Protection of acutely ischemic myocardium by controlled reperfusion

The goal of revascularization after acute occlusion of a coronary artery is the return of contractile function and the reduction of mortality. Although reperfusion of ischemic myocardium is a prerequisite for return of function, it may, in itself, cause further injury. Controlled blood cardioplegic reperfusion reduces this "reperfusion injury" and provides maximal myocardial protection. In this article, we review recent advances in surgically controlled reperfusion and speculate on future prospects for myocardial protective techniques in patients with acute coronary artery occlusion.     

Protection of the pediatric myocardium. Differential susceptibility to ischemic injury of the neonatal rat heart

Myocardial protection during pediatric cardiac operations has been suggested to be less successful than in adult hearts. In the present study we have compared the resistance of adult, infant, and neonatal rat hearts to various periods of ischemic arrest with normothermic (37 degrees C) crystalloid cardioplegia. Isolated hearts with intraventricular balloons, from adult (50 to 60 days of age, heart weight 865 +/- 13 mg), infant (20 to 25 days of age, heart weight 251 +/- 3 mg), and neonatal rats (3 to 5 days of age, heart weight 40 +/- 1 mg) were subjected to 10, 20, 30, 40, 50, 60, 80, and 100 minutes of ischemia (n = 6 hearts for each time point and for each age group). St. Thomas' Hospital cardioplegic solution was infused at the onset of the period of arrest. With increasing durations of ischemia there was a declining postischemic recovery of function. Up to 40 minutes of ischemia there was no significant difference between the three age groups in postischemic recovery of left ventricular developed pressure: 40.3% +/- 4.4%, 45.4% +/- 6.5%, and 44.4% +/- 2.2% of preischemic control for adult, infant, and neonatal hearts, respectively. Beyond 40 minutes adult and infant hearts showed an identical deterioration with effectively no recovery beyond 60 minutes of ischemia. By contrast, neonatal hearts were much more resistant to ischemia. After 100 minutes of ischemia the mean recovery of left ventricular developed pressure was 20.9% +/- 1.1%, whereas in infant and adult hearts the values were 0.6% +/- 0.3% after 80 minutes of ischemia and 0% after 100 minutes, respectively. Analysis of creatine kinase leakage also indicated that with ischemic durations in excess of 40 minutes, the neonatal heart was far more resistant to ischemia, and creatine kinase leakage per gram dry weight was much less than in infant or adult rats. Analysis of the rates of recovery during reperfusion again revealed differences between neonatal hearts and hearts from the other two age groups. We conclude that in the normal rat the neonatal heart has a greater inherent tolerance to ischemia than that of the infant or adult rat.     

心肌缺血期肢体缺血处理对大鼠心肌的保护作用

目的 观察心肌缺血期肢体缺血处理是否具有心肌保护作用.方法 将24只成年雄性Wistar大鼠随机分为心肌缺血/再灌注组(IR组)、假手术组(S组)、缺血期肢体缺血处理组(RP组).经胸骨下段切口建立大鼠心肌缺血再灌注损伤(IRI)模型,监测心电、左心室压力,比较心律失常评分、左心室压力变化率、左心室压峰值及血清磷酸肌酸激酶(CK)和心肌肌钙蛋白T(c-TNT)等.结果 再灌注早期RP组心律失常评分为(1.50±0.97),与IR组(2.33±0.71)差异有统计学意义(P<0.05);RP组的左心室压峰值及变化率均介于S组与IR组之间,但与IR组的差异无统计学意义(P>0.05).3组间CK差异无统计学意义(P>0.05),IR组与S组的c-TNT差异有统计学意义(P<0.05),但RP与IR及S组间差异均无统计学意义(P>0.05).结论 大鼠心肌缺血期肢体缺血处理具有一定的心肌保护作用,主要表现为减轻再灌注性心律失常.     

Protection of ischemic myocardium by exogenous phosphocreatine. II. Clinical, ultrastructural, and biochemical evaluations

In valve replacement operations on 78 patients with acquired heart disease, the efficiency of phosphocreatine in intraoperative protection of ischemic myocardium was evaluated by clinical, morphologic, and biochemical methods. Phosphocreatine (8 to 10 mmol/L) in a blood cardioplegic solution was used in operations on 41 patients; in the control group (37 patients) standard blood cardioplegia was used. In the group with phosphocreatine treatment we observed more rapid recovery of hemodynamics after release of the aortic cross-clamp, a decreased frequency of fibrillation, and more frequent restoration of sinus rhythm even if there were sinus rhythm disturbances before aortic cross-clamping. Analysis of the biopsy samples taken from the right ventricle showed protection of the sarcolemma against ischemic damage afforded by phosphocreatine and complete preservation of high-energy phosphates. The results obtained confirm the conclusion made by Robinson, Braimbridge, and Hearse (J Thorac Cardiovasc Surg 1984; 87:190-200) that phosphocreatine is an effective additional cardioprotective agent when used in cardioplegic solutions.     

Protection of the myocardium during surgery.

The methods of protection of the myocardium during surgical operations on the heart are described. The relative merits of coronary perfusion and cold arrest of the heart are discussed together with the disadvantages of each technique. The possible place of induced chemical arrest is discussed in relation to coronary perfusion. The technical considerations which affect the choice of method is also considered.     

Myocardial protection during ischemic cardiac arrest. Possible deleterious effects of glucose and mannitol in coronary infusates

Cardioplegic protective infusates are designed to induce rapid diastolic arrest and also to reduce or delay the onset of ischemic damage. As this study shows, the use of such infusates can greatly improve postischemic recovery of cardiac function. A number of investigators include glucose, insulin, or mannitol in their infusates in an attempt to increase the amount of protection afforded to the ischemic myocardium. Using an isolated, working rat heart model of cardiopulmonary bypass and ischemic cardiac arrest, we have shown that under certain conditions these additives can be deterimental to tissue protection. The deleterious effects of glucose and mannitol are dose dependent and can be modified by the inclusion of insulin in the infusate. The damaging effects of glucose appear to be both osmotic and metabolic in origin and those of mannitol, purely osmotic. The effects of insulin are complex and may affect a number of cellular processes.     

远程预处理对心肌缺血-再灌注损伤的保护作用

目的 观察远程预处理对急性心肌缺血-再灌注损伤的保护作用及对心肌信号转导和转录活化因子3 (STAT3)蛋白的影响.方法 健康雄性Wistar大鼠48只,体重240～280 g,随机均分为三组:对照组(N组)、缺血-再灌注组(IR组)、远程预处理组(rIPC2组).N组仅穿线不结扎血管;IR组结扎左冠状动脉前降支(LAD) 30 min,再灌注120min;rIPC组在LAD结扎前以止血带捆绑双下肢阻断血流5 min,放松5 min,反复4次.实验结束后用TTC染色法测定大鼠心肌梗死面积;取下腔静脉血3 ml离心后测定血中磷酸肌酸酶(CK)及乳酸脱氧酶(LDH)含量;Western Blot 法测定总STAT3(t-STAT3)和磷酸化STAT3(p-STAT3)蛋白表达水平.结果 rIPC组心肌梗死面积较IR组明显缩小(P＜0.05),N组无心肌梗死;IR组CK及LDH含量较N组显著升高(P＜0.01),rIPC组CK及LDH含量较IR组明显降低(P＜0.01);三组之间t-STAT3表达差异无统计学意义,IR组p-STAT3表达较N组显著降低(P＜0.05),rIPC组p-STAT3表达较IR组明显升高(P＜0.05).结论 远程预处理对心脏缺血-再灌注损伤具有早期保护作用,其机制可能与增加心肌p-STAT3蛋白表达有关.     

Protection of the hypertrophied myocardium by crystalloid cardioplegia.

Patients with left ventricular hypertrophy (LVH) have a worse outcome after cardiac surgery than those without hypertrophy. We studied protection of hearts with LVH in an isolated rat heart model using multidose, cold, oxygenated cardioplegia. LVH was produced by banding the abdominal aorta in young rats. Six weeks after banding, this produced a 31% increase in the left ventricular dry weight/body weight ratio compared to two age-matched control groups comprising sham-operated and nonoperated animals. The recovery of cardiac output after arrest was higher in LVH (82 +/- 4% of prearrest) than in sham-operated (69 +/- 4%) or nonoperated (66 +/- 3%) control groups. The improved functional recovery in LVH occurred although there were no differences among the groups in myocardial adenosine triphosphate (ATP) and phosphocreatine (PCr) prior to arrest, at the end of arrest, or after reperfusion. Glycogen levels were also similar among the three groups prior to arrest and after reperfusion but were highest in LVH after arrest. Myocardial oxygen consumption (MVO2) and efficiency, expressed as cardiac output/MVO2, were similar among the groups prior to arrest. Myocardial efficiency after reperfusion declined in all groups but was best preserved in LVH. We also compared the sensitivity of hypertrophied and control hearts to the deleterious effects of calcium in cardioplegia. Calcium in the cardioplegia increased myocardial lactate production during arrest in a dose-related fashion and depressed myocardial levels of ATP, PCr, and glycogen at end arrest in all groups. Cardiac output recovery was also depressed by calcium but was still best in LVH. We conclude that the hypertrophied myocardium is well protected by standard cardioplegia and that calcium in cardioplegia does not preferentially depress recovery in LVH.     

Experimental evaluation of coronary infusates in dogs.

In a study involving dogs, a coronary infusate containing a variety of substances including cardiac substrates, metabolic inhibitors, membrane stabilizers, electrolytes, and anticoagulants was evaluated in terms of protection afforded to the myocardium for up to 90 minutes of normothermic anoxic arrest. Electron microscopical studies and tissue adenosine triphosphate measurements revealed this coronary infusate to be considerably beneficial to the myocardium. Infused myocardium was better preserved compared to myocardium that was not infused or infused with two other "control" infusates. The individual components of our infusate are known cardiac preservatives. The rationale for combining a number of them in our infusate is to produce an additive or synergetic effect through beneficial intervention at several points in the cardiac metabolic cycle. This objective appears to have been fulfilled under the conditions of the present experiment.     

Salvage of ischemic myocardium by nonsynchronized retroperfusion in the pig.

Salvage of ischemic myocardium, with the aid of a nonsynchronized coronary sinus retroperfusion system, was studied in a pig infarct model. In anesthetized open chested animals, the left anterior descending coronary artery was occluded for 4 hours and then reperfused for 1 hour before the animals were killed. In the control group (n = 12) no therapy was used. In the experimental group (n = 13), nonsynchronized retrovenous coronary sinus perfusion was applied during the 4 hours of coronary artery occlusion. Therapy consisted of intermittent balloon occlusion of the coronary sinus (5-second inflation, 5-second deflation) with retroperfusion of arterial blood at 60 ml/min during the inflation part of the cycle. Infarct size, expressed as a percentage of the area at risk (+/- standard deviation), was significantly smaller in the experimental group (41.5% +/- 15.0%) than in the control group (80.5% +/- 6.1%) (p less than 0.001). Mean coronary sinus pressure (+/- standard deviation) was 51 +/- 12 mm Hg in the experimental group but was not elevated in the control animals. We conclude that nonsynchronized retrovenous coronary sinus perfusion was able to significantly salvage ischemic myocardium in a model of minimal intercoronary collateral circulation.     

Protection of the myocardium during global ischemia. Is crystalloid cardioplegia effective in the immature myocardium?

In pediatric cardiac operations, a high proportion of hospital deaths are believed to result from inadequate myocardial protection during the period of global ischemia. To investigate whether this may be due to an inherently lower resistance to myocardial ischemia or to the failure of conventional cardioplegia to afford adequate protection in the immature heart, we have conducted a series of studies with isolated hearts from neonatal (3 to 5 days old, body weight 6.3 to 13.4 gm) and adult (84 to 112 days old, 260 to 340 gm) rats. The efficacy of cardioplegia was assessed in neonatal hearts (n = 6 per group) subjected to various durations of normothermic ischemia, with and without a 2-minute preischemic infusion of the St. Thomas' Hospital cardioplegic solution. At all times studied, the use of cardioplegia resulted in a greater postischemic recovery of left ventricular developed pressure and first derivative of left ventricular pressure. After periods of ischemia lasting 30, 60, 90, 120, and 150 minutes in the absence of cardioplegia, left ventricular developed pressure recovered to 80% +/- 10%, 66% +/- 11%, 53% +/- 7%, 33% +/- 6%, and 21% +/- 4% of preischemic values, respectively; in the presence of cardioplegia, the values were 89% +/- 6%, 83% +/- 8%, 74% +/- 6% (p less than 0.05), 58% +/- 5% (p less than 0.05), and 41% +/- 7% (p less than 0.05), respectively. The corresponding values for first derivative of left ventricular pressure were 78% +/- 9%, 67% +/- 12%, 54% +/- 7%, 30% +/- 5%, and 19% +/- 3% in the absence of cardioplegia and 92% +/- 7%, 88% +/- 8%, 75% +/- 8%, 56% +/- 5% (p less than 0.05) and 39% +/- 6% (p less than 0.05) in the presence of cardioplegia. In the noncardioplegia groups, 90% of hearts exhibited ischemic contracture (mean time to onset = 24.7 +/- 1.1 minutes), whereas in the cardioplegia groups, only 63% exhibited contracture, and of a significantly delayed onset (37.0 +/- 1.5 min, p less than 0.05). Adult hearts (n = 5) subjected to 30 minutes of normothermic ischemic arrest, in the absence of cardioplegia, recovered 36% +/- 7% of the preischemic left ventricular developed pressure and 37% +/- 9% of the preischemic first derivative of left ventricular pressure on reperfusion; 100% of these hearts exhibited some degree of contracture (mean time to onset = 15.4 +/- 1.1 minutes) by the end of the ischemic period.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of dobutamine and diltiazem on the reperfused ischemic myocardium

Twenty-two anesthetized open-chest mongrel dogs were studied to evaluate the effect of dobutamine, dobutamine and diltiazem on the ischemic-reperfused myocardium assessed by cardiac function, myocardial metabolism such as tissue ATP, Ca and water content and ultrastructure. The left anterior descending coronary artery was ligated for 40 minutes and then reperfused for 15 minutes. Experiments were divided into 3 groups by infusion of physical saline solution (C), dobutamine 5 micrograms/kg/m in (DOB) and dobutamine 5 micrograms/kg/min+diltiazem 0.1mg/kg bolus IV at the beginning of reperfusion and followed by continuous infusion with 30 micrograms/kg/min (DOB+D) during reperfusion period. DOB increased SAP and CI, however it also increased heart rate. CI, LVSWI and coronary blood flow in non ischemic area increased significantly in DOB+D than either C or DOB. Myocardial ATP in the ischemic endocardium was much more preserved in DOB and DOB+D than C. Myocardial Ca and water content were lower level in DOB+D, but not significantly different among 3 groups. Mitochondrial score by Sunamori's method in DOB+D was higher than that in C (p less than 0.05). These results suggest that low dose of dobutamine during reperfusion is effective to enhance hemodynamic parameters without deterioration of myocardial metabolism, and furthermore combined use of dobutamine and diltiazem is more effective to protect myocardial metabolism and ultrastructure from reperfusion damage in addition to improvement of hemodynamic parameters.     

RAGE and modulation of ischemic injury in the diabetic myocardium

OBJECTIVE—Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared with nondiabetic age-matched individuals. The receptor for advanced glycation end products (RAGE) is upregulated in diabetic tissues. In this study, we tested the hypothesis that RAGE affected ischemia/reperfusion (I/R) injury in the diabetic myocardium. In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes.RESEARCH DESIGN AND METHODS—To specifically dissect the impact of RAGE, homozygous RAGE-null mice and transgenic (Tg) mice expressing cytoplasmic domain-deleted RAGE (DN RAGE), in which RAGE-dependent signal transduction was deficient in endothelial cells or mononuclear phagocytes, were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to I/R.RESULTS—Diabetic RAGE-null mice were significantly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH and lower glycoxidation products carboxymethyl-lysine (CML) and pentosidine, improved functional recovery, and increased ATP. In diabetic Tg mice expressing DN RAGE in endothelial cells or mononuclear phagocytes, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared with littermate diabetic controls. Furthermore, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared with wild-type diabetic littermates in I/R.CONCLUSIONS—These findings demonstrate novel and key roles for RAGE in I/R injury in the diabetic heart.Cardiac complications remain a leading cause of morbidity and mortality in subjects with diabetes (1–3). Although many factors contribute to depressed cardiac function in diabetes, innate disturbances within the diabetic heart contribute importantly to progressive dysfunction, which often leads to irreversible failure and death (3). Alterations in substrate metabolism and increased levels of oxygen free radicals have been observed in diabetic tissues. Inflammatory cytokines may exert direct negative inotropic effects on cardiac myocytes and contribute to aberrant remodeling in the failed heart (4–8). The pathophysiology of diabetes-associated cardiac complications is complex and involves a host of factors linked to metabolic and immune/inflammatory cell activation.The accumulation of late-stage glycoxidation adducts of proteins, termed advanced glycation end products (AGEs), occurs in diabetic tissues. AGEs modify long-lived molecules in the blood vessel wall and structural tissues of the heart considerably earlier than symptomatic cardiac dysfunction occurs (9). A major way in which AGEs exert their cellular effects is by ligation of the multiligand receptor for AGE (RAGE) (10–13).We tested the role of RAGE in rodent models of type 1 diabetes, and we show that pharmacological blockade of ligand-RAGE interaction or genetic modulation of RAGE suppresses ischemia/reperfusion (I/R) injury in the isolated perfused heart, at least in part secondary to critical contributions evoked from RAGE-expressing endothelial cells and mononuclear phagocytes in the diabetic heart.     

Left ventricular reconstruction benefits patients with ischemic cardiomyopathy and non-viable myocardium.

OBJECTIVE: There are subsets of patients with ischemic cardiomyopathy for whom the optimal treatment strategies are not clear. The objective of this study was to delineate the relationship between clinical outcomes and surgical procedure in patients who were treated either with a coronary artery bypass graft or with a coronary artery bypass graft and additional ventricular restoration. METHODS: The study population comprised 137 consecutive patients with anterior myocardial infarction. All patients had an ejection fraction <50% and left ventricle end-systolic volume index >80 ml/m(2). The patients were divided into a viable and a non-viable group according to anterior myocardium viability, which was determined by a thallium-201 test. The viable group underwent a revascularization and was randomized into two groups for additional ventricular reconstruction. Group 1a comprised 35 patients with viable anterior wall who underwent surgical revascularization. Group 1b comprised 39 patients with viable anterior wall who underwent surgical revascularization and ventricular restoration. Group 2 comprised 69 patients with non-viable anterior wall who underwent revascularization and ventricular reconstruction. The preoperative and postoperative ejection fractions, end-systolic volume, mitral regurgitation, mortality, and heart failure symptoms were compared among groups. RESULTS: Complete 2-year follow-up was achieved in 127 (92.7%) patients. Ejection fraction improved in all groups compared with preoperative values and it was greater in group 1b than in group 1a (p<0.001) at 2 years. There were no postoperative deaths in group 1a, one in group 1b, and two in group 2. After 2 years, group 1b was significantly smaller than group 1a (p<0.01) in relation to mitral regurgitation of grades 1 to 2+. End-systolic volume was significantly smaller in group 1b than in group 1a (p<0.001), it was smaller in group 1a than in group 2 (p<0.001), and it was smaller in group 1b than in group 2 (p<0.001). Heart failure class (NYHA) was reduced in all groups and events were significantly smaller in patients with end-systolic volume lesser than 120 ml/m(2) (p<0.05). CONCLUSION: We have demonstrated that the short-term and mid-term outcomes of coronary artery surgery alone in patients with a large left ventricle are inferior to coronary artery surgery plus ventricular restoration.