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。     

Angioscopic and virtual histology intravascular ultrasound characteristics of culprit lesion morphology underlying coronary artery thrombosis

Although rupture of vulnerable plaque with subsequent thrombosis is the most common mechanism of acute coronary syndromes, a significant percentage of patients with acute coronary syndrome may not have plaque rupture. We used angioscopy and virtual histology intravascular ultrasound (VH-IVUS) to investigate the underlying morphology of coronary thrombosis. We correlated the angioscopic diagnosis of coronary thrombosis in 42 lesions (37 patients) with gray-scale and VH-IVUS findings of the underlying plaque. By angioscopy plaque rupture was present in 19 thrombotic lesions (45.2%), whereas 23 (54.8%) had no rupture. VH-IVUS findings comparing thrombotic lesions with to those without angioscopic plaque rupture were remarkably similar except that angioscopic nonruptures tended to have more necrotic core (NC) at the minimum lumen area site (22.2 ± 12.5% vs 16.3 ± 9.3%, p=0.09) and at the maximum NC site (32.7 ± 12.8% vs 25.0 ± 12.1%, p=0.053) compared to angioscopic ruptures. Furthermore, among 19 lesions with angioscopic plaque rupture, there were 11 VH thin-cap fibroatheromas (TCFAs; 57.9%); among 23 lesions without angioscopic rupture, there were 17 VH-TCFAs (73.9%, p=0.22). In conclusion, the similarity of VH-IVUS plaque composition (percentage of NC and percentage of VH-TCFA) in lesions with or without angioscopic plaque rupture suggest a spectrum of underlying morphologies to explain thrombosis in the absence of a ruptured plaque including classic erosions, small (and undetectable) plaque ruptures, and potentially unruptured TCFAs with superimposed thrombosis.     

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.     

Platelets and Atherothrombosis: An Essential Role for Inflammation in Vascular Disease — A Review

Atherothrombosis is the common link between clinical manifestations of arterial vascular disease including ischemic stroke and acute coronary syndromes, such as unstable angina and acute myocardial infarction. Our understanding of the common pathologic mechanisms underlying these conditions has significantly increased during the past ten years, yet atherothrombosis as the “root cause” of a large proportion of cardiovascular and cerebrovascular diseases is largely underappreciated. Although the classical risk factors of dyslipidemia, smoking, diabetes, hypertension, obesity, and sedentary lifestyle are widely recognized as being associated with a heightened risk of vascular disease, inflammation of the vascular system during the past decade has become increasingly regarded as the principal underlying mechanism in the development of clinical atherothrombotic disease. In addition, platelet-derived inflammatory mediators play an essential role in the pathogenesis of cardiovascular disease, being involved at all stages of plaque development until their eventual rupture and subsequent formation of a platelet-rich thrombus. Mounting evidence supports the role of both localized and systemic inflammation in these events. Platelets are central to vascular inflammatory processes. Thus, inflammation can stimulate local thrombosis and thrombosis can amplify inflammation. Consequently, antiplatelet therapy for the prevention of serious vascular events may provide a double benefit via an anti-inflammatory action of the antiplatelet agent in modifying plaque formation and stability and antiplatelet activity that inhibits platelet aggregation and thrombus formation from occurring following plaque rupture.     

Effects of Abciximab as adjunctive therapy in primary percutaneous coronary intervention patients (results from the DANAMI‐2 trial)

Atherosclerosis is a progressive process with potentially devastating consequences and has been identified as the leading cause of morbidity and mortality, especially in the industrial countries. The underlying mechanisms include endothelial dysfunction, lipid accumulation and enhanced inflammatory involvement resulting in plaque disruption or plaque erosion and subsequent thrombosis. However, it has been made evident, that the majority of rupture prone plaques that produce acute coronary syndromes are not severely stenotic. Conversely, lipid‐rich plaques with thin fibrous cap, heavily infiltrated by inflammatory cells have been shown to predispose to rupture and thrombosis, independently of the degree of stenosis. Therefore, given the importance of plaque composition, a continuously growing interest in the development and improvement of diagnostic modalities will promptly and most importantly, accurately detect and characterize the high‐risk atheromatous plaque. Use of these techniques may help risk stratification and allow the selection of the most appropriate therapeutic approach.     

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.     

Specific characteristics of sudden death in a mediterranean Spanish population

Most of the data reported on sudden cardiac death has been from studies of Anglo-Saxon patients. We conducted a study to ascertain the relation between sudden death (SD) and some epidemiologic, clinical, and biochemical parameters and to assess the coronary histopathologic aspects of subjects in a Spanish population who had died suddenly. A total of 204 subjects (86% men), aged 12 to 80 years (mean 54 ± 15), who had died from out-of-hospital natural SD were evaluated. Only 15% of subjects had been previously diagnosed with heart disease. Pathologic evidence of underlying cardiovascular disease was found in 90% of cases, with coronary heart disease (CHD) the most frequent (58%). The CHD was acute coronary thrombosis in 41% and a stable plaque with luminal narrowing of ≥75% in 59%. An old myocardial infarction was found in 31% of the SD victims. Cardiac hypertrophy was found in 48%, with no relation between the presence of cardiac hypertrophy and CHD. Patients with stable plaques had a greater heart weight than did those with acute coronary thrombosis (p = 0.02). Male gender, older age, smoking, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio of ≥3 were associated with CHD. A greater percentage of patients with an eroded and/or ruptured plaque than patients with a stable plaque were smokers. Only smoking and a low-density lipoprotein/high-density lipoprotein cholesterol ratio of ≥3 were associated with an eroded and/or ruptured plaque. In conclusion, compared with the findings from studies of Anglo-Saxon patients, a lower incidence of CHD and acute coronary thrombosis and a greater incidence of cardiac hypertrophy were found in SD victims of a Mediterranean Spanish population.     

Vulnerable atherosclerotic plaque: emerging challenge for animal models

A recent shift in the clinical paradigm of acute coronary syndromes led to a burst of activity in developing animal models related to plaque vulnerability. In the present review, animal models of spontaneous and induced plaque rupture, thrombosis, and hemorrhage and "vulnerability endpoints" in conventional models of atherosclerosis are discussed. These endpoints include readouts related to biomechanical properties of the plaques, collagen turnover, underlying inflammation, and lipid accumulation. Challenges in model validation are emphasized. Development of new animal models and new tools of monitoring plaque vulnerability will facilitate design of plaque-stabilizing therapies.     

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.     

Biologic aspects of vulnerable plaque

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in the industrialized world. The progression of atherosclerotic plaques in coronary circulation is modulated by several risk factors. It is now clear that plaque composition is a major determinant of plaque disruption and superimposed thrombosis. Plaque vulnerability, defined as the propensity of plaques to disrupt, is further determined by intrinsic and extrinsic triggering factors. After disruption, 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 disruption can be clinically silent or cause symptoms of ischemia depending on thrombus burden and the degree of vessel occlusion. In addition, plaque disruption and subsequent healing are recognized to play key roles in the 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 as potential targets for future research.     

The pathophysiology of acute myocardial infarction

Recent work has now clearly established that coronary arterial thrombosis is the direct cause of acute myocardial infarction. This thrombotic event occurs when a pre-existing atherosclerotic plaque ruptures or fissures, thereby exposing underlying thrombogenic material to the circulation. Platelets are thus activated and the clotting cascade is initiated. It is as yet unclear why a previously stable atherosclerotic plaque should fissure or rupture. However, suggested mechanisms include release of vasoactive substances from activated platelets, coronary arterial vasomotion, mechanical stress fatigue of the atherosclerotic plaque, and rupture of vasa vasorum within the atherosclerotic plaque. The resultant cessation of myocardial blood flow produces specific biochemical and physiological alterations secondary to myocardial ischemia. Intracellular acidosis, loss of high-energy phosphates, reduced sensitivity of contractile proteins to calcium, and accumulation of inorganic phosphate and lipid, all occur within the ischemic myocyte. Diastolic compliance is markedly reduced by ischemia followed by cessation of systolic contractile activity. Most of these alterations are reversible if ischemia is relieved promptly. Prolonged ischemia leads to delayed biochemical and physiological recovery and/or cell necrosis.     

Emerging diagnostic and therapeutic molecular imaging applications in vascular disease

Assessment of vascular disease has evolved from mere indirect and direct measurements of luminal stenosis to sophisticated imaging methods to depict millimeter structural changes of the vasculature. In the near future, the emergence of multimodal molecular imaging strategies may enable robust therapeutic and diagnostic ('theragnostic') approaches to vascular diseases that comprehensively consider structural, functional, biological and genomic characteristics of the disease in individualized risk assessment, early diagnosis and delivery of targeted interventions.This review presents a summary of recent preclinical and clinical developments in molecular imaging and theragnostic applications covering diverse atherosclerosis events such as endothelial activation, macrophage inflammatory activity, plaque neovascularization and arterial thrombosis. The main focus is on molecular targets designed for imaging platforms commonly used in clinical medicine including magnetic resonance, computed tomography and positron emission tomography. A special emphasis is given to vascular ultrasound applications, considering the important role this imaging platform plays in the clinical and research practice of the vascular medicine specialty.     

CD40/CD40L系统与动脉粥样硬化

动脉粥样硬化是一种慢性炎症性疾病.动脉粥样硬化斑块破裂和血栓形成可导致急性心脑血管事件.炎性介质CD40/CD40L广泛存在于与动脉粥样硬化相关的细胞,参与斑块内炎症反应,释放促炎细胞因子,降解细胞外基质,提高促凝活性,促进动脉粥样硬化的进展和斑块易损性.干预CD40/CD40L信号系统可能成为减缓动脉粥样硬化进展和稳定动脉粥样硬化斑块的一种有效治疗策略.     

The vulnerable plaque: Current concepts and future perspectives on coronary morphology,composition and wall stress imaging

Cardiovascular imaging plays an important role in the identification and characterization of the vulnerable plaque. A major goal is the ability to identify individuals at risk of plaque rupture and developing an acute coronary syndrome. Early recognition of rupture‐prone atherosclerotic plaques may lead to the development of pharmacologic and interventional strategies to reduce acute coronary events.We review state‐of‐the‐art cardiovascular imaging for identification of the vulnerable plaque. There is ample evidence of a close relationship between plaque morphology and patient outcome, but molecular imaging can add significant information on tissue characterization, inflammation and subclinical thrombosis. Additionally, identifying arterial wall exposed to high shear stress may further identify rupture‐prone arterial segments. These new modalities may help reduce the individual, social and economic burden of cardiovascular disease.     

Tissue factor expression in the morphologic spectrum of vulnerable atherosclerotic plaques

Inflammation and thrombosis are key events in the long-lasting sequence of atherosclerotic plaque initiation, plaque growth, and eventual onset of complications leading to clinically manifest disease. Recent cellular and molecular studies have indicated that inside the plaque tissue complex, proinflammatory and prothrombotic mechanisms are intimately associated, and tissue factor (TF) is one of the main proteins that may link both processes. It is therefore not surprising that TF expression appeared to be a prominent feature in various types of vulnerable atherosclerotic plaques (i.e., lesions that specifically predispose to the onset of symptomatic atherosclerotic disease).     

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.     

Hereditary defects in fibrinolysis associated with thrombosis.

The plasminogen-plasmin system involves proteolytic enzymes which are primarily responsible for the degradation of fibrin deposits in blood vessels. Through intricate interactions between the various components and inhibitors, a balance is maintained between profibrinolysis and impaired fibrinolytic activity. Several hereditary defects have been described affecting functional plasminogen concentrations, plasminogen activator levels, and plasminogen activator inhibitor activity. These defects have been implicated as risk factors for thrombosis based on a multitude of case reports associating impaired fibrinolysis with thrombosis. However, under close scrutiny, the role of decreased fibrinolysis as an etiologic factor in thrombosis has not been firmly established. Rather, dysfibrinolysis may manifest itself through an accentuation of an underlying thrombophilic state such as recurrent thrombotic episodes. Further evaluation of impaired fibrinolytic activity in conjunction with an underlying thrombophilic condition is warranted.     

Laser angioplasty and laser-induced thrombolysis in revascularization of anomalous coronary arteries

Acute coronary syndromes such as unstable angina and myocardial infarction are attributed to a pathophysiologic process that involves rupture of atherosclerotic plaque and subsequent thrombosis. Percutaneous intervention of anomalous coronary arteries in patients who present with acute coronary syndromes impose unique technical challenges related to the specific anatomic course and morphology of these vessels. Selection of appropriate guiding catheter configuration, choice of supportive guidewire, and proper delivery and activation of debulking devices and stents are important steps toward achieving adequate results. Excimer laser angioplasty is a debulking technology for removal of atherosclerotic plaque and associated thrombi. To date, application of laser angioplasty in anomalous coronary arteries is unreported. We herein present clinical data and discuss technical aspects related to performance of excimer laser angioplasty in three symptomatic patients with acute coronary syndrome, two having an anomalous right coronary artery and one with an anomalous circumflex artery. The delivery of laser energy in these cases resulted in rapid thrombolysis of an occlusive thrombus, successful debulking of the underlying atherosclerotic plaque, facilitation of adjunct balloon angioplasty and stenting, and ultimately, improved clinical condition.     

Thrombosis and Fibrinolysis in Acute Myocardial Infarction

The development of coronary thrombosis in response to rupture of atherosclerotic plaques is the primary determinant of the evolution of stable atherosclerotic coronary disease to unstable ischemic syndromes and acute myocardial infarction. Activation of the tissue factor pathway of coagulation and adhesion of platelets are critical events in the initiation of thrombosis. However, subsequently, other factors may determine the extent of thrombosis by modulating the intensity of procoagulant and fibrinolytic activity. Marked procoagulant activity, attenuation of physiologic fibrinolytic activity, or both appear to be risk factors for myocardial infarction. The results of recent studies have provided considerable insight into potential mechanisms for thrombosis in response to rupture of atherosclerotic plaque and have identified potential novel antithrombotic interventions to inhibit the progression of coronary thrombosis.