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.     

Myocardial infarction and thrombophilia: Do not miss the right diagnosis!

Protein C deficiency is a coagulation cascade disorder often resulting in venous thromboembolic events but is also a possible contributor to arterial thrombosis. To date, approximately ten cases of myocardial infarction (MI) due to protein C deficiency have been reported in the literature. However, affirming this mechanism requires ruling out the most common causes of MI, i.e. the rupture or erosion of an atherosclerotic plaque. Intravascular imaging of coronary arteries can be of help to identify angiographically undetected atherosclerosis. We report a case of an ST-segment elevation myocardial infarction (STEMI) in a young man with apparent evidence of arterial thrombosis resulting from protein C deficiency and heterozygous factor Leiden mutation which was contradicted by intravascular imaging demonstrating atherosclerosis.     

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.     

炎症因子与急性心肌梗死的研究进展

急性心肌梗死是临床较为常见的心血管疾病之一,是在冠状动脉粥样硬化发生发展基础上,因血栓形成、斑块破裂所致心肌持久性缺血缺氧,造成局部心肌坏死。炎症因子参与冠状动脉粥样硬化斑块的形成和进展,与急性心肌梗死的发生发展存在密切的关系。本文就相关炎症因子在急性心肌梗死中的研究进展进行综述。     

Morphologic features of unstable atherothrombotic plaques underlying acute coronary syndromes

Unstable angina appears to be a good clinical marker for rapidly progressing coronary artery disease. Pathologically, an unstable atherothrombotic coronary lesion, represented by a raised atherosclerotic plaque with ruptured surface causing variable degree of hemorrhage into the plaque and luminal thrombosis (rapid plaque progression), usually is present in patients at autopsy after a period of unstable angina. The thrombus at the rupture site may be mural and limited (just sealing the rupture) or occlusive, depending on the degree of preexisting atherosclerotic stenosis. An occlusive thrombus is seldom seen over ruptured plaques causing less than 75% stenosis (histologic cross-sectional area reduction), but it is found with increasing frequency when severity of stenosis increases beyond 75%. Most occlusive thrombi have a layered structure with thrombus material of differing age indicating an episodic growth by repeated mural deposits, and microemboli/microinfarcts are frequently found in the myocardium downstream to coronary thrombi, indicating intermittent thrombus fragmentation with peripheral embolization. Such a "dynamic thrombosis" (with or without a concomitant focal vasospastic phenomenon) at the site of an unstable (ruptured) atherosclerotic lesion obviously may lead to the other thrombus-related acute coronary events: myocardial infarction or sudden death. Accordingly, progression of unstable angina to myocardial infarction or sudden death should, in principle, be preventable by the correct timing of current available therapies aimed to prevent or eliminate (1) the chronic atherosclerotic obstruction, (2) the acute plaque disruption, (3) luminal thrombosis, and (4) vasospasm.     

Type 2 myocardial infarction due to supply–demand mismatch

The best-accepted definition of myocardial infarction (MI) is provided by statements from the Universal Definition of MI Global Task force. This article, now in its third iteration, defines MI as myocardial cell death due to prolonged myocardial ischemia. It further delineates an increasingly incident subclassification of MI known as type 2 MI (T2MI). T2MI identifies instances of myocardial necrosis in which an imbalance between myocardial oxygen supply and/or demand occurs for reasons other than atherosclerotic plaque disruption. While associated with considerable risk (comparable to that of type 1 MI, which has well-defined management strategies), the spectrum of potential etiologies for T2MI makes development of precise diagnostic criteria and therapeutic implications of the diagnosis challenging.     

Genesis of myocardial infarction

The causes of myocardial infarction (MI) are complex and multiple and may eventually be associated. Two main types of mechanism are thought to be implicated: Functional mechanisms: these are operative in prolonged angina: the difference between MI and angina pectoris is related to the duration of these phenomena and to the resistance of the myocardial cells to anoxia: unsatisfied increase in myocardial oxygen demand, as for example in exercise-induced myocardial infarction; sudden reduction in oxygen supply due to an excessive fall in coronary flow, inadequate vasodilatation, platelet aggregation or coronary spasm. Priviledged cases are presented to demonstrate the reality of these phenomena. These mechanisms can sometimes cause MI by themselves, even when the coronary arteries are normal (5% of cases), and nearly always complicate and aggravate obstruction due to an atheromatous plaque. Organic obstructive lesions: coronary obstruction observed in about 2/3 of cases, sometimes caused by rupture of an atheromatous plaque, is usually the result of coronary thrombosis. The predominance of this mechanism is an argument in favour of it being the principal cause of MI. However, other workers believe that thrombosis is a secondary phenomenon induced by stasis, functional mechanisms or severe stenosis. The clot itself would then cause obstruction even if the primary cause were to regress. Irrespective of the roles of each of these factors it would appear logical to treat the functional mechanisms assumed to be responsible and the coronary thrombosis before the myocardial cells are destroyed by the anoxia.     

冠状动脉粥样硬化斑块破裂的临床危险因素分析

目的　研究临床危险因素与冠状动脉粥样硬化斑块破裂的关系 ,探讨斑块破裂的危险因素。方法　选取 1992～ 1998年间的尸检病例 ,急性心肌梗死 (AMI) 2 0例 ,不稳定心绞痛 (UA) 10例 ,稳定心绞痛 (SA) 12例 ,对所有冠状动脉连续取材制片 ,常规及免疫组化染色 ,光镜观察斑块破裂的形态改变及血栓伴随情况 ,并调查 8个相应的临床危险因素。结果　 8个危险因素中 ,血浆甘油三酯水平与斑块破裂有关 (P <0 .0 5 )。结论　高血浆甘油三酯是国人急性冠状动脉综合征患者斑块破裂的一个重要危险因素。     

Arteriographic evidence of coronary arterial spasm in acute myocardial infarction.

Coronary arteriography was performed before and after the intracoronary injection of nitroglycerin to determine the presence or absence of spasm in patients within the first 12 hours of acute myocardial infarction. Coronary arterial spasm was demonstrated in six of fifteen (40%) acute myocardial infarctions associated with coronary artery disease. In five of the six instances the interval from the onset of symptoms to arteriography was less than 6 hours. Spasm was superimposed on a high-grade atherosclerotic obstruction and was separated from the catheter tip by a segment of normal vessel in each instance. The coronary artery remained patent (following the initial relief of spasm) in two patients maintained on sublingual nitrates and heparin. Spasm, superimposed on an atherosclerotic obstruction, may be the primary event or a secondary occurrence in the pathophysiology of acute myocardial infarction. Catecholamines could play an important role in the early pathophysiology of acute myocardial infarction by producing spasm and/or platelet aggregation at the site of an atherosclerotic obstruction. A dynamic interaction between spasm, platelet aggregates and the atherosclerotic plaque may precede coronary thrombosis.     

Multimodality Intravascular Imaging of High-Risk Coronary Plaque

The majority of coronary atherothrombotic events presenting as myocardial infarction (MI) occur as a result of plaque rupture or erosion. Understanding the evolution from a stable plaque into a life-threatening, high-risk plaque is required for advancing clinical approaches to predict atherothrombotic events, and better treat coronary atherosclerosis. Unfortunately, none of the coronary imaging approaches used in clinical practice can reliably predict which plaques will cause an MI. Currently used imaging techniques mostly identify morphological features of plaques, but are not capable of detecting essential molecular characteristics known to be important drivers of future risk. To address this challenge, engineers, scientists, and clinicians have been working hand-in-hand to advance a variety of multimodality intravascular imaging techniques, whereby 2 or more complementary modalities are integrated into the same imaging catheter. Some of these have already been tested in early clinical studies, with other next-generation techniques also in development. This review examines these emerging hybrid intracoronary imaging techniques and discusses their strengths, limitations, and potential for clinical translation from both an engineering and clinical perspective.     

Akutes Koronarsyndrom und Entzündung

Inflammation plays a pivotal role in atherosclerosis and coronary heart disease. Inflammatory processes of the coronary arterial wall are involved in plaque formation, progression and, finally, plaque instability consecutively leading to the clinical manifestations of stable coronary artery disease or acute coronary syndromes (unstable angina, non-ST elevation and ST elevation myocardial infarction). Acute coronary syndromes result from plaque rupture or erosion leading to local thrombus formation with consecutive necrosis of myocytes due to ischemia, which is associated with widespread and diffuse pancoronary and panmyocardial inflammation. Accordingly, markers of myocardial necrosis (e. g., cardiac troponins) do have crucial diagnostic and prognostic value. In case of troponin-negative acute coronary syndromes, however, markers of inflammation emerged as potentially useful tools for risk stratification. C-reactive protein has been shown to serve as a powerful predictor of future cardiovascular events following acute coronary syndromes, even if troponins are not (yet) positive. Moreover, a variety of pro- (soluble CD40 ligand, placental growth factor, interleukin-6, pregnancy-associated plasma protein A, myeloperoxidase, monocyte chemoattractant protein-1) and anti-inflammatory markers (interleukin-10, activin A) have been suggested to provide relevant prognostic information in patients with acute coronary syndrome. However, the clinical utility of these novel markers has not been established so far.     

Intravascular ultrasound assessment of the association between spatial orientation of ruptured coronary plaques and remodeling morphology of culprit plaques in ST-elevation acute myocardial infarction

The aim of this study was to assess the association between the spatial location of plaque rupture and remodeling pattern of culprit lesions in acute anterior myocardial infarction (MI). Positive remodeling suggests a potential surrogate marker of plaque vulnerability, whereas plaque rupture causes thrombus formation followed by coronary occlusion and MI. Intravascular ultrasound (IVUS) can determine the precise spatial orientation of coronary plaque formation. We studied 52 consecutive patients with acute anterior MI caused by plaque rupture of the culprit lesion as assessed by preintervention IVUS. The plaques were divided into those with and without positive remodeling. We divided the plaques into three categories according to the spatial orientation of plaque rupture site: myocardial (inner curve), epicardial (outer curve), and lateral quadrants (2 intermediate quadrants). Among 52 plaque ruptures in 52 lesions, 27 ruptures were oriented toward the epicardial side (52%), 18 toward the myocardial side (35%), and 7 in the 2 lateral quadrants (13%). Among 35 plaques with positive remodeling, plaque rupture was observed in 21 (52%) on the epicardial side, 12 (34%) on the myocardial side, and 2 (6%) on the lateral side. However, among 17 plaques without positive remodeling, plaque rupture was observed in 6 (35%), 6 (35%), and 5 (30%), respectively (p?=?0.047). Atherosclerotic plaques with positive remodeling showed more frequent plaque rupture on the epicardial side of the coronary vessel wall in anterior MI than those without positive remodeling.     

Morphologic and angiographic features of coronary plaque rupture detected by intravascular ultrasound

OBJECTIVES: This study was designed to report the clinical and angiographic correlates of plaque rupture detected by intravascular ultrasound (IVUS). BACKGROUND: Acute coronary syndromes result from spontaneous plaque rupture and thrombosis. METHODS: We report 300 plaque ruptures in 257 arteries in 254 patients. Plaque ruptures were detected during pre-intervention IVUS. Standard clinical, angiographic, and IVUS parameters were collected and/or measured. One lesion per patient was analyzed. RESULTS: Multiple ruptures were observed in 39 of 254 patients (15%), 36 in the same artery. Plaque rupture occurred not only in patients with unstable angina (46%) or myocardial infarction (MI, 33%), but also stable angina (11%) or no symptoms (11%). The tear in the fibrous cap could be identified in 157 of 254 patients; 63% occurred at the shoulder of the plaque and 37% in the center of the plaque. Thrombi were more common in patients with unstable angina or MI (p = 0.02) and in multiple ruptures (p = 0.04). The plaque rupture site contained the minimum lumen area (MLA) site in only 28% of patients; rupture sites had larger arterial and lumen areas and more positive remodeling than MLA sites. Intravascular ultrasound plaque rupture strongly correlated with complex angiographic lesion morphology: ulceration in 81%, intimal flap in 40%, thrombus in 7%, and aneurysm in 7%. CONCLUSIONS: Plaque ruptures occur with varying clinical presentations, strongly correlate with angiographic complex lesion morphology, may be multiple, and usually do not cause lumen compromise.     

Rapid disappearance of an endothelial ulceration in the left main coronary artery

A case is presented of a 65-year-old male who presented with an acute anterior wall myocardial infarction. An initial coronary angiogram demonstrated an ulcerated atherosclerotic plaque in the left main coronary artery. After 48 h of aggressive medical therapy including a 2b3a glycoprotein blocking agent, repeat angiography demonstrated resolution of the ulcerated plaque. The process of atherosclerotic plaque rupture is of dynamic nature.     

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.     

Angiographic assessment of the culprit coronary artery lesion before acute myocardial infarction

Serial angiographic studies of patients with myocardial infarction and unstable angina suggest that the culprit plaque underlying a thrombus need not have produced severe luminal obstruction before onset of the event. An atherosclerotic coronary artery lesion can, therefore, have 2 important characteristics. First, it may be obstructive. Second, it may be "vulnerable" in that it has the potential to become thrombogenic if exposed to the appropriate triggering stimulus. A lesion need not be obstructive to become thrombogenic, nor do all obstructive lesions have thrombogenic potential. The cause of an infarction may thus be rupture of a nonobstructive plaque leading to occlusive thrombus formation. Because it may be difficult to predict the site of a subsequent occlusion from a coronary angiogram, coronary bypass surgery or angioplasty directed only at discernible stenotic lesions may not be effective for preventing subsequent myocardial infarctions. Appropriate therapy may need to be directed at the entire coronary tree. Such therapy might include cholesterol lowering, beta blockade and aspirin.     

The heart in fatal unstable angina pectoris

Compared to patients with sudden coronary death and acute myocardial infarction, relatively little morphologic data has been reported in patients with unstable angina pectoris. This article reviews necropsy data collected from one laboratory on unstable angina pectoris. From these data, several observations are appropriate: (1) Patients with unstable angina as a group have more coronary narrowing by atherosclerotic plaque than do patients with sudden coronary death or acute or healed myocardial infarction. (2) Patients with unstable angina have a much higher frequency of severe narrowing of the left main coronary artery than do patients in other coronary subsets. (3) The coronary atherosclerotic plaques in unstable angina consist primarily of fibrous tissue, and they are more similar to those found in patients with sudden coronary death than in patients with acute myocardial infarction. (4) The frequency of acute coronary lesions (thrombi, plaque rupture, and plaque hemorrhage) is similar to that observed in patients with sudden coronary death and significantly less than that observed in acute myocardial infarction. (5) The frequency of multiluminal channels throughout the major coronary arteries is significantly higher in unstable angina compared to sudden coronary death or acute myocardial infarction. (6) The major epicardial arteries and the heart are smaller in patients with unstable angina than in patients with sudden coronary death or acute myocardial infarction. (7) The left ventricular cavity is usually of normal size in patients with unstable angina and therefore left ventricular function is usually normal.     

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.     

Nonatherosclerotic causes of coronary artery narrowing—Part III

Approximately 5% of patients with acute myocardial infarction do not have atherosclerotic coronary artery disease but have other causes for their luminal narrowing. The third part of this three-part review of nonatherosclerotic causes of coronary narrowing focuses on coronary vasculitis, infectious diseases, Kawasaki's disease, metabolic disorders, metastatic disease, and substance abuse (cocaine). coronary arteritis: (1) focal artery necrosis with or without calcification, (2) acute coronary artery thrombosis or recanal-ized thrombus unassociated with underlying atherosclerotic plaque, (3) rupture of the vessel wall unassociated with trauma or an interventional procedure, (4) coronary artery wall thickening with secondary luminal narrowing, and (5) wall thinning with aneurysm formation.³ Specific coronary lesions also may be seen in specific systemic diseases (e.g., pol-yarteritis nodosa).     

Circadian variation and triggers of onset of acute cardiovascular disease

Information obtained during the past decade suggests the need to reexamine the possibility that the onset of myocardial infarction and sudden cardiac death is frequently triggered by daily activities. The importance of physical or mental stress in triggering onset of coronary thrombosis is supported by the findings that 1) the frequencies of onset of myocardial infarction, sudden cardiac death, and stroke show marked circadian variations with parallel increases in the period from 6:00 AM to noon, 2) transient myocardial ischemia shows a similar morning increase, and episodes are often preceded by mental or physical triggers, 3) a ruptured atherosclerotic plaque, often nonobstructive by itself, lies at the base of most coronary thrombi, 4) a number of physiologic processes that could lead to plaque rupture, a hypercoagulable state or coronary vasoconstriction, are accentuated in the morning, and 5) aspirin and beta-adrenergic blocking agents, which block certain of these processes, have been shown to prevent disease onset. The hypothesis is presented that occlusive coronary thrombosis occurs when 1) an atherosclerotic plaque becomes vulnerable to rupture, 2) mental or physical stress causes the plaque to rupture, and 3) increases in coagulability or vasoconstriction, triggered by daily activities, contribute to complete occlusion of the coronary artery lumen. Recognition of the circadian variation--and the possibility of frequent triggering--of onset of acute disease suggests the need for pharmacologic protection of patients during vulnerable periods, and provides clues to mechanism, the investigations of which may lead to improved methods of prevention.