心肌的缺血预适应现象

<正> 有效地限制急性心肌梗塞范围,是治疗心肌梗塞和提高存活率的重要措施.随着溶栓治疗和冠脉搭桥及成形术的发展,成功地恢复了缺血心肌的血流灌注.晚近发现的心肌缺血预适应现象,是一种心肌自我保护机制,它业已引起人们的广泛关注.围绕心肌缺血预适应这一重要发现展开的基础与临床研究,为有效地改善心肌供血开辟了一条新途径,本文就心肌缺血预适应的研究作一概述.     

人心肌缺血预适应的研究进展

本文结合近年来文献报道，综合分析心肌缺血预适应人类体内，外存存的证据。对人心肌缺血预适应发生的可能机理进行讨论。提出了人心肌缺血预适应在临床的几个潜在应用前景。     

药理性预适应在心肌缺血再灌注损伤中的保护作用

心肌较长时间缺血造成一定损伤后，恢复供血后不但不能减轻或逆转损伤，反而加重损伤，称为心肌缺血再灌注损伤。心内直视手术主动脉阻断期间，冠脉供血中断，心肌细胞进入无氧代谢，心肌恢复氧供后，大量自由基生成，导致脂质过氧化产物丙二醛（MDA）明显增加，细胞中肌酸磷酸激酶（CPK）及乳酸脱氢酶（LDH）释放增加，心肌遭受再灌注损伤。引起心肌缺血再灌注损伤的主要因素就是氧自由基释放和细胞内Ca^2＋超负荷。1986年Murry等首次报道犬心肌短时反复缺血可缩小随后长时间缺血造成的心肌梗死范围，即心肌缺血预适应（MIP）。MIP的保护作用是机体产生了某些活性物质增强了细胞或组织器官对不良刺激的耐受性和适应性，对抗缺血再灌注引起的损伤。应用外源性活性物质的药理作用模拟MIP，产生心肌保护作用为药理性预适应。药理性预适应以药物替代缺血刺激，克服缺血损伤的弊端，为心肌保护开创了广阔的前景。现将常见可行药理性预适应的药物作用综述如下。     

细胞信号转导在心肌缺血预适应中的研究进展

心肌缺血预适应是指心脏短暂缺血后能耐受较长时间的缺血现象,是一种有效的心肌保护方法。心肌缺血预适应与细胞信号转导密切相关。细胞信号转导系统包括:受体、转导途径及作用效应并通过这三个方面介导心肌缺血预适应。     

心肌缺血预适应对缩小老年心肌梗塞范围的临床研究

目的探讨心肌缺血预适应对老年急性心肌梗塞（ＡＭＩ）患者梗塞面积的影响。方法对照分析心肌梗塞前６６例有心肌缺血预适应与４４例无心肌缺血预适应老年ＡＭＩ患者的临床资料。结果有心肌缺血预适应老年ＡＭＩ患者其肌酸磷酸激酶（ＣＰＫ）与肌酸磷酸激酶同功酶ＭＢ（ＣＫ－ＭＢ）峰值，复杂室性期前收缩、泵功能障碍发生率与近期死亡率等均显著低于无心肌缺血预适应老年ＡＭＩ患者（Ｐ＜０．０１与Ｐ＜０．０５）。结论心肌缺血预适应有缩小老年心肌梗塞面积的作用，故对其近期预后可产生有益的影响。     

心肌缺血预适应对急性心肌梗死预后的影响

目的观察心肌缺血预适应对急性心肌梗死的保护作用。方法将急性心肌梗死70例,根据梗死前有无心绞痛发作史分为缺血预适应组42例和无缺血预适应组28例,将两组临床资料进行对比分析。结果缺血预适应组小面积心肌梗死的发生率明显高于无缺血预适应组,而心律失常、心衰、心源性休克和再梗死等发生率和病死率明显低于无缺血预适应组。结论心肌缺血预适应对AMI具有保护作用,可限制梗死范围扩大,维护心功能,降低心律失常等并发症的发生率及住院病死率。     

缺血预适应对心肌梗死的保护作用

心肌缺血预适应(ischemic precondition，IP)是指反复短暂的心肌缺血和再灌注可明显增强心肌对较长时间持续缺血和再灌注损伤的耐受能力。动物实验表明，心肌缺血预适应能够延迟缺血造成的致命性细胞损伤，缩小梗死面积，降低心律失常和心衰的发生率，从而降低病死率，对患者产生有益的保护作用。笔者对我院近年来收治的急性心肌梗死患者的临床资料进行了回顾性分析，进一步认识缺血预适应对急性心肌梗死患者产生的有益影响，现报告如下。     

浅论缺血预适应

浅论缺血预适应牟善初缺血预适应（ｉｓｃｈｅｍｉｃｐｒｅｃｏｎｄｉｔｉｏｎｉｎｇ）或称缺血预处理，是１９８６年Ｍｕｒｒｙ、Ｒｅｉｍｅｒ、Ｊｅｎｎｉｎｇｓ等提出的概念。他们在动物的心肌缺血性损伤试验中发现，如果先造成多次短暂的缺血（阻断冠状动脉回旋支每次...     

心肌缺血预适应与再灌注损伤

心肌缺血预适应现象的发现使其成为心肌缺血 再灌注损伤的一种有效的治疗措施 ,近 3 0年的基础和临床研究逐步阐明了这种现象发生的机制。本文综述了该现象研究的历史和最新进展 ,以及缺血预适应对心肌细胞、内皮细胞的保护作用 ,并阐述了其与心肌梗死、心肌顿抑和心律失常的临床关系 ,文章中也涉及到了最新的麻醉剂预适应和远隔保护作用     

临床应用心肌缺血预适应与后适应的哲学理论

及时恢复缺血区的血液灌注即再灌注是临床上挽救缺血心肌的最有效措施,但再灌注会引起严重的再灌注损伤。心肌缺血预适应和后适应可以减轻缺血再灌注损伤后心肌的坏死与心肌功能障碍,减少恶性心律失常的发生,是减轻缺血再灌注损伤的有效内源性保护手段。心肌缺血预适应和后适应的机制主要是通过诱导触发因子释放,经多条细胞内信号转导途径的介导,作用于多种效应器,影响缺血再灌注损伤的关键环节而发挥心肌细胞保护作用。心肌缺血预适应和后适应是内因和外因的辩证统一,也蕴含矛盾双方互相转化的规律。     

Clinical effects of ischemic preconditioning.

A variety of experimental studies have confirmed that preconditioning the myocardium by brief periods of ischemia represents a powerful cardioprotective effect resulting in a reduction of infarct size. After 15 years of research in the experimental laboratory, some evidence shows the existence of preconditioning in human patients with coronary artery disease: repeated balloon inflations before coronary angioplasty induce preconditioning-like effects; moreover, some studies demonstrate better clinical outcome in patients with angina before acute myocardial infarction, resembling a preconditioning effect. So far, a few drugs have been identified as potential mediators of preconditioning, e.g., adenosine, adenosine receptor agonists, and adenosine triphosphate-sensitive potassium channel openers. Before coronary angioplasty and heart surgery, these preconditioning mimetics might be used to protect myocardial tissue by means of preconditioning. Further research is required before preconditioning mimetics could be used for therapy in patients with chronic myocardial ischemia. Possible antipreconditioning effects of several drugs, e.g., sulfonylurea drugs have to be considered in the treatment of patients with coronary artery disease.     

Electrical Plasticity and Cardioprotection in Myocardial Ischemia—Role of Selective Sodium Channel Blockers

The concept of electrical protection of the ischemic myocardium is in constant evolution and has recently been supported by experimental and clinical studies. Historically, antiplatelet agents, angiotensin‐converting enzyme inhibitors, β‐blockers, and statins have been all proposed as drugs conferring anti‐ischemic cardioprotection. This was supported by the evidence consistently indicating that all these drugs were capable of reducing mortality and the risk of repeat myocardial infarction. The electrical plasticity paradigm is, however, a novel concept that depicts the benefits of improved sodium channel blockade with drugs such as ranolazine and cariporide. Although it has been hypothesized that the protective role of ranolazine depends on decreased fatty acid β‐oxidation affecting preconditioning, we speculate against such a hypothesis, because inhibition of β‐oxidation requires higher concentrations of the drug, above the therapeutic range. Rather, we discuss the key role of calcium overload reduction through inhibition of the late sodium current (I_Na). Mechanisms driving cardioprotection involve the block of a cascade of complex ionic exchanges that can result in intracellular acidosis, excess cytosolic calcium, myocardial cellular dysfunction, and eventually cell injury and death. In this review we discuss the studies that demonstrate how electrical plasticity through sodium channel blockers can promote cardioprotection against ischemia in coronary heart disease.     

Preinfarction angina and myocardial preconditioning

In the current era of pharmacologic and mechanical reperfusion therapy, several studies have consistently shown that patients with myocardial infarction preceded by angina have smaller infarcts and a better in-hospital outcome after thrombolytic therapy than patients without preinfarction angina. At least three mechanisms may explain these differences between infarctions that are preceded by angina and those that are not: coronary collaterals, reperfusion rate, and ischemic preconditioning. Collaterals alone do not seem to explain the beneficial effects of preinfarction angina, although it is difficult to completely rule out their role in the clinical setting. The possibility that preinfarction angina is not protective per se, but rather is a predictor of a more rapid coronary reperfusion is attractive; however, it should be addressed by further clinical studies. Finally, it is likely that the beneficial effects of preinfarction angina are related to ischemic preconditioning. Although a direct demonstration of this hypothesis is still lacking, clinical features of preinfarction angina, which is characterized by anginal attacks preceding acute myocardial infarction, are very similar to those of ischemic preconditioning, in which brief ischemic episodes precede a prolonged ischemic period. Indeed, the demonstration of ischemic preconditioning in different clinical models of ischemia and reperfusion and the identification of some of its mediators suggest that in patients at high risk of myocardial infarction drugs known to block this endogenous form of protection should be used with caution, while drugs known to elicit preconditioning might have a relevant therapeutic role. However, the optimal timing, administration, and dosage for preconditioning-mimetic drugs in the appropriate clinical setting are still under debate and warrant further investigation.     

Ischaemic preconditioning: from molecular characterisation to clinical application--part II

Ischaemic preconditioning was originally described in animal hearts as histological infarct-size limitation by a previous brief episode of ischaemia. In humans, ischaemic preconditioning has been demonstrated in several in vitro and in vivo models, including coronary artery bypass grafting and percutaneous transluminal coronary angiograplasty, using surrogate markers of ischaemia and reperfusion injury. Increasing knowledge of the molecular signalling pathways mediating protection by ischaemic preconditioning has provided rational targets for pharmacological intervention. Several widely used drugs are able to mimic ischaemic preconditioning (e.g. adenosine, adenosine-uptake inhibitors, ACE inhibitors, angiotensin II antagonists, statins, opioids, volatile anaesthetics and ethanol), whereas others inhibit ischaemic preconditioning-induced protection (e.g. sulphonylureas and adenosine antagonists). The present review focuses on these different classes of drugs. Prudent use or avoidance of these drugs in patients who are at risk for myocardial infarction could theoretically limit ischaemia and reperfusion injury.     

肢体无创缺血预处理对冠状动脉保护作用的临床研究进展

临床研究表明,肢体远端缺血预处理对心肌有保护作用,表现为心肌梗死面积的减小或者心肌酶指标（肌钙蛋白Ⅰ、肌钙蛋白T）的下降。缺血预处理对心肌的保护作用可能和其冠状动脉保护作用有关。临床研究已经证实缺血预处理可以减轻上肢动脉内膜损伤引起的内皮依赖性血管舒张反应的异常。但是其对冠状动脉的保护作用尚存争议,这一问题值得进一步大规模临床试验探讨,冠状动脉侧支循环的血流动力学变化尤其值得关注。     

Preconditioning, postconditioning and their application to clinical cardiology

Ischemic preconditioning is a well-established phenomenon first described in experimental preparations in which brief episodes of ischemia/reperfusion applied prior to a longer coronary artery occlusion reduce myocardial infarct size. There are ample correlates of ischemic preconditioning in the clinical realm. Preconditioning mimetic agents that stimulate the biochemical pathways of ischemic preconditioning and protect the heart without inducing ischemia have been examined in numerous experimental studies. However, despite the effectiveness of ischemic preconditioning and preconditioning mimetics for protecting ischemic myocardium, there are no preconditioning-based therapies that are routinely used in clinical medicine at the current time. Part of the problem is the need to administer therapy prior to the known ischemic event. Other issues are that percutaneous coronary intervention technology has advanced so far (with the development of stents and drug-eluting stents) that ischemic preconditioning or preconditioning mimetics have not been needed in most interventional cases. Recent clinical trials such as AMISTAD I and II (Acute Myocardial Infarction STudy of ADenosine) suggest that some preconditioning mimetics may reduce myocardial infarct size when given along with reperfusion or, as in the IONA trial, have benefit on clinical events when administered chronically in patients with known coronary artery disease. It is possible that some of the benefit described for adenosine in the AMISTAD 1 and 2 trials represents a manifestation of the recently described postconditioning phenomenon. It is probable that postconditioning--in which reperfusion is interrupted with brief coronary occlusions and reperfusion sequences--is more likely than preconditioning to be feasible as a clinical application to patients undergoing percutaneous coronary intervention for acute myocardial infarction.     

Pré-condicionamento isquémico remoto do miocárdio: dos mecanismos fisiopatológicos à aplicação na prática clínica

Short periods of myocardial ischemia followed by reperfusion induce a cardioprotective mechanism when the myocardium is subsequently subjected to a prolonged period of ischemia, a phenomenon known as ischemic preconditioning.As well as its application in the myocardium, ischemic preconditioning can also be induced by brief interruptions of blood flow to other organs, particularly skeletal muscle. Transient ischemia induced noninvasively by inflating a cuff on a limb, followed by reperfusion, helps reduce the damage caused to the myocardium by interruption of the coronary circulation.Remote ischemic preconditioning involves activation of humoral and/or neural pathways that open mitochondrial ATP-sensitive potassium channels in the myocardium and close mitochondrial permeability transition pores, making cardiomyocytes less vulnerable to ischemia-induced cell death.This cardioprotective mechanism is now being translated into clinical practice, with positive results in several clinical trials in coronary artery bypass surgery, surgical repair of abdominal aortic aneurysms, valve replacement surgery and percutaneous coronary intervention. However, certain factors weaken the subcellular mechanisms of preconditioning - age, comorbidities, medication, anesthetic protocol - and appear to explain the heterogeneity of results in some studies.Detailed understanding of the pathways involved in cardioprotection induced by ischemic preconditioning is expected to lead to the development of new drugs to reduce the consequences of prolonged ischemia.     

Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery.

OBJECTIVE: To investigate whether ischaemic preconditioning could reduce myocardial injury, as manifest by troponin T release, in patients undergoing elective coronary artery bypass surgery. DESIGN: Randomised controlled trial. SETTING: Cardiothoracic unit of a tertiary care centre. PATIENTS: Patients with three vessel coronary artery disease and stable angina admitted for first time elective coronary artery bypass surgery were invited to take part in the study; 33 patients were randomised into control or preconditioning groups. INTERVENTION: Patients in the preconditioning group were exposed to two additional three minute periods of myocardial ischaemia at the beginning of the revascularisation operation, before the ischaemic period used for the first coronary artery bypass graft distal anastomosis. MAIN OUTCOME MEASURE: Serum troponin T concentration at 72 hours after cardiopulmonary bypass. RESULTS: The troponin T assays were performed by blinded observers at a different hospital. All patients had undetectable serum troponin T (< 0.1 microgram/l) before cardiopulmonary bypass, and troponin T was raised postoperatively in all patients. At 72 hours, serum troponin T was lower (P = 0.05) in the preconditioned group (median 0.3 microgram/l) than in the control group (median 1.4 micrograms/l). CONCLUSIONS: The direct application of a preconditioning stimulus in clinical practice has been shown, for the first time, to protect patients against irreversible myocyte injury.     

Ischemic preconditioning: Clinical relevance and investigative studies

Experimental animal studies have shown that repetitive brief coronary occlusions render the heart resistant to myocardial infarction from subsequent, more prolonged, coronary occlusions. This phenomenon in animal models has been called ischemic preconditioning. In a number pf clinical scenarios, the second in a series of ischemic episodes appears to be less severe than the first, suggesting that ischemic preconditioning also occurs in humans. If the mediator of preconditioning could be identified, it is conceivable that this agent could be administered to patients with coronary artery disease as a myocardial protectant. However, the definite clinical relevance of this interesting experimental finding remains unknown. Unlike the case in animal models subjected to an abrupt occlusion, preconditioning is difficult to study in the clinical setting. This article reviews the findings and limitations of the relevant clinical studies looking for ischemic preconditioning in humans.     

Effect of a hypoglycemic agent on ischemic preconditioning in patients with type 2 diabetes and stable angina pectoris

OBJECTIVE: Ischemic preconditioning is an increased tolerance to myocardial ischemia during the second of two consecutive exercise tests. ATP-sensitive K(+) channel blockers, such as glinides and sulfonylurea drugs, can induce loss of ischemic preconditioning. This study aimed to investigate the effects of repaglinide, a hypoglycemic agent with an affinity for myocardial ATP-sensitive K (+)channels, on the results of consecutive exercise tests in patients with diabetes and multivessel coronary artery disease. METHODS: Forty-two patients with type 2 diabetes and chronic stable angina pectoris, and two-vessel or three-vessel disease participated in this study. The patients underwent two consecutive treadmill exercise tests (phase 1). On the day after these exercise tests, 2 mg of oral repaglinide was given to the patients. One week later, two exercise tests were repeated consecutively (phase 2). RESULTS: All patients achieved 1.0-mm ST-segment depression during the four exercise tests (T1, T2, T3, and T4). In phase 2, seven patients improved in time to onset of 1.0-mm ST-segment depression. The worsening of the time to onset of 1.0-mm ST-segment depression in phase 2 demonstrated ischemic preconditioning block in 83.3% of patients (P=0.0001). Even the postexercise electrocardiographic parameters (ST-segment depression morphology and magnitude and arrhythmias) were significantly different between the groups with and without pharmacologic ischemic preconditioning block (P=0.031). CONCLUSIONS: Repaglinide, an oral hypoglycemic agent with ATP-sensitive K(+) channel-blocker activity, eliminated the myocardial ischemic preconditioning in patients with coronary disease and diabetes.