Pathogenesis Of Acute Coronary Syndromes Research Articles

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.

Prediction of cardiovascular risk using soluble cell adhesion molecules.

Inflammation is now considered a critical pathogenic component of the atherosclerotic process. This is characterized histopathologically by leukocyte infiltration of the vascular endothelial wall. The vascular endothelium is a dynamic organ system, which has natural antiadhesive and anticoagulant properties. However, in response to injury the endothelium promotes coagulation and mediates the binding and transendothelial migration of activated leukocytes. These pathological processes are believed to be critical to the initiation and progression of atherosclerosis as well as the pathogenesis of acute coronary syndromes and are mediated by a group of molecules referred to collectively as cell adhesion molecules. Cell adhesion molecules are a diverse system of proteins and adhesive receptors, which orchestrate vital biological phenomena such as embryogenesis, cell growth and differentiation as well as inflammatory processes. Over the past decade there has been considerable progress in our understanding of adhesion molecules and their complex interactions. Among the many types of adhesion receptors on the cell surface, four main families are described (Fig.1).

Genes potentially involved in plaque rupture.

Rupture of an atherosclerotic plaque is the predominant underlying event in the pathogenesis of acute coronary syndromes and stroke. While ruptured plaques are morphologically well described, the precise molecular mechanisms involved in plaque rupture are still incompletely understood. Over the last few years, techniques like microarray, suppression subtractive hybridization and differential display enabled us to study complex gene expression profiles that occur during the process of atherogenesis. In this review we focus on recent large-scale gene expression profiles performed on whole mount vascular specimens. The gene expression profiles on whole mount vascular tissue confirmed that at least three mechanisms are involved in plaque rupture: (1) a disturbed balance in extracellular matrix turnover, (2) disturbed regulation of cell turnover and (3) processes involved in lipid metabolism. Animal models exhibiting features of plaque rupture reflect the involvement of these three mechanisms. The most dramatic mouse phenotypes were observed after interventions in at least two of these mechanisms. The observation of plaque rupture in recent mice models is indicative of the multifactorial process of plaque rupture. This multifactorial character of plaque rupture suggests that interventions may be most effective when they influence more than one mechanisms at a time.

Association of aortic stenosis with platelet hyperaggregability and impaired responsiveness to nitric oxide

Aortic stenosis (AS), even in its early phases, may be associated with the pathogenesis of acute coronary syndromes,1–3 which are usually paralleled by platelet hyperaggregability.4 Furthermore, patients with AS exhibit increased levels of platelet reactivity;5 thrombus formation has been documented on calcific and severely stenosed valves.6,7 We investigated whether AS, either with or without concomitant coronary artery disease (CAD), is associated with abnormalities in platelet aggregation. We also investigated nitric oxide (NO) responsiveness of the circulating platelets, and whether these abnormalities can be affected by therapy with perhexiline, a potent “metabolic” prophylactic antianginal agent8 for which there are data suggesting improved symptomatic status in patients with inoperable AS.9 The objectives were: (1) to study adenosine 5′-diphosphate (ADP)-induced aggregation in blood samples obtained from normal subjects and patients with AS of varying severity; (2) to assess the inhibition of platelet aggregation by the NO donor sodium nitroprusside (SNP) in these samples; and (3) to examine the effect of perhexiline therapy on platelet responsiveness to SNP in patients with AS.

Statin therapy in acute coronary syndromes: mechanistic insight into clinical benefit.

Randomized trials have established that statin treatment reduces coronary events in primary prevention and in patients with stable coronary artery disease. In unstable coronary artery disease, however, the pathophysiological background is distinct, and the potential benefits of statin therapy have not been evaluated until recently. Data from animal models and clinical studies indicate that statin treatment can influence a spectrum of molecular and cellular mechanisms that are intimately related to the pathogenesis of acute coronary syndromes; these include the reduction of circulating levels of atherogenic lipoproteins (very low density lipoprotein, very low density lipoprotein remnants, intermediate density lipoprotein, and low density lipoprotein) and thus of arterial lipid deposition and the attenuation of inflammation, modulation of thrombogenesis and thrombolysis, improvement of endothelial dysfunction, and reduction of ischemia/reperfusion injury. Indeed, findings from prospective and observational studies have demonstrated that statin treatment significantly improves clinical outcome after acute coronary syndromes. Therefore, early initiation of statin therapy after an acute coronary event not only enhances adherence to treatment but also preempts the occurrence of new events. In this review, we discuss recent important developments in our knowledge of the clinical evidence of the beneficial effects of early statin therapy in acute coronary syndromes and the biological mechanisms that underlie them.

Monitoring of platelet function in the setting of glycoprotein IIb/IIIa inhibitor therapy.

The role of the platelet in the pathogenesis of acute coronary syndromes is clearly established. In addition, the beneficial effects of oral and intravenous platelet inhibitor therapies were demonstrated in multiple, large, randomized clinical trials. However, despite these advances, current antiplatelet therapy fails to prevent coronary events in a substantial proportion of patients. One possible explanation for this phenomenon is that antiplatelet medications are administered without monitoring of the response to therapy. For example, oral antiplatelet therapy is administered as a standard dose for all patients, while intravenous inhibitors of the platelet glycoprotein (GP) IIb/IIIa receptor are dosed based on patient body weight. A major limitation of measuring platelet function has been that no practical test exists. The historic gold standard, bleeding time, was a very crude measure of platelet function with limited clinical utility. The current "gold standard," turbidimetric aggregometery, requires a central laboratory and is cumbersome to perform. Fortunately, a number of new tests with rapid turnaround time can be performed at the patient's bedside. This article discusses the details regarding the performance, advantages, disadvantages, and available data related to clinical use of each test in populations with coronary disease and patients treated with antiplatelet therapy.

Expression of tissue transglutaminase and elafin in human coronary artery: Implication for plaque instability

Background: the extracellular matrix (ECM) is an important determinant of plaque instability. Since tissue transglutaminase (tTG) and elafin act as stabilizing factors, they might play a crucial role in the pathogenesis of acute coronary syndrome. We examined their expression in human coronary arteries and the regulation of tTG expression in cultured vascular smooth muscle cells (SMCs). Methods and results: immunohistochemical studies on autopsy samples of human coronary arteries revealed the expression of tTG and elafin in the endothelium, medial SMCs, and the ECM in non-atherosclerotic coronary arteries. Their expression in SMCs, endothelium, and ECM was enhanced in atherosclerotic coronary arteries. In contrast, they were hardly detectable in accumulating macrophages or at the lipid core. Double staining demonstrated that elafin was co-localized with tTG. Moreover, some tTG-expressing cells were positive for TNF-α, suggesting that this cytokine might play an important role in the regulation of tTG. Treatment of cultured rat aortic SMCs with TNF-α increased their tTG mRNA, protein expression and enzyme activity. Conclusions: the expression of tTG and elafin increased in atherosclerotic coronary arteries. The investigation with cultured SMCs suggested that TNF-α might mediate the upregulation of tTG. Our findings may provide new insights into the mechanism of plaque instability and the pathogenesis of acute coronary syndrome.

Nuclear factor-κB immunoreactivity is present in human coronary plaque and enhanced in patients with unstable angina pectoris

Background: Nuclear factor-κB (NF-κB) is a transcription factor which plays a coordinating role in inflammation and cellular proliferation and is thought to be involved in the pathogenesis of atherosclerosis. Its role in unstable coronary plaque in humans is unknown. Methods and results: Coronary atherectomy plaque was obtained via directional coronary atherectomy from 32 patients [16 with unstable angina pectoris (UAP) and 16 with stable angina pectoris (SAP)]. The predominant pathology in UAP consisted of richly cellular areas with atheromatous gruel or loose intimal proliferative tissue within a myxoid matrix ( P<0.05 compared with SAP). By contrast, SAP plaques showed more dense fibrosis ( P<0.01 compared with UAP). Sections were then stained with a monoclonal antibody to the activated p65 subunit of NF-κB and this staining was present in 31/32 specimens, localized to smooth muscle cells, macrophages and foam cells. Staining was then graded semiquantitatively by three independent observers. Immunostaining grades for activated NF-κB were significantly higher in UAP compared with SAP (2.60±0.1 vs. 1.98±0.18; P<0.01). Conclusions: NF-κB immunoreactivity is present in coronary atherosclerotic plaque and is increased among patients with unstable coronary syndromes. These data support a role for NF-κB in the pathogenesis of acute coronary syndromes in humans.

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. Copyright © 2001 by W.B. Saunders CompanyProgress in Cardiovascular Diseases, Vol. 44, No. 3, (November/December) 2001: pp 217-230

Increased plasminogen activator inhibitor-1 and apolipoprotein (a) in coronary atherectomy specimens in acute coronary syndromes.

Although increased tissue factor expression is known in vulnerable plaques, there is no reported study to compare plaque fibrinolysis in stable and unstable plaques. This study investigates the extent of plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein (a) [apo(a)] in the plaques of different types of coronary artery disease as well as the correlation between these molecules and infiltration of macrophages to plaques. Using immunohistochemical staining, we examined PAI-1 expression and apo(a) deposition in coronary atherosclerotic specimens obtained by directional coronary atherectomy from 19 patients with acute myocardial infarction (AMI), 12 with unstable angina pectoris (UAP), and 13 with stable angina pectoris (SAP). The percentages of the total areas of specimens stained with PAI-1 or apo(a) were estimated by an NIH image program. The proportion of macrophages as a percentage of all cells in plaques was calculated as the macrophage density. We found significantly higher percentages of total areas of specimens stained with PAI-1 in AMI (25.5 +/- 8.6%, P < 0.001) and UAP (22.2 +/- 10.4%, P < 0.005) than in SAP (9.5 +/- 5.0%), as well as with apo(a) (AMI; 11.7 +/- 7.1%, P < 0.005, UAP; 11.1 +/- 5.5%, P < 0.01 versus SAP; 3.9 +/- 1.5%). Linear regression analysis of all the samples showed a correlation between PAI-1 or apo(a) and macrophage density (PAI-1: r = 0.75, P < 0.001 and apo(a): r = 0.56, P < 0.001). Our results suggest a possible contribution of increased PAI-1 and apo(a) in plaques to the pathogenesis of acute coronary syndromes including impaired fibrinolysis.

What is the role of intensive cholesterol lowering in the treatment of acute coronary syndromes?

Cholesterol lowering with statins reduces coronary events in a primary-prevention setting and in patients with stable coronary disease. However, where the risk of a coronary event is highest, in the early months after an episode of unstable angina or non–Q-wave infarction, the effect of statin therapy has not been evaluated until recently. The lack of an early benefit in the 3 main statin trials in stable coronary disease may have discouraged this type of investigation. Yet, evidence suggests that intensive cholesterol lowering can rapidly influence several mechanisms intimately related to the pathogenesis of acute coronary syndromes; specifically, improvement in endothelial function, decreased propensity for platelet thrombus formation, and reduced inflammation. Furthermore, 3 nonrandomized, observational studies have recently reported an improved outcome in statin-treated compared with untreated patients after acute coronary syndromes.

Inflammatory mechanisms.

Traditional concepts of the pathogenesis of acute coronary syndromes have changed over the last few years. In particular it has been demonstrated that high-risk lesions are not necessarily angiographically severe. Rather, unstable high risk lesions are the ones composed of large lipid cores and thin fibrous caps. It is now widely accepted that plaque instability is related to the development of inflammation within the intima. A consequence of this is that stabilization of lesions provides a new therapeutic target. Furthermore, there is growing evidence that statins may stabilize lesions by altering the inflammatory response. A brief overview of these developments and their impact on clinical practice is presented.

Autoantibodies against oxidized low density lipoproteins in patients with stable angina, unstable angina or peripheral vascular disease; pathophysiological implications.

Antibody antioxidized low density lipoproteins (oxLDL) might play a role both in atherogenesis and in the pathogenesis of acute coronary syndromes. Antibody titres to oxLDL and levels of C-reactive protein were compared in unstable angina, stable angina or peripheral artery disease. Antibody titres to LDL oxidated by CuSO(4)for 2, 4 and 18 h (Cu-oxLDL-Ab(2-4-18)) or by peroxidase (HRP-oxLDL-Ab) were assessed by ELISA. Cu-oxLDL-Ab(2-4-18)were consistently higher in peripheral artery disease than in unstable angina (P<0.001, P<0.001, P=0.01, respectively) or in stable angina (P<0.001, P=0.01, P=ns) but similar in unstable and stable angina. Accordingly, HRP-oxLDL-Ab were higher in peripheral artery disease than in unstable angina (P<0.001) or stable angina (P=0.04) but similar in unstable and stable angina. The number of arterial stenoses was higher in peripheral artery disease than unstable and stable angina (P<0.01). Cu-oxLDL-Ab and HRP-oxLDL-Ab correlated with the severity of atherosclerosis (P<0.01, R=0.4;P=0.02, R=0.3 respectively). Conversely, C-reactive protein levels were higher in unstable than in stable angina (P<0.001) or in peripheral artery disease (P<0.03) but similar in stable angina and peripheral artery disease and did not correlate with the severity of atherosclerosis. The autoimmune response to oxLDL is likely to play an important role in atherogenesis but not in precipitating acute coronary syndromes.

Systemic Inflammation: The Central Factor in Pathogenesis of Unstable Angina.

To the Editor: In their recent review, Hamm and Braunwald1 stated that inflammation is an integral component in the pathogenesis of unstable angina. However, a detailed explanation is missing. The current literature is also unclear about the role of different components of inflammation in the pathogenesis of acute coronary syndromes (ACS).2 Being able to explain only half of the ACS, the localized acute vessel wall inflammation leading to plaque rupture fails to generate a …

Orbofiban: an orally active GPIIb/IIIa platelet receptor antagonist.

A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t(1/2) of 18 hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials.

Antithrombotic therapy in acute coronary syndromes: Key notes from ESSENCE and TIMI 11B

Platelet activation and thrombus formation are key events in the pathogenesis of acute coronary syndromes (unstable angina and non-Q-wave myocardial infarction). Therefore, current management of these conditions consists of antithrombotic and antiplatelet therapy, principally heparin and oral aspirin. However, such treatment is unsuccessful in a significant proportion of patients. Two recent large studies with the low-molecular-weight heparin (LMWH) enoxaparin have shown that this agent significantly reduces the risk of major ischemic events compared with unfractionated heparin. In the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) study, treatment with enoxaparin for 2 to 8 days reduced the risk of death, myocardial infarction, or recurrent angina by 20% at 14 days compared with treatment with unfractionated heparin. In the Thrombolysis in Myocardial Infarction (TIMI) 11B study, enoxaparin was associated with a significant reduction in the risk of death, myocardial infarction, or urgent revascularization compared with unfractionated heparin, which became apparent within 48 hours; this benefit was maintained during outpatient treatment for 5 weeks. A meta-analysis of these two studies showed that the risk of death or myocardial infarction was consistently approximately 20% lower in enoxaparin-treated patients than in heparin-treated patients. In contrast, studies with other LMWHs have not shown consistent superiority over unfractionated heparin. This may reflect the pharmacologic heterogeneity of LMWH and/or differences in trial design.

Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes

OBJECTIVESWe sought to study the relationships between chemokines and oxidative stress in acute coronary syndrome.BACKGROUNDIn view of existing knowledge on the participation of leukocytes and oxidative stress in the pathogenesis of acute coronary syndrome, we hypothesized that chemokines may play a role in recruiting and activating leukocytes in this disorder.METHODSThe levels of chemokines and oxidative stress were studied in 38 patients with stable and 38 with unstable angina and in 20 controls. In separate in vitro experiments the effect of chemokines on reactive oxygen species in monocytes and the effect of antioxidants on chemokine levels in these cells were also studied.RESULTS1) Angina patients had raised serum levels of chemokines in both cross-sectional and longitudinal testing, with particularly high levels of interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory peptide (MIP)-1-alpha in unstable disease. 2) T cells, and particularly monocytes, seem to contribute to the raised IL-8, MCP-1 and MIP-1-alpha levels in unstable angina. 3) Concomitantly, and significantly correlated with MCP-1 and IL-8 levels, stable and particularly unstable angina patients had decreased plasma levels of antioxidants and increased lipid peroxidation, suggesting enhanced oxidative stress. 4) Monocyte chemoattractant protein-1 enhanced the generation of O2−in monocytes from unstable angina patients, and the antioxidant glutathione-monoethyl ester suppressed the production of IL-8 and MCP-1 in these cells.CONCLUSIONSOur findings suggest an interaction between chemokines and oxidative stress in unstable angina. This interaction may represent a vicious circle involved in the pathogenesis of acute coronary syndromes.

Mechanisms of acute coronary syndromes and the potential role of statins

The conventional concepts of the pathogenesis of acute coronary syndromes are changing. High-risk lesions are not necessarily the angiographicaly ‘tight’ stenoses. Rather, vulnerable lesions are those that are unstable, with a large lipid core and a thin fibrous cap. Plaque instability is closely related to the development of inflammation within the intima and acute coronary syndromes result from rupture of a vulnerable atherosclerotic plaque. Stabilization of lesions by modification of structure and content, rather than simple improvement in the luminal diameter, provides a new therapeutic target. Stabilization may be accomplished through lifestyle changes and appropriate pharmacologic therapy. In the past few years, it has become evident that a major beneficial effect of statins is to induce plaque stability and regression. In fact, statins, in addition to lowering low-density lipoprotein cholesterol, have a variety of pleiotropic, or cholesterol-independent, effects that make them a particularly suitable choice in patients with acute coronary syndromes. Among these are improvements in endothelial function, smooth muscle cells, thrombus formation/platelet function, and inflammation.

The Prognostic Value of Small-Sized Platelet Aggregates in Unstable Angina: Detection by a Novel Laser-Light Scattering Method

Platelet activation plays a pivotal role in the pathogenesis of acute coronary syndromes. This study was designed to evaluate the platelet aggregability in patients with unstable angina using a new aggregometer with laser-light scattering. We also examined whether there was a relationship between these platelet aggregabilities and unfavorable outcome during in-hospital stay. We measured platelet aggregability, in particular small-sized platelet aggregates in 31 patients with unstable angina, 31 patients with stable exertional angina, and 30 patients with chest pain syndrome. The patients with unstable angina were divided into two groups by their cardiac events during in-hospital stay, cardiac events (+)( n=11) group and cardiac events (−)( n=20) group. On admission, the number of small-sized platelet aggregates ( V) was higher in patients with unstable angina (3.0±0.5×10 4) than in those with stable exertional angina (1.4±0.3×10 4, P=.017) and chest pain syndrome (0.7±0.2×10 4, P=.0003). The number of small-sized platelet aggregates was higher in the cardiac events (+) group than in the cardiac events (−) group (5.5±0.9×10 4 vs. 1.6±0.4×10 4, P=.0001). A previous study elucidated that small-sized platelet aggregates ultimately developed into medium-sized and large-sized aggregates as platelet aggregation proceeds. Therefore, the production of small-sized platelet aggregates is more sensitive for hyperaggregability. Furthermore, the production of small-sized platelet aggregates increased significantly in patients with unstable angina than in those with stable exertional angina and chest pain syndrome. These findings suggest that a tendency toward thrombus formation increases markedly in patients with unstable angina and increased number of small-sized platelet aggregates on admission predicts poor prognosis during in-hospital stay in patients with unstable angina.

Thrombin as a regulator of inflammation and reparative processes in tissues.

Activation of blood coagulation and thrombin formation accompany inflammation, wound healing, atherogenesis, and other processes induced by endothelial injury. Systems of hemostasis and inflammation play an important role in the pathogenesis of acute coronary syndromes. This paper reviews thrombin functions involved in its interaction with PAR family receptors, activation of platelets, endothelial cells, leukocytes, smooth muscle cells, and mast cells. Mechanisms of regulatory effects of thrombin on mast cells associated with nitric oxide release are discussed.