Reduction in myocardial infarct size: prevention of heart cell death.

The course of myocardial necrosis, the clinical syndrome, and methods of treatment are presented. Heart cell death may be prevented by maintaining the balance between myocardial oxygen and energy supply and consumption. New technics of improving this balance by reducing myocardial energy demand, altering metabolism, increasing myocardial substrate supply, and protecting cellular integrity are discussed.     

Antagonism of leukotriene B4 receptors does not limit canine myocardial infarct size

Injection of leukotriene (LT)B4 (0.1-3 micrograms/kg i.v.) in normal anesthetized dogs produced dose-related leukopenia that was accompanied by arterial hypotension and tachycardia at higher tested doses. LTD4 (0.1-3 micrograms/kg i.v.), in contrast, increased arterial blood pressure, lowered cardiac rate and produced little change in arterial blood leukocyte count. Continuous infusion of LY255283 [(1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)- heptyloxy)phenyl)ethanone] (0.33 mg/kg/min i.v.), a selective LTB4 receptor antagonist, resulted in near complete inhibition of leukopenic, hypotensive and tachycardic responses to LTB4 (3 micrograms/kg i.v.) challenge over a 6-hr test period. Persistent antagonism of canine LTB4 receptors was associated with high circulating levels of LY255283 that were bound extensively to plasma proteins. In subsequent experiments, myocardial infarct size was measured following 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with vehicle, and in dogs receiving LY255283 (0.33 mg/kg/min i.v.). Drug and vehicle were infused continuously beginning 15 min before coronary artery occlusion. LY255283 treatment essentially did not alter base-line cardiovascular parameters or myocardial oxygen demand when alterations were compared to time-related changes observed in control dogs. LY255283 infusion also did not alter the degree of myocardial ischemia or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant infarct sizes were 43 +/- 5% of the left ventricle placed at risk in control dogs and 32 +/- 5% in dogs given LY255283; this difference was not statistically significant. The extent of left ventricle placed at risk was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prostaglandin E1 on canine nasal vascular and airway resistances

We have developed a technique which can measure directly and simultaneously changes in both nasal vascular and airway resistances in the dog. Nasal vascular resistance was measured by either direct monitoring of the arterial inflow or a change in the perfusion pressure of the nasal vascular bed with blood flow maintained constant. Nasal airway resistance was measured by a rhinomanometric method. Intra-arterial infusion of prostaglandin (PG) E1 at the rate of 1 ml/min in doses of 0.001 to 10 micrograms/min caused a dose-dependent decrease in both nasal vascular and airway resistances. When compared with the control, the average maximal effect of PGE1 on vascular resistance was -38.4%, whereas on airway resistance it was -16.4%. The present studies demonstrate that PGE1 has significant vasodilatatory activity in the canine nasal vascular bed and suggest that the vascular and airway responses to PGE1 may be due to a decrease in inflow and outflow vascular resistance and/or opening of arteriovenous anastomoses.     

The measurement and cotrrol of myocardial infarct size

Direct, chemical, electrocardiographic and radio-isotopic methods are described for the estimation of myocardial infarct size in animals and man. Their relative points and failings are discussed. The effects of interventions, physical, metabolic and pharmacological, upon the size of myocardial infarcts, are examined and work attempting to reduce myocardial infarct size in man reviewed.     

Beneficial effects of prostaglandin E1 infusion in experimental traumatic shock

The effects of prostaglandin E1 (PGE1) were studied in a standardized model of traumatic shock in rats. Pentobarbital anesthetized rats were subjected to standardized drum trauma of 525 revolutions in a Noble-Collip drum. These traumatized rats were characterized by a survival time of 108 +/- 19 min, a 12-fold increase in plasma cathepsin D activity, and a three-fold increase in plasma myocardial depressant factor (MDF) activity. PGE1 (1.2 micrograms/kg X min) significantly improved survival time during traumatic shock (191 +/- 29 vs. 108 +/- 19 min), drug vs. vehicle, respectively (p less than .03). In addition, PGE1 significantly attenuated plasma MDF activity during traumatic shock (58 +/- 10 vs. 27 +/- 7 U/ml), vehicle vs. drug, respectively (p less than .02). Plasma cathepsin D activity was also significantly retarded (12.1 +/- 1.8 vs. 1.70 +/- 1.50 U/ml), vehicle vs. drug, respectively (p less than .01). PGE1 appears to exert a membrane stabilizing effect, decreasing plasma cathepsin D and attenuating MDF production. PGE1 thus appears to have significant antishock activity.     

Reduction of ischemia--reperfusion induced myocardial infarct size in rats by caffeic acid phenethyl ester (CAPE)

Myocardial ischemia--reperfusion (MI/R) represents a clinically relevant problem associated with thrombolysis, angioplasty, and coronary bypass surgery. MI/R injury is known to occur on restoration of coronary flow after a period of myocardial ischemia. Injury of myocardium caused by I/R includes cardiac contractile dysfunction, arrhythmias, as well as irreversible myocyte damage. Prevention of myocardial death in acute coronary syndromes is the immediate goal of therapy. The main factor concerned with the experimental generation of reperfusion damage is oxygen-derived free radicals. This MI/R injury has been shown to be salvaged by supplementing antioxidants to diseased hearts. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has antioxidant and anti-inflammatory properties, and may function in cardiac protection against I/R-induced damage. To test this hypothesis, we randomly assigned 14 male Wistar rats for necrosis experiments. To produce myocardial necrosis, the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion in anesthetized rats. CAPE (50 microM kg-1) was given intravenously 10 min before occlusion and continued during ischemia by infusion pump. The volume of infarct and the risk zone was determined by planimentry of each tracing and multiplying by the slice thickness. Infarct was normalized by expressing it as a percentage of the area at risk. Compared to control group, CAPE administration statistically reduced the myocardial infarct size/area of risk zone (50 +/- 4% and 32 +/- 6%, respectively) and the myocardial infarct size (23 +/- 3% and 9 +/- 4%, respectively) in rat model of ischemia-reperfusion. In conclusion, this result shows that CAPE is important in reducing I/R-induced myocardial damage.     

Reduction of infarct size in a rat model of regional myocardial ischemia and reperfusion by the synthetic peptide DAHK

OBJECTIVE: The increased mobilization of iron and copper during ischemia is reported to contribute to postischemic injury. DMI-4983 is a small synthetic peptide, Asp-Ala-His-Lys (DAHK), that mimics the high-affinity copper-binding site of the N-terminus of human albumin. This peptide was reported to inhibit copper-induced formation of reactive oxygen species in vitro, reduce interleukin-8 formation in cultured endothelial cells, and improve left ventricular function after global ischemia and reperfusion in the isolated blood-perfused heart of the rat. The aim of this study was to investigate the effects of DMI-4983 on myocardial infarct size caused by regional ischemia and reperfusion in vivo. DESIGN: Rats were subjected to regional myocardial ischemia (25 mins) followed by reperfusion (2 hrs). Randomized groups received either vehicle or DMI-4983 administered as a 5, 10, or 20 mg/kg intravenous bolus along with a 10 mg/kg/hr continuous infusion starting just before reperfusion and continuing throughout the experiment. Infarct size was determined at the end of the experiment. SETTING: Basic research institute and trauma research laboratory. SUBJECTS: Anesthetized male Wistar rats. MEASUREMENTS AND MAIN RESULTS: The area at risk of infarction and hemodynamic variables were similar in all groups. Rats treated with vehicle resulted in an infarct size of 64% +/- 3% of the area at risk of infarction. Intravenous administration of DMI-4983 reduced infarct size to 52% +/- 3%, 50% +/- 2%, and 45% +/- 3% of the area at risk of infarction for 5, 10, and 20 mg/kg, respectively (p < .05 compared with vehicle for each dosage). CONCLUSIONS: Intravenous DMI-4983 administered before the onset of reperfusion and continuously throughout the reperfusion period caused a significant reduction in tissue necrosis in this in vivo model of regional myocardial ischemia and reperfusion, suggesting that DMI-4983 may represent a novel approach for the treatment of myocardial ischemia and reperfusion injury.     

Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct

The development of clinically beneficial myocardial gene therapy has been slowed by reliance on the use of viral carriers and non-physiologic, constitutive gene expression. To specifically address these issues, we have developed a non-viral gene carrier, water-soluble lipopolymer (WSLP), and an ischemia-inducible plasmid construct expressing vascular endothelial growth factor (VEGF), pRTP801-VEGF, to treat myocardial ischemia and infarction. Rabbits underwent ligation of the circumflex artery followed by injection of (a) an ischemia-inducible VEGF gene construct in a WSLP carrier; (b) a constitutively expressed, or unregulated, SV-VEGF gene construct in a WSLP carrier; (c) WSLP carrier alone; or (d) no injection therapy. Following 4 weeks treatment, ligation alone resulted in infarction of 48+/-7% of the left ventricle. With injection of WSLP carrier alone, 49+/-6% of the left ventricle was infarcted (P=NS). The constitutively expressed gene construct, SV-VEGF, reduced the infarct size to 32+/-7% of the left ventricle (P=0.007). The ischemia-inducible gene construct, RTP801-VEGF, further reduced the infarct size to 13+/-4% of the left ventricle (P<0.001). The use of a non-viral carrier to deliver an ischemia-inducible VEGF construct is effective in the treatment of acutely ischemic myocardium.     

心肌缺血预适应对急性心肌梗死面积及近期预后的影响

目的 :观察急性心肌梗死前心绞痛发作与梗死范围及近期预后的关系。方法 :选择 178例急性心肌梗死患者 ,根据梗死前 72h以上有无心绞痛 ,分为A组 (有心绞痛 ) 76例 ,B组 (无心绞痛 ) 10 2例。对两组的梗死面积、并发症和病死率进行统计分析。结果 :A组梗死面积小 (两组间有显著差异 ,P <0 0 5 ) ,住院期间严重心律失常、心力衰竭、心原性休克发生率及病死率均低于B组 (两组间有显著差异 ,P <0 0 5 )。结论 :急性心肌梗死前有心绞痛发作对心肌有明显的保护作用     

前列腺素E1对犬缺血心肌的保护作用

探讨前列腺素Ｅ１对缺血心肌的保护作用。将２０只左冠状动脉前降支结扎犬分成２组，Ｉ组在ＬＡＤ结扎后静滴ＰＧＥ１，Ⅱ组静滴一时卤水作为对照组。２组犬均于ＬＡＤ结扎前，结扎后３０分钟、４小时，２４小时和４８小时采集周围静脉血，检测血浆血小板表面α－颗粒膜蛋白和血栓素Ｂ２含量；ＬＡＤ结扎４８小时后处死动物，取出心脏检测心肌组织内髓过氧化物酶活性，并将心肌切片后行氯化三苯基四氮唑染以，确定梗塞面积大小。     

间歇二次谐波全氟显超声造影评价心肌缺血与坏死的价值

目的 评价间歇二次谐波心肌声学造影（ｍｙｏｃａｒｄｉａｌ ｃｏｎｔｒａｓｔ ｅｃｈｏｃａｒｄｉｏｇｒａｐｈｙ,ＭＣＥ）在梗死心财灌注研究中的价值。方法 用前降支冠状动脉套扎建立开胸犬模型。分两组：缺血再灌注组于血流阻断１ｈ后再灌注２ｈ．;缺血预适应组则在缺血１ｈ前预缺血和再灌注各５ｍｉｎ,反复４次。两组均于再灌注２ｈ后经静脉注射全氟显进行ＭＣＥ,随后取出心脏用Ｅｖａｎ蓝和ＴＴＣ染色,对照两种方法所     

Effect of prostaglandin E1 on the formation of experimental arterial and venous thrombosis

The effect of prostaglandin E1 on thrombus formation and haemostasis was investigated in a standardized experimental model in 20 rabbits. Arterial thrombus formation was reduced significantly by 70% and venous thrombosis by 68% in comparison with the controls. Collagen- and ADP-induced platelet aggregation was also inhibited significantly. Additionally, the time lag until onset of collagen-induced aggregation was significantly prolonged. Platelet count however, and plasma coagulation time showed no change. The data demonstrate a clear inhibition of arterial and venous thrombus formation, suggesting a powerful antithrombotic activity of prostaglandin E1. The effect may be explained by an influence on platelet function. The data further indicate that a full antithrombotic effect is achieved during prostaglandin E1 infusion.     

心力衰竭病人前列腺素E1治疗效果与其受体水平的相关性研究

目的 观察前列腺素E1(PGE1)对心力衰竭病人的治疗效果,同时通过血小板上EP 受体改变,探讨其可能机制.方法 86 例病人被随机分为两组:常规治疗组(A 组)48 例,PGE1 治疗组(B 组)38 例.常规治疗组采用目前常规抗心力衰竭治疗,而治疗组加用了PGE1 20 μg 于5%葡萄糖注射液稀释后泵静注14 d 为1 个疗程.以治疗前后心功能改善作为判断标准,同时用PCR 法测定血小板上EP 受体改变.结果 B 组总有效率为92.11%,显著高于A 组75.00%,差异有统计学意义(χ2=3.86,P<0.05);PGE1 治疗的慢性阻塞性肺病、高血压和冠心病病人疗效比较,差异无统计学意义(χ2=0.50,P＞0.05);B 组治疗后EP2 和EP4 水平显著增高,与治疗前比较,差异有统计学意义(t 分别=7.86、3.92,P 均<0.05).结论 PGE1 对慢性阻塞性肺病、高血压和冠心病所致的心力衰竭有较好的疗效,其机制可能与治疗后EP2 和EP4 受体表达增加有关.