMMD1^CMC▲/▲) was generated using the Cre-LoxP recombination system. COMMD1^CMC▲/▲ and wild-type littermates were subjected to the same permanent ligation of left anterior descending coronary artery. At the 7th day after ischemic insult, COMMD1 deficiency suppressed copper loss in the heart, along with preservation of vascular endothelial growth factor and vascular endothelial growth factor receptor 1 expression and the integrity of the vascular system in the ischemic myocardium. Corresponding to this change, infarct size of ischemic heart was reduced and myocardial contractile function was well preserved in COMMD1^CMC▲/▲ mice. These results thus demonstrate that upregulation of COMMD1 is at least partially responsible for copper efflux from the ischemic heart. Cardiomyocyte-specific deletion of COMMD1 helps preserve the availability of copper for angiogenesis, thus suppressing myocardial ischemic dysfunction.     

Selenium in cardiology and angiology

The effect selenium in the form of sodium selenite on central hemodynamic conditions and coronary artery flow was studied in pig hearts infarcted by a ligature of the ramus interventricularis anterior. Infusions of sodium selenite solutions at levels of 1–3 mg/kg body wt improved the survival of infarcted pigs. Both short-term and long-term protective effects of selenite could be demonstrated. It is of potential therapeutic importance that sodium selenite administration suppresses the electrical vulnerability of the cell membrane, notably the occurrence of ventricular late potentials in the ischemic border zone. Coronary blood circulation, as evidenced by an increase of heart rate and coronary artery dilatation and peripheral vasodilatation was also improved. The pulsatile coronary blood flow thus is altered, increasing total perfusion of the infarcted heart. Initial observations with human subjects suggest that selenium deficiency is a factor in the pathogenesis of ischemic and arteriosclerotic heart disease. In 54 hospitalized patients with clinical diagnosis of acute myocardial infarction, serum selenium levels were 670±266 nmol/L, as compared to 981±209 nmol/L in 93 healthy controls. In 32 patients with general arteriosclerosis, the serum Se level was 375±85 nmol/L, in 64 patients with arteriosclerotic occlusional disease in the leg region, 366±85 nmol/L, respectively. Serum selenium levels of healthy subjects were found to be age-and sex dependent. In men, the selenium concentrations reached maximum levels of 1083 nmol/L in the 41–50 y age group. In women in the same age group, the serum Se level was 1385 nmol/L. Evidence is presented to suggest that selenium is preventing oxidative damage of heart cell membranes by lipid peroxidation.     

An echocardiogram-based 16-segment model for predicting left ventricular ejection fraction improvement

An important goal of cardiac revascularization is to improve the left ventricular ejection fraction, which is an important clinical determinant of the long-term outcome for patients with coronary artery disease. Regional myocardium function improvement may be expected from revascularization when viable myocardium is detected using non-invasive cardiac imaging. However, the quantitative relation between regional myocardial function recovery and global heart function improvement has not been determined and there is no tool to predict the amount of ejection fraction improvement prior to revascularization. A 16 segment biomechanical model of the left ventricle is proposed to establish the relationship between the ejection fraction improvement and the viable segments detected by echocardiography. With the assumption that the viable segments would potentially improve contractility after revascularization, the ejection fraction improvement is estimated for all possible wall motion score improvement in viable segments. The model shows that the ejection fraction improvement is linearly related to the contractility in the normal segments and a weighted sum of the numbers of viable segments that recover to normal or hypokinetic contractility. The predictive value of the model is illustrated for a group of patients reported in the literature. The model predictions of the post-revascularization ejection fraction are very close to the follow-up data with a very strong correlation (R2 = 0.92). By predicting the ejection fraction improvement, the model may provide a tool for evaluating the efficacy of revascularization and for selecting patients who would benefit from revascularization.     

Functional state of the left ventricle of the heart in cardiocytotoxic shock]

Changes in the cardiodynamics and the contractile myocardium function under experimental shock caused by intracoronary injection of the anticardial cytotoxic serum were studied on 20 anesthetized dogs. Along with the symptoms of disturbance of the left ventricle function (a decrease of the systolic index, stroke work index of the left ventricle, rate of the intraventricular pressure rise, indices of myocardial contractility, ejection fraction) a decrease of the end-diastolic volume and pressure in the left ventricle was observed. These data show that disturbances in the cardiodynamics were cause not only by the cytotoxic heart damage, but also by derangement of the blood flow to the left heart.     

Quantification of Blood Supply to the Left Ventricular Myocardium in Normal Subjects and Patients with Coronary Heart Disease

The subjects who underwent diagnostic coronarography and detailed examination included 274 patients with lesions in the left coronary artery and its branches and 50 subjects without pathological changes in the coronary arteries or left ventricle. The authors also examined 149 patients with unchanged coronary arteries (67 with small vessel disease 42 with cardiomyopathy of various etiology; and 40 with other pathologies, such as the WPW syndrome, arterial hypertension, aortic stenosis, etc.). In addition to routine retrograde left heart catheterization and recording of the hemodynamic parameters demonstrated by ventriculography, the coronary blood flow was measured in all patients. Its normalized (specific) values are a basis for the coronary blood flow quantification in normal subjects, patients with the coronary heart disease (with insufficient oxygen supply to the myocardium), and those with cardiomyopathy of various genesis (when the myocardial oxygen demand increases together with the left ventricular myocardium mass).     

A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury

HBOC-201 (Biopure; Cambridge, MA) is a glutaraldehyde-polymerized bovine hemoglobin (Hb) solution that is stroma free, has lower viscosity than blood, and promotes O(2) unloading. We investigated the effects of HBOC-201 in a canine model of myocardial ischemia-reperfusion injury. Dogs were anesthetized and subjected to 90 min of regional myocardial ischemia and 270 min of reperfusion. HBOC-201 or 0.9% saline vehicle equivalent to 10% total blood volume was infused 30 min before myocardial ischemia. Hemodynamic data and peripheral blood samples were taken at baseline, 1 h of myocardial ischemia, and 1, 2, and 4 h of reperfusion. At 270 min of reperfusion, the area at risk (AAR) per left ventricle and the area of infarction (Inf) per AAR were determined. The myocardial AARs in the two study groups were similar. In addition, myocardial blood flow (as measured by radioactive microspheres) in the ischemic zone was similar between the vehicle and HBOC-201 groups. HBOC-201-infused dogs demonstrated a significant (P < 0.01) 56% reduction in Inf/AAR. Analysis of blood samples taken at 4 h of reperfusion showed a significant (P < 0.05) reduction in creatine kinase MB isoform for the HBOC-201 group. Histological analysis of the myocardium demonstrated significant (P < 0.01) reductions in neutrophil infiltration in the HBOC-201 group. These data indicate that treatment with HBOC-201 before myocardial ischemia-reperfusion reduces the extent of myocardial inflammation and ischemia-reperfusion injury in the canine myocardium.