Coronary microembolization

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the entire epicardial coronary artery with subsequent acute myocardial infarction; however, in milder forms it may result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. The present report summarizes the available morphologic evidence for coronary microembolization in patients who died of coronary artery disease, especially sudden death. The report then goes on to address the experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes and heart failure. Finally, the report presents the available clinical evidence for coronary microembolization, highlights its key features--arrhythmias, contractile dysfunction, infarctlets and reduced coronary reserve--and addresses prevention by mechanical protection devices and glycoprotein IIb/IIIa antagonism.     

Coronary microembolization

Atherosclerotic plaque rupture is the key event in the pathogenesis of acute coronary syndromes and it also occurs during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the epicardial coronary artery with subsequent impending myocardial infarction, but may in milder forms result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation.This review summarizes the present experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes and highlights the main consequences of coronary microembolization--reduced coronary reserve, microinfarction, inflammation and oxidative modification of contractile proteins, contractile dysfunction and perfusion-contraction mismatch.Furthermore, the review presents the available clinical evidence for coronary microembolization in patients and compares the clinical observations with observations in the experimental model.     

Coronary microembolization.

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. However, it does not always result in complete thrombotic occlusion of the entire epicardial coronary artery with subsequent acute myocardial infarction; in milder forms the result can be embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. This review summarizes the available morphological evidence for coronary microembolization in patients who died from coronary artery disease, most notably from sudden death, and then goes on to address the experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes and heart failure. Finally, the review presents the available clinical evidence for coronary microembolization in patients, highlights its key features (ie, arrhythmias, contractile dysfunction, infarctlets and reduced coronary reserve) and addresses its prevention by mechanical protection devices and glycoprotein IIb/IIIa antagonism.     

Koronare Mikroembolisation: Perfusions-Kontraktions-Mismatch durch inflammatorische Reaktion des Myokards

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Atherosclerotic plaque rupture does not necessarily lead to thrombotic occlusion of a coronary artery and subsequent myocardial infarction. Milder forms may result in the embolization of atherosclerotic and/or thrombotic debris into the coronary microcirculation. The characteristic consequences of coronary microembolization are arrhythmias, microinfarcts, and a reduced coronary reserve. Experimental studies revealed that an inflammatory reaction is causally involved in the progressive contractile dysfunction following coronary microembolization. Thus, anti-inflammatory treatment appears as a promising strategy to protect patients from the consequences of coronary microembolization.     

Myokardiale Mikroinfarkte

Atherosclerotic plaque rupture is the key event in the pathogenesis of acute coronary syndromes and it also occurs during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the epicardial coronary artery with subsequent impending myocardial infarction, but may in milder forms result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. The consequences of coronary microembolization are arrhythmias, reduced coronary reserve, microinfarction, inflammation and oxidative modification of contractile proteins, contractile dysfunction, and perfusion-contraction mismatch. TNF-α has a bidirectional role in this context. TNF-α is responsible for the contractile dysfunction, but simultaneously induces protection against infarction after ischemia/reperfusion.     

冠状动脉介入治疗术中的微循环灌注及其检测手段

临床广泛应用的再灌注治疗评价指标主要针对的是心内膜下冠状动脉,近年来越来越多的证据表明,冠状动脉微循环在心肌的血供中起着重要作用。有些急性心肌梗死患者,虽然通过血流重建治疗使梗死相关冠脉开通。但由于相关的冠脉微循环出现微栓塞,使近远期心血管事件发生率和死亡率增加;相反,另外一些急性心肌梗死患者虽然相关冠脉仍闭塞,但其灌注区的心肌微循环却可通过侧支循环得到灌注,预后良好。因此越来越多的临床医生开始关注微循环的灌注,出现了一系列针对微循环的评价指标。但是目前的技术尚无法在人体内直接观察微血管,微血管血流的测定也非常复杂,现回顾和展望微循环灌注的检测手段以及应用。     

Coronary artery imaging in the new millennium

Atherosclerotic disease and its thrombotic complications remain the leading causes of mortality and morbidity in Western society. In Australia, cardiovascular disease is responsible for one in every 2.4 (41%) deaths and is the leading single cause of mortality. The crucial final common process for the conversion of a non-occlusive, often clinically silent, atherosclerotic lesion to a potentially fatal condition is plaque disruption. The mortality associated with atherosclerotic disease relates to the acute coronary syndromes, including acute myocardial infarction, unstable angina pectoris and sudden cardiac death. There is substantial clinical, experimental and postmortem evidence demonstrating the role acute thrombosis upon a disrupted atherosclerotic plaque plays in the onset of acute coronary syndromes. Atherosclerotic plaque composition, rather than the stenotic severity, appears to be central in determining risk of both plaque rupture and subsequent thrombogenicity. In particular, a large lipid core and a thin fibrous cap render an atherosclerotic lesion susceptible or vulnerable to these complications. We are currently limited in our ability to accurately identify patients at risk for an acute coronary event. The armamentarium of diagnostic investigations, both non-invasive and invasive, currently clinically available is only able to provide us with data related to the stenotic severity of a coronary artery. The non-invasive testing includes stress-induced (exercise or pharmacological) ischaemic changes in electrical repolarisation, wall motion or myocardial radioactive-tracer uptake. The invasive test of coronary angiography, although the current 'gold standard' for the detection of coronary atherosclerotic disease, provides us with no data about the composition of the atherosclerotic lesion. However, the vast majority of acute coronary events involve a non-critically stenosed atherosclerotic lesion, and thus with currently available means of identification, these lesions would be undetected by stress testing/imaging techniques. Given the critical role that atherosclerotic lesion composition has been shown to play in the risk of both plaque rupture and subsequent thrombogenicity and, consequently, an acute coronary event, new detection techniques need to be investigated for the task of documenting atherosclerotic lesion composition. In the present review we will focus on the status of imaging modalities available for coronary artery imaging and how they may advance our understanding and management of patients with and at risk of coronary artery disease in the new millennium.     

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.     

Coronary Microembolization—Its Role in acute coronary syndromes and interventions

The diagnosis coronary artery disease is classically based on patient's symptoms and morphology, as analyzed by angiography. The importance of risk factors for the development of coronary atherosclerosis and disturbance of coronary vasomotion is clearly established. However, microembolization of the coronary circulation has also to be taken into account. Microembolization may occur as a single or as multiple, repetitive events, and it may induce inflammatory responses. Spontaneous microembolization may occur, when the fibrous cap of an atheroma or fibroatheroma (Stary i.v. and Va) ruptures and the lipid pool with or without additional thrombus formation is washed out of the atheroma into the microcirculation. Such events with progressive thrombus formation are known as cyclic flow variations. Plaque rupture occurs more frequently than previously assumed, i.e. in 9% of patients without known heart disease suffering a traffic accident and in 22% of patients with hypertension and diabetes. Also, in patients dying from sudden death microembolization is frequently found. Patients with stable and unstable angina show not only signs of coronary plaque rupture and thrombus formation, but also microemboli and microinfarcts, the only difference between those with stable and unstable angina being the number of events. Appreciation of microembolization may help to better understand the pathogenesis of ischemic cardiomyopathy, diabetic cardiomyopathy and acute coronary syndromes, in particular in patients with normal coronary angiograms, but plaque rupture detected by intravascular ultrasound. Also, the benefit from glycoprotein IIb/IIIa receptor antagonist is better understood, when not only the prevention of thrombus formation in the epicardial atherosclerotic plaque, but also that of microemboli is taken into account. Microembolization also occurs during PTCA, inducing elevations of troponin T and I and elevations of the ST segment in the EKG. Elevated baseline coronary blood flow velocity, as a potential consequence of reactive hyperemia in myocardium surrounding areas of microembolization, is more frequent in patients with high frequency rotablation than in patients with stenting and in patients with PTCA. The hypothesis of iafrogenic microembolization during coronary interventions is now supported by the use of aspiration and filtration devices, where particles with a size of up to 700 microns have been retrieved. In the experiment, microembolization is characterized by perfusion-contraction mismatch, as the proportionate reduction of flow and function seen with an epicardial stenosis is lost and replaced by contractile dysfunction in the absence of reduced flow. The analysis of the coronary microcirculation, in addition to that of the morphology and function of epicardial coronary arteries, and in particular appreciation of the concept of microembolization will further improve the understanding of the pathophysiology and clinical symptoms of coronary artery disease.     

Antiplatelet Management for Coronary Heart Disease: Advances and Challenges

Coronary heart disease (CHD) remains the leading cause of death in the USA. CHD accounts for 48 % of all cardiovascular mortality or approximately one of every seven deaths. Disruption of atherosclerotic plaques—usually by rupture or erosion—and superimposed thrombosis can result in acute coronary syndromes and sudden cardiac death. Silent plaque disruption may also occur and result in coronary plaque progression and ultimately the symptomatic manifestations of stable CHD. Antiplatelet agents remain the cornerstone therapy for acute thrombotic coronary syndromes and are essential for thromboprophylaxis against these events in patients with stable CHD. Antiplatelet drugs are also important adjunct therapies during percutaneous coronary intervention (PCI) as they mitigate equipment-associated thrombotic complications that are partially induced by iatrogenic plaque rupture by interventionalists during balloon angioplasty in the cardiac catheterization laboratory. Since the introduction of clopidogrel, there has been considerable development in this field with at least three novel P2Y₁₂ antagonists approved by the Food and Drug Administration (FDA) over the past decade. Rapidly accumulating evidence is helping to guide the optimal duration of treatment with dual antiplatelet therapy after stenting, especially with the newer drug-eluting stents. More data are also emerging on the hazards and long-term safety of these agents. It is therefore prudent for clinicians to remain current on treatment options and recent advances in this area. We herein review current and emerging antiplatelet therapies and summarize their characteristics and indications of use as well as challenges and areas of ongoing research.     

Effect of early statin therapy after acute coronary syndromes: a concise review of the recent data

HMG Co-A reductase inhibitors(statins) have been shown, in three large randomized trials, to decrease adverse cardiac events in patients with clinically evident coronary artery disease. All of these trials have excluded patients with an acute coronary syndrome within the three months prior to enrollment. Statin therapy is thought to stabilize coronary plaque and decrease the risk of plaque rupture. Statins have been shown to quickly reduce levels of LDL-C in addition to altering systemic inflammatory responses, improving endothelial function, and reducing platelet aggregation and activation. These mechanisms are potentially beneficial in the setting of acute coronary syndromes, a time of profound plaque instability. There is a growing body of evidence supporting the early initiation of statin therapy in the setting of acute coronary syndromes. This paper reviews the available data from randomized-controlled trials and observational studies evaluating the effect of early statin initiation during, or soon following, an acute coronary syndrome.     

Significance of characterization of non-culprit lesions: an underscored clinical problem

Sudden death or acute coronary syndromes are frequently the first manifestation of plaque rupture at non-culprit lesions. Thus, identification of high-risk non-culprit plaques may have significant impact on the prognosis of patients with coronary artery disease. At present a widely accepted diagnostic method to prospectively identify such 'high-risk' plaques is not available. Improved identification of high-risk plaques by novel imaging coronary modalities currently available is a goal of great importance since it will result in major decreases in coronary artery disease morbidity and mortality. Potential new treatments with systemic, regional, and local approaches have been proposed. In this review article we focus on common and different morphologic characteristics between culprit and non-culprit lesions, the natural history of non-culprit lesions, and potential methods to identify the high-risk lesions for future adverse cardiovascular events.     

Un syndrome coronaire aigu particulier : maladie de Horton

The pathophysiology of acute coronary syndromes is in most cases due to the erosion or rupture of a plaque with consequent thrombotic obstruction of coronary artery. In a few cases, the mechanism is different, this not modifying the initial management but imposing special techniques for diagnosis and therapeutic management. We report a clinical case of a patient supported for an acute coronary syndrome, in a context of impaired general condition and biological inflammatory syndrome revealing a Horton's disease.     

Utility of optical coherence tomography in acute coronary syndromes

Studies utilizing intravascular imaging have replicated the findings of histopathological studies, identifying the most common substrates for acute coronary syndromes (ACS) as plaque rupture, erosion, and calcified nodule, with spontaneous coronary artery dissection, coronary artery spasm, and coronary embolism constituting the less common etiologies. The purpose of this review is to summarize the data from clinical studies that have used high-resolution intravascular optical coherence tomography (OCT) to assess culprit plaque morphology in ACS. In addition, we discuss the utility of intravascular OCT for effective treatment of patients presenting with ACS, including the possibility of culprit lesion-based treatment by percutaneous coronary intervention.     

Coronary microembolization: the role of TNF-alpha in contractile dysfunction.

Coronary microembolization is a frequent complication of atherosclerotic plaque rupture in acute coronary syndromes and during coronary interventions. Experimental coronary microembolization results in progressive contractile dysfunction associated with a local inflammation. We studied the causal role of tumor necrosis factor-alpha (TNF-alpha) in the progressive contractile dysfunction resulting from coronary microembolization. Anesthetized dogs were subjected to either coronary microembolization with infusion of 3.000 microspheres (42 microm diameter) per ml coronary inflow into the left circumflex coronary artery (n=9), or to intracoronary infusion of recombinant human TNF-alpha without microembolization (n=4), or to treatment with anti-murine TNF-alpha sheep antibodies prior to microembolization (n=4). Posterior systolic wall thickening (PWT; sonomicrometry) decreased from 21.1+/-5.3% (s.d.) at baseline to 5.5+/-2.2% (P<0.05) at 8 h after microembolization. Infarct size (1.8+/-1.9%; TTC and histology) and the amount of apoptosis (<0.1%; TUNEL and DNA-laddering) were small. TNF-alpha at the protein level (WEHI cytolytic assay) was increased and localized to leukocytes (immunostaining), which were increased in number (quantitative histology). In situ hybridization for TNF-alpha mRNA identified viable cardiomyocytes surrounding the microinfarcts as the major source of TNF-alpha. Supporting the role of TNF-alpha, infusion of TNF-alpha without microembolization decreased PWT from 27.3+/-6.9% at baseline to 10.1+/-4.9% after 8 h (P<0.05); in contrast, in the presence of TNF-alpha antibodies, microembolization no longer reduced PWT (19.3+/-7.0% at baseline v 16.9+/-5.0% at 8 h). In conclusion, TNF-alpha is the mediator responsible for the profound contractile dysfunction following coronary microembolization.     

易损斑块的诊断进展

急性冠状动脉综合征患者具有较高的发病率,预后较差,而冠状动脉内易损斑块破裂伴随血栓形成是其主要原因.因此早期正确诊断易损斑块,对于急性冠脉综合征的防治具有重大意义.现就易损斑块的诊断进展作一综述.     

Secondary Prevention of CAD with ACE Inhibitors: A Struggle Between Life and Death of the Endothelium

Angiotensin-converting enzyme (ACE) inhibitors improve outcomes in patients with coronary artery disease (CAD), heart failure, and hypertension. This short review examines clinical evidence for such effects and the underlying mechanism of action. One potential mode of action for ACE inhibitors in CAD is blood pressure reduction. However, recent data suggest that the effects of ACE inhibitors on the endothelium may also be relevant in attenuating the progression of atherosclerosis. In CAD, chronic overexpression of tissue ACE disrupts the angiotensin II/bradykinin balance with a net result of endothelial dysfunction, mainly due to an increased rate of apoptosis. An imbalance between endothelial apoptosis (death) and its renewal from the bone marrow (life) causes discontinuity of the endothelial layer, favoring the initiation and progression of a biochemical sequence that leads to atherosclerosis, plaque rupture, and eventually acute coronary syndromes. There is clinical and experimental evidence that ACE inhibition improves the life and death cycle of the endothelium. By restoring the bradykinin/angiotensin II balance, ACE inhibition reduces the rate of endothelial apoptosis and experimental results suggest that ACE inhibition can also improve the production and mobilization of endothelial progenitor cells from bone marrow. We report our experience in this context with perindopril.     

Role of platelet inhibitor therapy in myocardial infarction

Summary Atherosclerotic plaque disruption is the predominant pathogenetic mechanism underlying the acute coronary syndromes. Plaque rupture leads to the exposure of collagen and vessel media, resulting in platelet and clotting activation, and occlusive thrombus formation. While drugs that interfere with platelet activation and function have been available for years, more powerful agents with novel mechanisms of action are being developed. Of the available platelet inhibitor drugs, only aspirin, sulfinpyrazone, and dipyridamole have undergone extensive clinical testing in patients with cardiovascular disease. More recently ticlopidine, a new and potent platelet inhibitor, has been successfully tested in patients with coronary and vascular disease.In acute myocardial infaction, aspirin significantly reduces cardiovascular mortality and reinfarction. Furthermore, the combination of aspirin and a thrombolytic agent produces maximal benefit. A role for heparin in the prevention of early mortality and reinfaction is emerging. This drug is effective for the prevention of left ventricular thrombosis in patients with anterior myocardial infarction.In the secondary prevention of reinfarction and cardiovascular mortality, available data support the use of a platelet inhibitor. Trials have shown that aspirin is as effective alone as in combination with dipyridamole, and is probably more effective than sulfinpyrazone. Long-term anticoagulant therapy also appears to be beneficial, but is associated with a high cost, need for extensive monitoring, and potential for hemorrhagic side effects.The role of aspirin in primary prevention is controversial. It may be indicated for patients at high risk for coronary disease in whom the benefit of therapy may outweigh the potential risk of cerebral bleeding.Coronary atherosclerotic plaque rupture, associated with thrombus formation, is fundamental to the development of acute myocardial infarction. Based on this concept, the role of antithrombotic therapy for the prevention or treatment of ischemic events in patients with coronary artery disease has stimulated enormous interest among clinicians and basic investigators. In this review we will examine: a) the pathogenesis of coronary thrombosis, b) the pharmacology of plateletinhibitor agents, and c) their role in the management of patients with acute myocardial infarction and in primary and secondary prevention of cardiovascular disease.Platelets interact with both the coagulation and fibrinolytic systems in the pathogenesis of thrombosis. While the purpose of this review is to discuss the role of platelets and platelet inhibitors in coronary disease, the use of anticoagulant or thrombolytic agents will be analyzed briefly when pertinent.     

Role of anti-inflammatory drugs in the treatment of acute coronary syndromes. From athero-inflammation to athero-thrombosis

Coronary thrombosis is the most important cause of morbidity and mortality and the most severe manifestation of atherosclerosis. Knowledge of the pathophysiology of atheroma formation and the causes of atheroma accidents have allowed the development of new therapeutic measures for reducing thrombotic events after a coronary episode. Treating the thrombosis after plaque rupture is useful, but a late measure once coronary flow is disturbed. Therefore, treatment at an earlier stage, which we call athero-inflammation, a central event in atheroma progression leading to atherothrombosis, seems wise. There is evidence of an inflammatory component in the pathogenesis of atheroma rupture in acute coronary events. Earlier studies of anti-inflammatory medication have not demonstrated a reduction in thrombotic complications after an acute coronary episode. However, there are pathophysiological arguments and clinical findings that suggest that it would be advisable to include anti-inflammatory medications, especially those that inhibit preferentially COX-2, in the therapeutic arsenal for this pathology. We postulated that blocking athero-inflammation could prevent thrombosis. A pilot study was carried out in 120 patients with acute coronary syndrome without ST-segment elevation in which 60 patients were treated with meloxicam, a preferential COX-2 inhibitor. All patients received heparin and aspirin. During the stay in the coronary care unit, as well as after 90 days, meloxicam lowered composite outcomes (myocardial infarction, death and revascularization procedures) compared with the control group. These results and available pathophysiological and clinical evidence support the hypothesis of potential benefits of non-steroidal anti-inflammatory drugs with preferential inhibitory activity on COX-2 in patients with acute coronary syndromes. More trials are needed to confirm their preventive effect.     

Coronary Angioscopy Revealing Ruptured Plaque and Thrombus Causing Acute Anterior Myocardial Infarction With a Subsequent Acute Inferior Myocardial Infarction — A Case Report

We report a unique case that suggests that a thrombotic coronary occlusion was caused by local plaque rupture in the left anterior descending coronary artery (LAD), with subsequent thrombotic occlusion in the right coronary artery (RCA), and presented with simultaneous double coronary artery occlusions. ST-segment elevations in the precordial leads and cardiac tamponade were observed first, followed by ST-segment elevations in the inferior leads. Emergency coronary intervention for the RCA lesion resulted in further ST-segment elevation, suggesting an acute inferior infarction. A left ventricular rupture was found in the anterolateral wall, consistent with acute anterior infarction. Angioscopy one month later revealed the presence of ruptured plaque with thrombus, in both the LAD and the RCA. Yuji Okuyama and Masaya Usami, contributed equally to this report