冠状动脉血栓形成的病理生理学——斑块破裂和斑块糜烂的作用

本文综述了冠状动脉粥样硬化血栓形成的病理生理学 ,斑块破裂和斑块糜烂在冠状动脉血栓形成中的作用 ,斑块破裂的机制和稳定斑块的治疗原则     

The role of plaque rupture and thrombosis in coronary artery disease

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in the industrialized world. The progression of atherosclerotic plaques in the coronary circulation is dependent on several risk factors. It is now clear that plaque composition is a major determinant of the risk of subsequent plaque rupture and superimposed thrombosis. The vulnerability of plaques to rupture is further determined by extrinsic triggering factors. Following rupture, the fatty core of the plaque and its high content of tissue factor provide a powerful substrate for the activation of the coagulation cascade. Plaque rupture can be clinically silent or cause symptoms of ischaemia depending on thrombus burden and the degree of vessel occlusion. In addition, plaque rupture and subsequent healing is recognized to be a major cause of further rapid plaque progression. This review looks at the mechanisms underlying the development and progression of atherosclerotic plaques, factors leading to plaque rupture and subsequent thrombosis and their clinical consequences. Finally, we speculate on targets for future research.     

Pathophysiology of plaque rupture and the concept of plaque stabilization

Atherosclerotic coronary artery disease is the major cause of death, in men and women, in the United States and in much of the Western world. Atherosclerosis is responsible for coronary heart disease, limb ischemia, and most strokes. Although luminal narrowing by an atherosclerotic plaque and exaggerated or anomalous vasoconstriction contribute to some of the clinical manifestations of atherosclerotic arterial disease, it is the superim-position of a thrombus over an underlying ruptured or eroded plaque that results in the acute coronary syndromes (unstable angina, acute myocardial infarction, and sudden death) that are the most serious clinical manifestations of this disease.     

Myeloperoxidase may help to differentiate coronary plaque erosion from plaque rupture in patients with acute coronary syndromes

Coronary thrombosis is the most frequent final event leading to an acute coronary syndrome. In approximately two-thirds of cases, the thrombus overlies a ruptured plaque, whereas in one-third of cases it overlies an intact plaque with superficial endothelial erosion, a finding showed initially by histopathological postmortem studies and more recently confirmed by in vivo optical coherence tomography imaging. Interestingly, recent observations suggest that mechanisms leading to plaque rupture or erosion are different. In fact, in a recent study, we showed that myeloperoxidase levels in peripheral blood and expression within thrombi overlying the culprit plaque are much higher in patients with plaque erosion than in those with plaque rupture. These observations suggest that innate immunity activation is likely to play a key role, in particular, in plaque erosion and might become a therapeutic target in this subset of patients.     

Pathophysiology of atherosclerotic plaque development and rupture: an overview

Atherosclerosis is predominantly a clinically silent process, and a substantial percentage of patients are first aware of its consequences through the acute and catastrophic event of thrombosis. Extensive basic and clinical research in the 1990s revealed that plaque disruption initiates the majority of thromboses. Furthermore, recent studies indicate that inflammation plays a major role in the pathophysiology, from initiation of the atheroma to the actual thrombosis itself. Attention has now focused on morphological, mechanical, and biochemical characteristics that increase plaque vulnerability, as determination of these features may allow identification of plaques that are most likely to cause symptoms and acute events in the future. This article reviews basic pathophysiologic aspects of atherosclerotic plaque development and rupture to provide the necessary background for understanding the crucial role of inflammation in acute coronary syndromes.     

Pathophysiology of coronary thrombosis.

Detailed knowledge of the pathophysiology as well as the dynamic nature of coronary thrombus formation provides a valuable tool for correct management and proper adjunctive therapy in patients with acute coronary syndromes. Coronary thrombosis is in the majority of cases caused by disruption or fissuring of an atherosclerotic plaque. At the lesion thrombogenic material will be exposed to the flowing blood leading to activation of platelets and the formation of a platelet clot. Simultaneously, the coagulation system is activated resulting in increased thrombin formation. Thrombin is a key mediator in arterial thrombosis, due to its effect on both platelets and fibrin generation. Thrombin contributes to the stabilization of an initially loose platelet clot by generating cross-bound fibrin within the thrombus. During the course of an acute coronary syndrome, the patient presents changing chest pain and dynamic ischaemic ECG findings. This is likely to be related to the dynamic nature of the pathophysiology. The presence of a non-occlusive coronary thrombus may deprive the myocardium its normal blood flow and oxygen supply, leading to ischaemic pain. During lysis or embolization, blood supply may be restored, but the presence of thrombus fragments in the microcirculation holds the potential to sustained interference with myocardial metabolism. The emboli contain activated platelets which release vasoconstrictors that may compromise the microcirculation. Recurrent thrombus formation at the lesion site may result in occlusion of the artery adding to the dynamic nature of the clinical presentation. In conclusion, platelets, the coagulation system, and the endothelium cause a dynamic process of intermittent occlusion, vasospasm and embolization of thrombus material.     

Pathophysiology and clinical significance of atherosclerotic plaque rupture.

Atherosclerotic plaque rupture and resulting intracoronary thrombosis are thought to account for most acute coronary syndromes. These syndromes include unstable angina, non-Q-wave myocardial infarction (MI) and Q-wave MI. In addition, many cases of sudden cardiac death may be attributable to atherosclerotic plaque disruption and its immediate complications. Our understanding of the atherosclerotic process and the pathophysiology of plaque disruption has advanced remarkably. Despite these advances, event rates after acute coronary syndromes remain unacceptably high. This review will focus on the pathophysiology underlying atherosclerotic plaque development, the sequellae of coronary plaque rupture, and current therapies designed to treat the acute coronary syndromes. It is hoped that as our understanding of the atherosclerotic plaque improves, treatment strategies for the acute coronary syndromes will advance.     

The severity of coronary atherosclerosis at sites of plaque rupture with occlusive thrombosis

Atherosclerotic plaque rupture with superimposed thrombosis is recognized as the lesion causing greater than 90% of acute myocardial infarctions. To determine the severity of atherosclerosis at the site of plaque rupture, 184 coronary arteries from autopsies of 162 patients who died of acute myocardial infarction were studied. There were 102 men, 72 +/- 10 years old (mean +/- SD), and 60 women, 75 +/- 8 years old. All arteries were dissected from the heart, fixed, decalcified, cut at 2 to 3 mm intervals and processed routinely for histologic examination. A planimeter was used to measure artery, plaque, thrombus and luminal cross-sectional area at the site of plaque rupture with thrombosis in sections projected at x13.8 magnification. At the site of atherosclerotic plaque rupture with superimposed thrombosis, the degree of stenosis due to plaque was: 90 +/- 7% for the right (n = 67), 91 +/- 6% for the left anterior descending (n = 79) and 91 +/- 6% for the left circumflex (n = 38) coronary arteries. Plaque rupture in fatal acute myocardial infarction occurs at sites of severe narrowing (mean 91%, range 67% to 99%). Thus, plaque rupture with thrombosis is unlikely to cause the fatal acute myocardial infarction in patients with mild to moderate coronary stenosis.     

Triggers of transient myocardial ischemia: circadian variation and relation to plaque rupture and coronary thrombosis in stable coronary artery disease

The phenomenon of transient myocardial ischemia is common in patients with stable coronary disease and appears to be due both to increases in myocardial demand and to episodic coronary vasoconstriction. The circadian variation of transient ischemic episodes closely parallels the circadian variation of acute coronary syndromes associated with plaque rupture, such as myocardial infarction and sudden death. These concordant temporal patterns of transient ischemia, myocardial infarction and sudden cardiac death probably represent independent manifestations stemming from the consequences of increased sympathetic activity.     

光学相干断层成像与血管内超声对比检测冠状动脉斑块破裂和血栓形成

目的评价光学相干断层成像(OCT)和血管内超声(IVUS)检测冠状动脉斑块破裂和继发血栓形成的准确性。方法选择2008年2—9月间的27例患者,进行冠状动脉造影、OCT及IVUS检查,共检查了30处病变,其中8处为药物支架植入后病变,其余22处为未经介入治疗干预的病变,对其中19处病变进行了支架植入术。结果对22例未经介入治疗干预的病变行OCT及IVUS检查,结果显示OCT检出富含脂质斑块伴薄纤维帽12例,IVUS检出2例;其中斑块破裂形成内膜轻微撕裂4例,IVUS未检出;斑块破裂伴夹层形成5例,IVUS检出1例;OCT检出血栓形成5例,其中红色血栓3例,白色血栓2例,IVUS检出1例,不能判断是红色血栓还是白色血栓。结论OCT在检测不稳定斑块方面优于IVUS,在检测斑块破裂致轻微内膜撕裂或夹层形成,以及继发血栓形成方面呈现优于IVUS趋势。     

斑块侵蚀在急性冠状动脉综合征中的作用及机制研究进展

急性冠状动脉综合征是世界范围内发病率和死亡率较高的一组临床综合征。目前,越来越多的证据表明,带有完整纤维帽的斑块侵蚀是导致急性冠状动脉综合征的主要原因之一。基础实验已经揭示了斑块侵蚀的独特分子特征,已有研究表明,血流紊乱会引起内皮细胞损伤,从而导致基底膜丧失其完整性以及内皮细胞脱落,继而形成中性粒细胞胞外陷阱和血栓,导致斑块侵蚀。文章将讨论动脉粥样硬化斑块侵蚀的分子特征以及对斑块侵蚀患者未来精准医疗所需的转化研究。     

Cholesterol crystals cause mechanical damage to biological membranes: a proposed mechanism of plaque rupture and erosion leading to arterial thrombosis

BACKGROUND: Plaque rupture and/or erosion is the leading cause of cardiovascular events; however, the process is not well understood. Although certain morphologic characteristics have been associated with ruptured plaques, these observations are of static histological images and not of the dynamics of plaque rupture. To elucidate the process of plaque rupture, we investigated the transformation of cholesterol from liquid to solid crystal to determine whether growing crystals are capable of injuring the plaque cap. HYPOTHESIS: We hypothesized that during cholesterol crystallization the spatial configuration rapidly changes, causing forceful expansion of sharp-edged crystals that can damage the plaque cap. METHODS: Two experiments were performed in vitro: first, cholesterol powder was melted in graduated cylinders and allowed to crystallize at room temperature. Volume changes from liquid to solid state were measured and timed. Second, thin biological membranes (20-40 microm) were put in the path of growing crystals to determine damage during crystallization. RESULTS: As cholesterol crystallized, the peak volume increased rapidly by up to 45% over 3 min and sharp-tipped crystals cut through and tore membranes. The amount of cholesterol and peak level of crystal growth correlated directly (r = 0.98; p < 0.01), as did the amount of cholesterol and rate of crystal growth (r = 0.99; p < 0.01). CONCLUSIONS: These observations suggest that crystallization of supersaturated cholesterol in atherosclerotic plaques can induce cap rupture and/or erosion. This novel insight may help in the development of therapeutic strategies that can alter cholesterol crystallization and prevent acute cardiovascular events.     

Hemodynamic factors and atheromatic plaque rupture in the coronary arteries: from vulnerable plaque to vulnerable coronary segment

Coronary plaque disruption with superimposed thrombosis is the underlying pathology in the acute coronary syndromes and sudden death. Coronary plaques are constantly stressed by a variety of mechanical and hemodynamic forces that may precipitate or 'trigger' disruption of vulnerable or, at extreme conditions, even stable plaques. This paper reviews the exciting new evidence on the hemodynamic factors that may play a role in this process and provides the rationale for the introduction of the concept of the vulnerable coronary segment in the study of acute coronary syndromes.     

吡格列酮降低动脉粥样斑块破裂和血栓事件的实验研究

目的:探讨吡格列酮是否具有改善斑块易损性,降低易损斑块的破裂率的作用及其可能机制。方法:将20只家兔随机分为两组:药物干预组(n=10),对照组(n=10)。采用间断高脂饲养方法制造动脉粥样硬化模型,并进行斑块破裂激发试验。药物干预组于第1~18周在原饲料里添加吡格列酮(10 mg獉kg-1獉d-1)。于实验初期、中期、晚期分别留取血液标本进行MMP-9浓度测定。斑块破裂激发试验后处死动物,留取主动脉标本进行HE染色、巨噬细胞RAM-11及新生血管CD-31免疫组化染色,使用NIS-Elements AR Analysis病理图像分析系统分析斑块形态,测定斑块面积,进行巨噬细胞、新生血管计数。结果:实验中期及晚期,药物干预组血清(MMP-9)浓度均较对照组低[(2.25±0.11)vs.(2.60±0.19),P=0.040;(2.27±1.17)vs.(2.70±0.37),P=0.010]。实验晚期,药物干预组血清MMP-9浓度较对照组低[(2.27±1.17)vs.(2.70±0.37),P=0.010]。斑块破裂激发试验后,药物干预组组血栓形成率较对照组明显减少(14.62%vs.39.07%,P=0.000)。与对照组相比,药物干预组斑块面积小[(0.029±0.018)vs.(0.186±0.093),P=0.033]、巨噬细胞浸润少[(8.800±3.936)vs.(30.130±4.188),P=0.003]、新生血管数量少[(80.267±13.094)vs.(162.637±73.112),P=0.022]。结论:吡格列酮通过降低斑块内炎症程度提高斑块的稳定性,降低易损斑块的破裂率。