1. Understanding Acute Coronary Syndromes
N Pathophys ACS
11/28/2018 5:41:36 PM
Understanding Acute Coronary Syndromes
12.6 million Americans currently have heart disease
1.1 million people are expected to have a serious heart event each year.
An estimated 25% of all Americans have one or more risk factors for heart disease.
Patients with Diabetes have 3 fold risk of suffering ACS

2. N Pathophys ACS
11/28/2018 5:41:36 PM
Slide 1
Factors That Lead to Endothelial Dysfunction and Activation in ACS
The vascular endothelium plays an important role in the development of atherosclerosis. A variety of factors, such as lipoproteins, smoking, and turbulent flow, result in endothelial dysfunction. In patients with atherosclerosis, the endothelium is dysfunctional. Production of nitric oxide, which interferes with the production of adhesion molecules, is reduced and degradation of nitric oxide by superoxides is enhanced. A vicious circle results, with further endothelial cell activation and cell attraction and further decrease in nitric oxide. Reduction in vascular relaxation, enhanced platelet aggregation, and increased smooth muscle cell (SMC) proliferation are other results of reduced nitric oxide.1 This endothelial dysfunction is thought to be the early manifestation of atherosclerosis.
1 Liao JK. Endothelium and acute coronary syndromes. Clin Chem. 1998;44:1799–1808.

3. Slide 6 Plaque Cap Synthesis and Breakdown N98-305 Pathophys ACS
11/28/2018 5:41:36 PM
Slide 6
Plaque Cap Synthesis and Breakdown
In the plaque cap, synthesis and breakdown of collagen and elastin are regulated by various mediators. The collagen in the fibrous cap is primarily types I and III and is synthesized by vascular smooth muscle cells. The production of interferon- (IFN-) by the activated T cells decreases the production of collagen by smooth muscle cells and also inhibits smooth muscle cell proliferation. At the same time, IFN- also activates macrophages that produce matrix metalloproteinases (MMPs), such as collagenase, gelatinase, and stromelysin, which degrade the fibrous cap. Plaques contain other macrophage activators besides IFN-, such as tumor necrosis factor- (TNF-), macrophage colony stimulating factor (M-CSF), and macrophage chemoattractant protein-1 (MCP-1).4
4 Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–2850.

4. Slide 2 Atherosclerosis Timeline N98-305 Pathophys ACS
11/28/2018 5:41:36 PM
Slide 2
Atherosclerosis Timeline
Histologic studies have characterized the progression of atherosclerotic lesion types. The earliest lesions (from the first decade on) are characterized histologically by isolated foam cells or fatty streaks in the vessel wall. Lesion growth at this stage occurs mainly by lipid accumulation. Intermediate lesions, which may be associated with small extracellular lipid pools, progress to atheroma, which has a core of extracellular lipid. These lesions may be seen starting in the third decade. Starting in the fourth decade, lesions may progress to the fibrous plaque stage, which is characterized by accelerated increases in smooth muscle and collagen. Complicated lesions are characterized by thrombosis, fissure, and hematoma formation.2
2 Stary HC, Chander AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation. 1995;92:1355–1374.

5. Slide 3 Atherosclerotic Plaque Progression and Clinical Syndromes
N Pathophys ACS
11/28/2018 5:41:36 PM
Slide 3
Atherosclerotic Plaque Progression and Clinical Syndromes
Plaques cannot be classified purely on the basis of their size; other characteristics are also important. Classification of coronary plaques was undertaken by the Committee on Vascular Lesions, which identified eight different morphologies of plaques and grouped them into categories designated types I through V. Plaques that have a high lipid content and a high proportion of cholesterol esters are vulnerable to rupture. In some patients, plaque disruption may lead to a labile thrombus with transient or intermittent vessel occlusion and subsequent unstable angina. In other patients, more severe vascular injury may lead to the formation of a fixed thrombus, resulting in acute myocardial infarction (MI).2 Not all disrupted plaques result in clinically detectable thrombosis, and in fact, the rupture and healing cycle may represent an etiology of plaque progression.3
2 Stary HC, Chander AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation. 1995;92:1355–1374.
3 Fuster VF, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250.

6. Slide 4 “Vulnerable” Plaque and “Stable” Plaque N98-305 Pathophys ACS
11/28/2018 5:41:36 PM
Slide 4
“Vulnerable” Plaque and “Stable” Plaque
Atherosclerotic plaques typically consist of a lipid-rich core, which is found in the central portion of the eccentrically thickened intima. The lipid core is bounded on the luminal surface by a fibrous cap. The integrity of the fibrous cap determines the stability of the plaque. The vulnerable plaque typically has a substantial lipid core and a thin, friable fibrous cap. Shear stress is increased at sites of plaques prone to rupture. When there is plaque rupture, the antigen HLA-DR is expressed by smooth muscle cells (SMCs) and leukocytes. The expression of HLA-DR is felt to be a marker for activation of SMCs.4 In contrast, the stable atherosclerotic plaque typically has a relatively thick fibrous cap, which is more resistant to shear stress and less prone to rupture.
4 Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–2850.

7. Slide 5 Factors Contributing to Plaque Vulnerability
N Pathophys ACS
11/28/2018 5:41:36 PM
Slide 5
Factors Contributing to Plaque Vulnerability
Study of plaques from the human aorta and coronary arteries have been used to determine the characteristics of plaques at risk of disruption, e.g., vulnerable plaques. Studies of autopsy material and of material retrieved at atherectomy from patients with stable or unstable angina have shown vulnerability to be a function of increased numbers of macrophages, increased expression of tissue factor, reduced numbers of smooth muscle cells, a lipid core that occupies a high proportion of plaque volume, and a thin cap. When all of these factors coincide, the plaque is at high risk of disruption.5
5 Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture Circulation. 1996;94:2013–2020.

8. Slide 7 C-Reactive Protein and Acute Coronary Events
N Pathophys ACS
11/28/2018 5:41:36 PM
Slide 7
C-Reactive Protein and Acute Coronary Events
Evidence suggests that inflammation is a correlate of the development of atherosclerosis and that levels of the inflammatory marker C-reactive protein (CRP) are correlated with the occurrence of cardiovascular complications. In this study, an ultrasensitive immunoassay was used to measure CRP levels in subjects with definite coronary disease, patients with normal coronary angiograms, and healthy control subjects. CRP levels were higher in the group with coronary disease than in those with normal arteriograms or than in healthy controls. Furthermore, within the group of patients with coronary disease, CRP levels were significantly increased in those with recent (<2 months from time of study) MI or unstable angina compared with those patients who have stable symptoms.6
6 Abdelmouttaleb I, Dancin N, Ilardo C, et al. C-Reactive protein and coronary artery disease: additional evidence of the implication of an inflammatory process in acute coronary syndromes. Am Heart J. 1999;137:346–351.

9. N Pathophys ACS
11/28/2018 5:41:36 PM
Slide 8
Infectious Agents and Atherosclerosis: Detection of Chlamydia in Coronary Arteries
Evidence suggests that infectious agents may be associated with coronary atherosclerosis. Several studies have demonstrated serologic and tissue identification of Chlamydia pneumoniae in atherosclerotic coronary arteries. Campbell et al.7 studied atheromatous coronaries obtained by directional coronary atherectomy (DCA) from 37 patients with angina and MI. They documented the presence of C pneumoniae by polymerase chain reaction (PCR) testing, by immunocytochemistry, or both in 55% of the patients, with electron microscopy confirmation in 2 samples. Muhlestein et al.8 studied coronaries of 90 patients with atherosclerotic coronary artery disease (CAD) and 24 controls (12 patients without CAD and 12 patients with transplant arteriopathy). 73% of the patients with CAD had C pneumoniae documented by direct immunofluorescence in their coronaries, compared with 4% of the controls (P<0.001).
7 Campbell LA, O’Brien ER, Cappuccio AL, et al. Detection of Chlamydia pneumoniae TWAR in human coronary atherectomy tissues. J Infect Dis. 1995;172:585–588.
8 Muhlestein JB, Hammond EH, Carlquist JF, et al. Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerosis versus other forms of cardiovascular disease. J Am Coll Cardiol. 1996;27:1555–1561.

10. Slide 9 The Role of Platelets in ACS N98-305 Pathophys ACS
11/28/2018 5:41:36 PM
Slide 9
The Role of Platelets in ACS
Rupture of an atherosclerotic plaque results in exposure of the subendothelial matrix substrates, triggering adhesion of platelets to the area of disruption. Other platelet stimuli such as thrombin, serotonin (5HT), and collagen activate platelets to secrete adenosine diphosphate (ADP) and thromboxane A2 (TxA2), further amplifying activation and recruitment. Finally, platelets aggregate via binding of the glycoprotein (GP) IIb/IIIa receptors to fibrinogen and von Willebrand factor (vWF) to form an occlusive thrombus.9
9 Schafer AI. Antiplatelet therapy. Am J Med. 1996;101:199–209.

11. Slide 10 Thrombosis: Platelets and the Coagulation System
N Pathophys ACS
11/28/2018 5:41:36 PM
Slide 10
Thrombosis: Platelets and the Coagulation System
Plaque rupture and exposure of the lipid core can at times result in extensive thrombus formation that is clinically manifested as an unstable coronary syndrome. Initially, tissue factor, collagen, vWF, and fibronectin attract and attach platelets to the vessel wall, as well as activate them. vWF also binds platelets, causing a conformational change in the platelet itself. The platelet degranulates and secretes vasoconstrictive and chemoattractant substances. Exposure of the now-activated GP IIb/IIIa receptor site allows binding of fibrinogen to cause platelet aggregation by cross-linking of fibrin. In addition to adhering to the injured vascular wall and forming aggregates, activated platelets accelerate the generation of thrombin. This further promotes platelet aggregation and growth of the thrombus.10
10 Stein B, Fuster V, Israel DH, et al. Platelet inhibitor agents in cardiovascular disease: an update. J Am Coll Cardiol. 1989;14:813–836.

12. Slide 11 Red Clot and White Clot N98-305 Pathophys ACS
11/28/2018 5:41:36 PM
Slide 11
Red Clot and White Clot
Platelet adhesion to the atheromatous surface and subsequent binding of fibrinogen form the basis for the thrombus. Thrombus consists of a platelet core (white clot) on which is superimposed a fibrin-thrombin admixture with erythrocytes (red clot). Both white clot and red clot can be visualized on angioscopy as shown in this slide. Findings on angioscopy can be correlated with angiographic findings. White thrombus may be visualized as a hazy lesion, but frequently cannot be identified by standard coronary angiography. Red thrombus is associated with the presence of an angiographic filling defect.11
11 Abela GS, Eisenberg JD, Mittleman MA, et al. Detecting and differentiating white from red coronary thrombus by angiography in angina pectoris and in acute myocardial infarction. Am J Cardiol. 1999;83:94–97.

13. Slide 12 Acute Coronary Syndromes: Summary N98-305 Pathophys ACS
11/28/2018 5:41:36 PM
Slide 12
Acute Coronary Syndromes: Summary
Thus, numerous factors contribute to the development of plaque instability. Once unstable, plaques are prone to rupture, exposing the thrombogenic core to the hemostatic mechanisms. The adhesion, activation, and aggregation of platelets forms the nidus for thrombus development, interfering with blood flow, and ultimately resulting in symptoms which bring the patient to clinical attention. Interference with this platelet process is one step in halting the pathophysiologic mechanisms leading to myocardial damage.3,12
3 Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250.
12 Théroux P, Fuster V. Acute coronary syndromes: unstable angina and non–Q-wave myocardial infarction. Circulation. 1998;97:1195–1206.