Definition Acute Miocardial Infarction (AMI) is clinical syndrome that result from occlusion or coronary artery, with resultant

death of cardiac myocytes in the region supplied by that artery. Depending on the distribution of the affected coronary artery, acute MI can produce a wide range of clinical sequelae, varying from a small, clinically silent region of necrosis to a large overwhelming area of infarcted tissue resulting in cardiogenic shock and death.1 Epidemiology Acute Miocardial Infarction (AMI) is one of the most common diagnose in hospitalized patients in industrial countries. In United States, approximately 650.000 patients experience a new AMI and 450.000 experience a recurrent AMI each year. The early (30 day) mortality rate from AMI is 30%, with more than half of these deaths occuring before the stricken individual reaches the hospital.1 Worldwide, coronary artery disease (CAD) is the single most frequent cause of death. Over seven million people every year die from CAD, accounting for 12,8 % of all deaths. Every sixth man and every seventh woman in Europe will die from myocardial infarction. The incidencce of hospital dmissions for AMI with ST-segment elevations (STEMI) varies among countries that belong to ESC. The most comprehensive STEMI registry is probably in Sweden, where the incidence is 66 STEMI/ 100.000/ year.2

Clinical classification of myocardial infartion MI is classified into various types, based on pathological, clinical and prognostic differences, along with differenty treatment strategies.2 Table 1. Universal classification of myocardial infarction Type 1 : Spontaneous myocardial infarction Spontaneus myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries leaading to decreased myocardial blood flow or distal platel etemboli with ensuing myocyte necrosis. The patient may have underlying severe CAD buut on occasion non obstructive or no CAD Type 2 : Myocardial infarction secondary to an ischaemic imbalance In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, e.g. coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/-brady-arrhytmias, anaemia, respiratory failure, hypotension, and hypertension with or without LVH Type 3 : Myocardial infarction resulting in death when biomarker values are unavailabe Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new LBBB, but death occuring before blood sample could be obtained, before cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected. Type 4a : Myocardial infarction related to percutaneous coronary intervention (PCI) Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn values >5x99th percentile URL in patients with normal baseline values (99th percentile URL) or a rise of cTn values >20% if the baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischaemia, or (ii) new ischaemic ECG changes or new LBBB, or (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow or no-flow or embolization, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormally are required. Type 4 b: Myocardial infarction related to stent thrombosis Myocardial infarction associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischaemia and with a rise and/or fall of cardiac biomarkers values with at least one value above the 99th percentile URL. Type 5 : Myocardial infarction related to coronary artery bypass grafting (CABG) Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac biomarker value >10x99th percentile URL in patient with normal baseline cTn values (99th percentile URL). In addition, either (i) new pathological Q

waves or new LBBB, or (ii) angiographic, documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Diagnose Clinical features of myocardial ischaemia and infarction Onset of myocardial ischaemia is the initial step in the development of MI and results from an imbalance between oxygen supplay and demand. Myocardial ischaemia in a clinical setting can usually be identified from the patients history and from the ECG. Posibble ischaemic symptoms include various combinations of chest, upper extremity, mandibular or epigastric discomfort (with exertion or at rest) or an ischaemic equivalent such as dyspnoea or fatigue. The discomfort associated with acute MI usually last >20 min. Often, the discomfort is difuse not localized, nor positional, nor affected by movement of the region and it may be accompanied bccy diaphoresis, nausea or syncope. However these symptoms are not specific forr myocardial ischaemia. Accordingly, they may be misdiagnosed and attributed to gastrointestinal, neurological, pulmonary or musculoskletal disorders. MI may occur with atypical symptoms such as palpitation or cardiac arrest or even without symptoms; for example in women, the elderly, diabetics, or post operative and critically ill patiernts. Careful evaluation of the patient is advised, especially when there is a rising and/or falling pattern of cardiac biomarkers.2 Pathogenesis of Acute Coronary Syndroms More than 90 % of ACS results from disruption of an atheroslerotic plaque with subsquent platelet agregation and formation of an intracoronary trombs. The trombus transform a region of plaque narrowing to one of severe or complete occlution, and the impaired blood flow cause a marked imbalance between myocardial oxygen supply and demand. The form of ACS that results depend on the degree coronary obstruction and associated ischemia. A partially occlusive

trombus is the typical cause of the closely related syndrome unstable angina (UA) and non- ST elevation myocardial infartion (N-STEMI, also referred to as non-Q wave MI), with the latter being distinguished from the former by the presence of myocardial necrosis. At the other end of the spectrum, if the trombus completely obstructs, the coronary artery, the results are more severe ischemic and a larger amount of necrosis, manifesting as an elevation myocardial infarction (STEMI, also referred to as Q-wave MI).3 Normal Hemostasis When a normal blood vessel is injured, the endothelial surface becomes disrupted and trombogenic connective tissue is exposed. Primary hemostasis is the first line of defense against bleeding. This process begins wthin seconds of vessel injury and is mediated by circulating platelets, which adhere to collagen in the vascular subendothelial tissue factor triggers the plasma coagulation cascade, initiating the process of secondary hemostasis. The plasma coagulation proteins involved in secondary hemostasis are sequently activated at the site of injury and ultimately form a fibrin clot by the action of thrombin. The resulting clot stabilizes and strengthens platelet plug. The normal hemostatic system minimize blood loss from injured vessels, but there is little difference between this physiologic response and the patologic process of coronary thrombosis triggered by disruptionf atherosclerotic plaques. Endogenous Antithrombotic Mechanisms Normal blood vessels, including the coronary arteries, are replete with safeguards that prevent spontaneous thrombosis and occlution. a. Inactivation Clotting Factors Severe natural inhibitors tightly regulate the coagulation process to oppose clot formation and maintain blood fluididty. The most important of these are antithrombin III, protein C and S, and tissue factor pathway inhibitor.

Antithrombin III is a plasma protein that irreversibly binds to thrombin and other clotting factors, inactivating them and facilitating their clearance from the circulation. The effectiveness of antithrombin III is increase a thousandfold by binding to heparan sulfate, a heparin-like molecule normally present on the luminal surface of endothelial cells. Pretein C/protein S/thrombomodulin form a natural anticoagulant system that inactivates the acceleration factors of the coagulation pathway. Protein C is synthesized in the liver and circulates in an inactivate form. Thrombomodulin is a thrombin-binding receptor normally present on endothelial cells. Thrombin bound to thrombomodulin cannot convert fibrinogen to fibrin (the final reaction in clot formation). Instead, the thrombin-thrombomodulin complex activates protein C. Activates protein C degrades factors Va and VIIIa, thereby inhibiting coagulation. The presence of protein S in the circulation enhances the inhibitory function of protein C. Tissue factor pathway inhibitor (TFPI) is a plasma serine protease inhibitor that is activated by coagulation factor Xa. The combined factor Xa-TFPI binds to and inactivates the complex of tissue factor with factor VIIa that normally triggers the extrinsic coagulation pathway. Thus, TFPI serves as a negative feedback inhibitor that interferes with coagulation. b. Lysis of fibrin clots Tissue plasminogen activator (tPA) is a protein secreted by endothelial cells in response to many triggers of clot formation. tPA cleaves the protein plasminogen to form active plasminogen to form active plasmin, which in turn enzymatically degrades fibrin clots. When tPA binds to fibrin in a forming clot, its ability to converts plasminogen to plasmin is greatly enhanced. Endogenous Platelet Inhibition and Vasodilatation a. Prostacyclin

Prostacyclin is synthesized and secreted by endhotelial cells. Prostacyclin increases platelet levels of cyclic AMP and thereby strongly inhibits platelet activation and aggregation. It also indirectly inhibits coagulation via its potent vasodilating properties. Vasodilation helps guard againt thrombosis by augmenting blood flow (which minimizes contact between procoagulant factors) and by reducing shear stress (an inducer of platelet activation). b. Nitric Oxide (NO) Nitric Oxide is similarly secreted by endothelial cells. Its act locally to inhibit platelet activation, ad it too serves as a potent vasodilator.

Pathogenesis of Coronary Thrombosis Atheroslerosis contributes to thrombus formation by (1) plaque rupture, which expose the circulating blood elements to thrombogenic substances, and (2) endothelial disfunction with the loss of normal protective antithrombotic and vasodilatory properties. Atherosclerotic plaque rupture is considerd the major trigger of coronary thrombosis. The underlying cause of plaque disruption are (1) chemical factor that destabilize atherosclerotic lesion and (2) physical stresses to which the lesion are subjected. Atherosclerotic plaques consist of a lipid-laden core surrounded by a fibrous external cap. Substances released from inflamatory cells within the plaque can compromise the integrity of the fibrous cap. Fir example, T lymphocytes elaborate -interferon, which inhibit collagen synthesis by smooth muscle cells and thereby interferes with the usual strength of the cap. Additionally, cell within atherosclerotic lesions produce enzymes that degrade the interstitial matrix, further compromising plaque stability. A weakened or thin capped plaque is subject to rupture, particularly in its shoulder region (the border with the normal arterial wall that is subjected to high circumferential stress) either spontaneously

or by physical forces, such as intraluminal blood pressure and torsion from the beating myocardium. ACS sometimes occur in the setting of certain triggers, such as strenuous physical activity or emotional upset. The activation of the synpathetic nervous system in these situations increases the blood pressure, heart rate, and force of ventricular contraction actions that may stress the atherosclerotic lesion, thereby causing the plaque to fissure or rupture. In addition, MI is most likely to occur in the early morning hours. This observation may relate to the tendency of key physiologic stressors (such as systolic blood pressure, blood viscosity, and plasma epinephrine levels) to be most elevated at the time of day, and these factors subject vulnerable plaques to rupture. Dysfuctional endothelium, which is apparent even in mild atherosclerotic coronary disease, also increases the likehood of thrombus formation. In the setting of endothelial dysfunction, reduced amounts of vasodilators are released and inhibition of platelet aggregation by theses factors is impaired, resulting in the loss of a key defense againts thrombosis. Not only is dysfunctional endothhelium less equipped to prevent platelet aggregation, but also it is less able to counteract the vasoconstricting products of platelets. During thrombus formation, vasoconstrictor is promoted both by

platelet products (thromboxane and serotonin) and by thrombin within the developing clot. The normal platelet associated vascular response is

vasodilatation, because platelet products stimulate endothelial NO and protacyclin release, the influences of which predominate over direct platelet-derived vasoconstrictors. However, reduced secretion of endothelial vasodilators in atheroslerotis allows vasoconstriction to proceed unchecked. Similarly, thrombin in a forming clots is a potent vascular smooth muscle constrictor in the setting of dysfuctional endothelium. Vasoconstriction causes torsional stresses that can contribute to plaque rupture or can transiently occlude the stenotic vesssel through heightened arterial tone. The reduction in coronary blood flow caused by

vasoconstriction also reduces the washout of coagulation proteins, thereby enhancing thrombogenicity. Significance of coronary thrombosis The formation of an intracoronary thrombus results in one of several potential outcomes. For exanple, plaque rupture is sometimes superficial, minor, and seelf limited, such that only a small, nonacclusive thrombus forms. In this case, the thrombus may simply become incorporated into the growing atheromatous lesion through fibrotic organization, or it may be lysed by natural fibrinolytic mechanism. Recurrent asymptomatic plaque ruptures of this type may cause gradual progressive enlargement of the coronary stenosis. However, deeper plaque rupture may result ini greater exposure of subendothelial collagen and tissue factor, with formation of a larger thrombus that more substantially occludes the vessels lumen. Such obstruction may cause prolonged severe ischaemia and the development of an acute coronary syndrome. If the intraluminal thrombus at the site of plaque disruption totally occludes the vessel, blood flow beyond the obstruction will cease, prolonged ischaemia will occure, and an MI (usually an ST-elevation MI) will result. Conversely, if the thrombus partially occludes the vessel (or if it totally occludes the vessel but only transiently because of spontaneous recanalization or by relief of superimposed vasospasm), the severity and durationof ischaemia will be less, nd a smaller nonST-elevation MI or UA are the more likely outcomes. The distinction between a non-ST-elevation MI and UA is based on the degree of the ischaemia and

whether the event is severe enouuggh to cause necrosis, indicated by the presence of certain serum biomarkers. Nonatherosclerotic cause of acute coronary synddrome Rarely, mechanism other than acute thrombus formation can precipitate an acute coronary syndrome. These should be suspected when an ACS occurs in a young patient or a person with no coranary risk factors. For example, coronary emboli from mechanical or infected cardiac valves can lodge in the coronary circulation,

or inflamation from acute vasculitis can initiate coronary occlusion. Occasionally, intense transient coronary spasm can sufficiently reduce myocardial blood supply to result in UA or infarction Another cause of ACS is cocaine abuse. Cocaine increase sympathetic tone by blocking the presynaptic reuptake of norepinephrine and by enhancing the release of adrenal catecholamines, which can lead to vasospasm and therefore decreased myocardial oxygen supply. An acute coronary syndrome may ensue because of increased myocardial oxygen demand resulting from cocaine induced sympathetic myocardial stimulation (increased heart rate and blood pressure) in the face of the decreased oxygen supply. Pathology and pathophysiology MI (either STEMI or NSTEMI) results when myocardial ischaemia is sufficiently severe to cause myocyte necrosis. Although by definition UA does not result in necrosis, MI may subsequently ensue if the undderlying pathophysiology of the unstable pattern of angina is not promptly corrected. In addition to their clinical classifications, infarctions can be described pathologically by the extent of necrosis they produce within the myocardial wall. Transmural infarcts span the entire thickness of the myocardium and result from total, prolonged occlusion of an epicardial coronary artery. Conversely, subendocardial infarcts exclusively involve the innermost layers of the myocardium. The subendocardium is particularly susceptible to ischaemia because it is the zone subjected to the highest pressure from the ventricular chamber, has few colateral connections that supplt it, and is perfused by vessels that must pass through layers of contracting myocardium. Infarction represents the culmination of disastrous cascade of events, initiated by ischaemia, that progresses from a potentially reversible phase to irreversible cell death. Myocardium that is supplied directly by an occluded vessel may die quickly. The adjacent tissue may not necrose immedietly because