Enhancement of recovery of myocardial function by oxygen free-radical scavengers after reversible regional ischemia

Reperfusion after reversible regional ischemia has been shown to result in delayed recovery of myocardial function, but the mechanism responsible for this phenomenon remains unknown. We explored the potential role of oxygen-free radicals as mediators of postischemic dysfunction in open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery (LAD) followed by 2 hr of reperfusion. Treated animals (n = 19) received an infusion of the oxygen free-radical scavengers superoxide dismutase (SOD; 15,000 U/kg) and catalase (CAT; 55,000 U/kg) for 1 hr starting 15 min before LAD occlusion, while control animals (n = 20) received an equal volume of saline. SOD and CAT produced no discernible effect on heart rate, aortic pressure, or left atrial pressure. Collateral flow to the ischemic zone (radioactive microspheres) was 0.07 +/- 0.01 ml/min/g in both groups. The size of the occluded bed as determined by postmortem perfusion was 26.1 +/- 1.2% of the left ventricle in the control group and 26.5 +/- 0.9% in the treated group. Systolic wall thickening (an index of regional function) was assessed with an epicardial pulsed-Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesia during ischemia. Nevertheless, recovery of function (expressed as percent of baseline) was considerably greater in the treated dogs, both at 1 hr (43.8 +/- 14.3 vs 12.8 +/- 11.6) and 2 hr of reperfusion (74.2 +/- 8.4 vs 31.6 +/- 9.8, p less than .005). This improved recovery of function obtained with SOD and CAT suggests that oxygen-free radicals play an important role in the genesis of myocardial dysfunction after a brief episode of regional ischemia.     

Superoxide dismutase and catalase do not improve recovery of regional myocardial contractile function when given at the time of reperfusion after reversible regional ischemia in anesthetized dogs

Summary Earlier studies have demonstrated an improvement in the recovery of the regional myocardial function after reversible myocardial ischemia when dogs were treated with superoxide dismutase (SOD) + catalase (CAT). In all these studies, drug administration was started prior to the ischemic period. The aim of this study was to investigate the effects of SOD and CAT on the recovery of the regional contractile function in anesthetized beagle dogs when the drugs were administered at the time of reperfusion. The animals were subjected to 20 min of left coronary artery occlusion followed by 3 h reperfusion. The regional myocardial contractile function, measured as subendocardial segment shortening (SS, sonomicrometry) decreased to below zero and the regional blood flow in the ischemic subendocardium was reduced to about 5 % of pre-ischemic values during the coronary artery occlusion period. The size of the occluded bed was similar in the two groups. Saline (n = 8) or SOD (10 mg/kg) + CAT (3.4 mg/kg) (n = 8) were infused into the left atrium from 2.5 min prior to until 20 min after the start of reperfusion. The peak plasma level of SOD was 102 ± 15 mg/1 at 20 min reperfusion. There were no significant differences in the arterial blood pressure, cardiac contractile function and regional blood flow between the two groups at any time during the experiment. During reperfusion in the dogs given vehicle, SS recovered to 48 ± 7 % (mean ± SEM) after the first hour of reperfusion, and to 51 ± 6 % of pre-ischemic values after 3 h of reperfusion. The corresponding values in SOD + CAT treated dogs were 50 ± 5 % (1 h) and 53 ± 8 % (3 h), respectively. It is concluded that SOD + CAT, when given at the time of reperfusion, did not improve the regional contractile function after reversible ischemia in the anesthetized beagle dog.     

间歇有氧运动训练改善肥胖小鼠缺血后心脏功能恢复

目的 探讨有氧间歇运动训练（AIT）对高脂饮食诱导的肥胖小鼠心肌缺血再灌注（MI/R）损伤的影响和相关机制。 方法 30只2月龄C57小鼠随机分为:正常对照组;高脂饮食组;高脂饮食间歇训练组。喂养12周后,建立急性MI/R模型（缺血30 min,再灌注4 h）。于再灌注结束后不同时间点采用超声心动仪检测心脏功能,Western blot法检测心脏相关信号表达。 结果 与正常对照组相比,12周高脂饮食喂养导致小鼠肥胖,体质量显著增加（P<0.05）;AIT可有效降低高脂饮食肥胖小鼠的体质量,增加心脏质量/胫骨长度比率（P<0.05）;与正常对照组相比,高脂饮食肥胖小鼠MI/R损伤显著加重（P<0.05）;AIT可有效减轻肥胖小鼠心肌损伤,减小心肌梗死面积和血清LDH水平（均P<0.05）;AIT还显著改善MI/R后心肌功能恢复,有效提高左室射血分数（EF）和左室短轴缩短率（FS）（均P<0.05）。与高脂饮食组相比,AIT可显著增强高脂饮食肥胖小鼠心肌线粒体SIRT3和MnSOD表达,减少高脂饮食组MI/R心肌组织氧化应激（均P<0.05）。 结论 AIT可有效提高高脂饮食肥胖小鼠心肌线粒体SIRT3和MnSOD表达,增加线粒体抗氧化酶活性,进而减轻肥胖小鼠的MI/R损伤,促进缺血后心脏功能恢复。     

2-mercaptopropionylglycine improves aortic flow after reoxygenation in working rat hearts

Summary The cardioprotective concentration range of the thiol drug 2-mercaptopropionylglycine (MPG) was investigated during reoxygenation after 30 min of hypoxia. It was found that aortic flow and frequency were increased by 1 mM MPG. Coronary flow, systolic and diastolic pressure were not significantly influenced by the drug. Mitochondria, isolated from hearts after termination of the perfusion phases, revealed increased values of RCI, when MPG had been present in the previous reoxygenation phase at 1 mM concentration. 5 mM MPG no longer showed a protective influence on the above cardiac and mitochondrial parameters. ATPase activities were decreased at 1 mM MPG by 14% and at 5 mM MPG by 40% of the controls. The latter concentration of MPG also doubled the inhibitory action of carboxyatractyloside on ATPase activity, indicating a structural change of the adenine nucleotide carrier. 1 mM MPG is considered an optimal therapeutic range in this model. The mechanism of action most probably includes an SH/-S-S-interchange reaction as well as a free radical scavenging mechanism. For many thiols, the latter is known to occur in the presence of metal ions.This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Zi 80/19-2     

Exercise-induced T-wave normalization predicts recovery of regional contractile function after anterior myocardial infarction

Aims We investigated the ability of T-wave pseudo-normalization andST-segment elevation, which are demonstrated in infarct-relatedleads during submaximal exercise testing, to predict late recoveryof contractile function. Methods We studied 88 consecutive patients (73 males, mean age 59±8years) with anterior infarction, persistent T-wave inversionand a documented lesion of the proximal segment of the leftanterior descending coronary artery. They all underwent 2D-echocardiographyon admission, 4 weeks as well as 6 months after myocardial infarctionto evaluate the dysfunction score and the ejection fraction.Submaximal (75% of maximal predicted heart rate) exercise testingwas performed in 80 patients 2 weeks after myo-cardial infarctionfollowing discontinuation of treatment. Results During exercise testing, 59 of the 88 patients showing negativeT-waves on the resting electrocardiogram exhibited pseudonormalization(group A) in at least three adjacent precordial leads, whilst29 (group B) did not. Patients of group A more frequently exhibitedan early creatine kinase peak (41% vs 24%, P<0·05)and residual angiographic perfusion (97% vs 69%, P<0·05).The dysfunction score did not change in group B (from 19±7to 22±4), but decreased in group A (from 18±4to 11±6, P<0·05). The ejection fraction wassimilar in the two groups on admission (group A: 48±7%,group B: 45±10%), but was significantly different at4-week (52±99 vs 42±11%, P<0·05) and6-month follow-up (58±9 vs 44±10%, P<0·01).The concomitant presence of ST-segment elevation and T-wavenormalization showed the highest positive predictive value forleft ventricular function recovery (100%). Conclusions T-wave normalization induced by sub-maximal exercise test isfrequently associated with residual perfusion to the infarctarea and predicts progressive improvement in regional wall motion,especially if associated with ST-segment elevation. Therefore,these electrocardiographic findings may be used as easily obtainablemarkers of residual viability that predict late recovery incontractile function.     

Insulin addition after ischemia improves recovery of function equal to ischemic preconditioning in rat heart

Background Ischemic preconditioning (IPC) is considered the most potent mechanism to improve ischemia tolerance. We have demonstrated that insulin addition during reperfusion improves recovery of function in the isolated working rat heart. We herein compare the relative importance of these two mechanisms in improving recovery of postischemic function.Methods Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing glucose (5 mmol/l) plus oleate (0.4 mmol/l) for 20 min and were then subjected to 15 min of ischemia followed by 35 min of reperfusion. IPC was achieved by an ischemic period of ve minutes followed by 10 minutes of reperfusion before ischemia. Insulin (1 mU/ml) was or was not added at the beginning of reperfusion. Wortmannin (WM, 3 µmol/l), an inhibitor of phosphatidylinositol 3-kinase, was or was not present in the perfusate from the beginning of the experiments. We measured glucose uptake with [2-³H]glucose, cardiac power and tissue metabolite content at the end of the experiments.Results Cardiac power before ischemia ranged from 7.17 to 10.4 mW. After ischemia, cardiac power recovered to 65.7 ± 3.8% (Control). Insulin signicantly improved recovery (96.3 ± 10.8%, p < 0.05 vs. Control). This effect was also achieved by IPC (recovery 86.2 ± 6.2%, p < 0.05). The effects of insulin and IPC were not additive (recovery 83.4 ± 6.2%, p < 0.05). WM fully inihibited the effects of both insulin and IPC (69.5 ± 3.3, 72.0 ± 6.9, respectively). Basal glucose uptake ranged from 2.53 to 3.46 µmol/gdry, and was signicantly lower after ischemia in the presence of WM.Conclusions Insulin is a potent tool to improve postischemic contractile function. The improvement of recovery afforded by insulin added after ischemia may be mediated through a similar mechanism as ischemic preconditioning.     

一氧化氮合酶2抑制剂改善大鼠心肌梗死后心功能的作用

目的 :探讨一氧化氮合酶 2 (NOS2 )改善心肌梗死 (MI)后心功能障碍的作用。方法 :选用选择性NOS2抑制剂S 甲基硫脲 (SMT)抑制NOS2。于MI后 4周观察SMT对心功能的影响。结果 :MI组MI后 4周 ,心肌NOS2表达及血浆一氧化氮 (NO)水平均较假手术组升高 [(0 .2 6 1± 0 .0 2 5 )∶(0 .0 92± 0 .0 11)A·μm-2 ,P<0 .0 5 ];(4 6 .6± 4 .2 )∶(30 .6± 2 .1) μmol/L ,P <0 .0 5 ]。SMT干预 4周可使MI后血浆NO水平降低 [(2 6 .6±2 .2 )∶(4 6 .6± 4 .2 ) μmol/L ,P <0 .0 5 ],心室肥厚减轻 ,MI范围缩小 ,心功能改善 [左室舒张末压 (6 .1± 0 .7)∶(11.0± 1.2 )mmHg(1mmHg =0 .133kPa) ,P <0 .0 5 ];中心静脉压 (0 .8± 0 .1)∶(1.6± 0 .2 )mmHg ,P <0 .0 5 ]。结论 :抑制NOS2可以改善MI后心功能。NOS2及其产物NO在MI后心功能障碍的发生发展过程中起促进作用     

Phosphate loss during reversible myocardial ischemia

Reversible myocardial ischemia was produced in the dog by progressive reduction in left main coronary flow which was precisely controlled by a pump. The circulation was otherwise intact. After an 8 to 14 min period of ischemia, characterized by elevated left atrial pressure and S-T segment depression, flow was abruptly restored. Coronary sinus and arterial blood were continuously withdrawn and analyzed for potassium (K), lactate, and inorganic phosphate (P_i) by Auto-Analyzer. At the onset of ischemia, progressive P_i loss began simultaneously with K loss and lactate production, and was linearly related in magnitude to both. Molar ratio of lactate: K:P_i efflux was 5:2:1. The average rate of P_i loss during ischemia was 8.2 μm/min/100 g LV, or 2.06% per min of the estimated pre-ischemic myocardial P_i value. The maximum rate of P_i loss was 14.0 μm/min/100 g LV. Myocardial P_i and K uptake began 1 to 3 min after flow restoration and ceased after 37 min, more than completely replacing P_i and K loss. Twenty-five minutes were required to completely restore the P_i deficit. P_i loss accurately reflects the degree of myocardial ischemia, and is probably a result of simultaneous alterations in intracellular high-energy phosphate.     

Rescue use of abciximab improves regional left ventricular function after early incomplete reperfusion in acute myocardial infarction

BACKGROUND: Abciximab was shown to have important beneficial effects beyond the maintenance of epicardial coronary artery patency. However, it remains uncertain whether abciximab may lead to a better functional outcome in patients with acute myocardial infarction (AMI) and with incomplete reperfusion after primary angioplasty (PA). HYPOTHESIS: The study aimed to evaluate whether rescue use of abciximab may lead to a better functional outcome in such patients. METHODS: The study included 25 patients with first AMI who met the following criteria: (1) total occlusion of the infarct-related artery, (2) PA within 12 h of symptom onset, (3) postprocedural diameter stenosis < 30%, and final Thrombolysis in Myocardial Infarction (TIMI) flow grade 2. Echocardiographic examination was performed before and on Days 7 and 30 after PA. The study population was divided into two groups: Group 1 (usual care, n = 13) and Group 2 (rescue use of abciximab, n = 12). Baseline characteristics were similar between the two groups. RESULTS: Peak level of creatine kinase was higher in Group 1 than in Group 2 (5,800+/-2,700 vs. 3,800+/-2,000 U/I, p < 0.05). At 1 month follow-up, infarct zone wall motion score index (2.71+/-0.26 vs. 2.05+/-0.63, p < 0.01) and left ventricular (LV) volume indices were smaller in Group 2 than in Group 1, whereas LV ejection fraction was higher in Group 2 than in Group 1 (52.1+/-7.8 vs. 42.1+/-6.4, p < 0.01). At 1-month, abciximab was the only independent predictor of wall motion recovery index by multiple regression analysis. CONCLUSIONS: Rescue use of abciximab may reduce the infarct size in patients with AMI and TIMI grade 2 flow after PA, which may improve the recovery of regional LV function.     

The significance of underlying coronary stenosis for recovery of myocardial function after transient ischemia in the dog

The rate of recovery of myocardial function after transient coronary occlusion (CO) has been considered to depend on the duration and frequency of CO. However, underlying coronary stenosis has not been previously demonstrated to be a determinant of the rate of myocardial functional recovery. Thus, 12 open-chest dogs were studied to examine the influence of critical coronary stenosis (CCS) on functional recovery after transient CO. Regional functional recovery following 2-minute CO was examined under two different conditions in eight dogs: patent coronary artery stenosis and fixed CSS that exhausted coronary reserve but did not cause a deficit in resting coronary flow or regional function. Following reperfusion with the coronary artery patent, regional function in the ischemic zone was fully recovered (100 +/- 18.0% of pre-CO value) at 30 seconds and was significantly increased (postischemic hypercontraction) compared to pre-CO value at 1 and at 2 minutes after reperfusion. Following CO and reperfusion in the setting of CCS, regional functional recovery was delayed and regional function remained depressed until 2 minutes after reperfusion. No cumulative effect on functional recovery following repeated 2-minute CO was demonstrated in a control group of four dogs. We conclude that coronary artery patency is a determinant of the rate of myocardial function recovery after a transient ischemic episode, and postischemic hypercontractility was suppressed by the underlying CCS.     

Silent ischemia and loss of reversible myocardial dysfunction following myocardial infarction

Sixty-seven asymptomatic patients were enrolled after a first uncomplicated myocardial infarction (MI) so as to study the relevance of reversible myocardial dysfunction in determining left ventricular function soon after the acute episodes and 12 months later. Moreover, the potential role of silent ischemia in conditioning the evolutive aspects of contractile dysfunction has been investigated. Postextrasystolic potentiation during two-dimensional echocardiographic (2-D echo) monitoring has been used to detect the presence of viable myocardium in asynergic myocardial segments. Results of electrocardiographic (ECG) ambulatory monitoring at predischarge determined patient groups: Group A included 49 patients without ST changes during monitoring, while Group B included 18 patients with silent ischemia. Incidence of reversible myocardial dysfunction was similar in the two study groups (82 vs. 86%, p = NS). Group B patients were older (59.6 ± 6.7 vs. 50.6 ± 10.6 years, p < 0.015) and had lower ejection fractions (EFs, 43.4 ± 6.4% vs. 51.2 ± 8.3%, p = 0.026) and higher at-rest wall-motion scores (WMSs, 11.4 ± 5.9 vs. 7.2 ± 3.8, p = 0.019). Left ventricular end-diastolic volume (LVEDV) and potentiated WMS did not differ. At 1-year examination, Group B patients exhibited a greater LVEDV index (96 ± 6.5 vs. 70.7 ± 14 ml/m², p < 0.002) with a worsening both in rest and in potentiated wall-motion score index (12.8 ± 4.6 vs. 5.3 ± 1.8, p < 0.001; 9.2 ± 3.6 vs. 4.8 ± 2.2, p < 0.001, respectively). Left ventricular EF remained significantly depressed in Group B patients (42 ± 8.7% vs. 55.5 ± 8.1%, p < 0.002). Over the first year, spontaneous functional recovery of asynergic segments occurred in 60% of Group A patients with reversible myocardial dysfunction at early study. In Group B patients, only three (20%) showed functional recovery, and a small number (24%) maintained reversible contractile dysfunction. Thus, reversible contractile dysfunction is a common finding in asymptomatic patients without clinical ischemia soon after a first MI. The presence of silent ischemia during ambulatory ECG monitoring identifies a group of patients at high risk of further loss of myocardial viability and progressive left ventricular dilation over the first year.     

Effects of dobutamine and arbutamine on regional myocardial function in a porcine model of myocardial ischemia

Objectives. The present study was performed to determine the mechanisms for catecholamine-induced wall motion abnormalities and to compare the diagnostic efficacy of two catecholamines: arbutamine and dobutamine.Background. Catecholamine stress echocardiography is used to induce regional wall motion abnormalities for the detection of coronary artery disease, but the mechanism by which these abnormalities occur is unknown.Methods. Ten pigs were instrumented with left circumflex coronary artery ameroid constrictors, sonomicrometers to measure transmural wall thickening in the left circumflex (ischemic) and left anterior descending (control) coronary artery beds and a pressure gauge to measure left ventricular pressure and its first derivative (dP/dt). Myocardial blood flow was measured by microspheres.Results. At 38 ± 6 days (mean ± SEM) after surgery, percent wall thickening was normal at rest in both beds but abnormal in the left circumflex coronary artery bed during atrial pacing. These findings were associated with reduced myocardial blood flow in the ischemic bed during atrial pacing. Dobutamine infusion increased percent wall thickening, with no differences between the two beds (p = 0.63). In contrast, arbutamine infusion increased percent wall thickening only in the nonischemic bed, with no effect on percent wall thickening in the ischemic bed (p s 0.03). Although the endocardial/epicardial blood flow ratio tended to be reduced in the left circumflex artery bed during catecholamine infusion (p = 0.07), both agents were similar in this effect. Despite differences in function between the beds, there was no difference in transmural myocardial blood flow between the two beds during catecholamine infusion. When examined at matched metabolic demands, arbutamine elicited greater differences in percent wall thickening than dobutamine between the two beds (p < 0.01).Conclusions. Arbutamine was able to provoke regional differences in fonction in a manner superior to dobutamine. This occurred independently of altered transmural myocardial blood flow or differences in hemodynamic effects between the agents. Differences in their inotropic properties may be important in explaining their different effects on ischemic myocardium.     

caspase-3抑制剂联合钙离子拮抗剂对大鼠脑缺血后神经功能恢复的作用

目的 探讨caspase-3抑制剂联合钙离子拮抗剂对大鼠脑缺血后神经功能恢复的影响.方法 利用Longa线栓法制备大鼠脑缺血再灌注模型.实验分为生理盐水对照组、caspase-3抑制剂组、尼莫地平组和caspase-3抑制剂联合尼莫地平组（联合用药组）.利用Bederson法评价神经功能缺失,采用TUNEL染色和梗死面积评价神经细胞损害.结果 caspase-3抑制剂组、尼莫地平组和联合用药组与对照组相比均可显著改善神经功能缺失.联合用药组与尼莫地平组、对照组相比,TUNEL阳性细胞数明显减少.联合用药组、caspase-3抑制剂组和尼莫地平组与对照组相比,视交叉冠状面的梗死面积均明显减少（P＜0.01）;联合用药组与尼莫地平组相比,梗死面积亦明显减少.结论 在脑缺血再灌注情况下,联合caspase-3抑制剂和钙离子拮抗剂具有明显的神经保护作用.