Acute coronary syndromes (ACS) are lifethreatening conditions that can punctuate the course of patients with coronary artery disease at any time. These syndromes form a continuum that ranges from an unstable pattern of angina pectoris to the development of a large acute myocardial infarction (MI), a condition of irreversible necrosis of heart muscle ( Fig. 7.1). All ACS share a common initiating pathophysiologic mechanism, as this chapter will examine.
Figure 7.1. The continuum of acute coronary syndromes ranges from unstable angina, through non–ST-elevation myocardial infarction (MI), to ST-elevation MI.
The frequency of ACS is staggering: more than 1.4 million people are admitted to hospitals in the United States each year with these conditions. Approximately 38% of patients who experience an ACS will die as a result. Despite these daunting statistics, mortality associated with ACS has actually substantially and continuously declined in recent decades as a result of major therapeutic and preventive advances. This chapter considers the events that lead to ACS, the pathologic and functional changes that follow, and therapeutic approaches that ameliorate the aberrant pathophysiology.
Pathogenesis of Acute Coronary Syndromes
More than 90% of ACS result from disruption of an atherosclerotic plaque with subsequent platelet aggregation and formation of an intracoronary thrombus. The thrombus transforms a region of plaque narrowing to one of severe or complete occlusion, and the impaired blood flow causes a marked imbalance between myocardial oxygen supply and demand. The form of ACS that results depends on the degree of coronary obstruction and associated ischemia (see Fig. 7.1).
A partially occlusive thrombus is the typical cause of the closely related syndromes unstable angina (UA) and non–ST-elevation myocardial infarction (NSTEMI, historically 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 thrombus completely obstructs the coronary artery, the results are more severe ischemia and a larger amount of necrosis, manifesting as an ST-elevation myocardial infarction (STEMI, historically referred to as Q-wave MI).
The responsible thrombus in ACS is generated by interactions among the atherosclerotic plaque, the coronary endothelium, circulating platelets, and the dynamic vasomotor tone of the vessel wall, which overwhelm the natural antithrombotic mechanisms described in the next section.
When a normal blood vessel is injured, the endothelial surface becomes disrupted and thrombogenic connective tissue is exposed. Primary hemostasis is the first line of defense against bleeding. This process begins within seconds of vessel injury and is mediated by circulating platelets, which adhere to collagen in the vascular subendothelium and aggregate to form a “platelet plug.” While the primary hemostatic plug forms, the exposure of sub-endothelial tissue factor triggers the plasma coagulation cascade, initiating the process of secondary hemostasis. The plasma coagulation proteins involved in secondary hemostasis are sequentially activated at the site of injury and ultimately form a fibrin clot by the action of thrombin. The resulting clot stabilizes and strengthens the platelet plug.
The normal hemostatic system minimizes blood loss from injured vessels, but there is little difference between this physiologic response and the pathologic process of coronary thrombosis triggered by disruption of atherosclerotic plaques.
Endogenous Antithrombotic Mechanisms
Normal blood vessels, including the coronary arteries, are replete with safeguards that prevent spontaneous thrombosis and occlusion, some examples of which are shown in Figure 7.2.
Figure 7.2. Endogenous protective mechanisms against thrombosis and vessel occlusion.
(1) Inactivation of thrombin by antithrombin (AT), the effectiveness of which is enhanced by binding of AT to heparan sulfate. (2) Inactivation of clotting factors Va and VIIIa by activated protein C (protein C*), an action that is enhanced by protein S. Protein C is activated by the thrombomodulin (TM)–thrombin complex. (3) Inactivation of factor VII/tissue factor complex by tissue factor pathway inhibitor (TFPI). (4) Lysis of fibrin clots by tissue plasminogen activator (tPA). (5) Inhibition of platelet activation by prostacyclin and NO.
Inactivation of Clotting Factors
Several natural inhibitors tightly regulate the coagulation process to oppose clot formation and maintain blood fluidity. The most important of these are antithrombin, proteins C and S, and tissue factor pathway inhibitor (TFPI).
Antithrombin is a plasma protein that irreversibly binds to thrombin and other clotting factors, inactivating them and facilitating their clearance from the circulation (see mechanism 1 in Fig. 7.2). The effectiveness of antithrombin is increased 1,000-fold by binding to heparan sulfate, a heparin-like molecule normally present on the luminal surface of endothelial cells.
Protein C/protein S/thrombomodulin form a natural anticoagulant system that inactivates the “acceleration” factors of the coagulation pathway (i.e., factors Va and VIIIa). Protein C is synthesized in the liver and circulates in an inactive form. Thrombomodulin is a thrombinbinding 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. Activated protein C degrades factors Va and VIIIa (see mechanism 2 in Fig. 7.2), thereby inhibiting coagulation. The presence of protein S in the circulation enhances the inhibitory function of protein C.
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 (see mechanism 3 in Fig. 7.2). Thus, TFPI serves as a negative feedback inhibitor that interferes with coagulation.
Lysis of Fibrin Clots
Tissue plasminogen activator (tPA) is a protein secreted by endothelial cells in response to many triggers of clot formation. It cleaves the protein plasminogen to form active plas-min, which in turn enzymatically degrades fi-brin clots (see mechanism 4 in Fig. 7.2). When tPA binds to fibrin in a forming clot, its ability to convert plasminogen to plasmin is greatly enhanced.
Endogenous Platelet Inhibition and Vasodilatation
Prostacyclin is synthesized and secreted by endothelial cells (see mechanism 5 in Fig. 7.2), as described in Chapter 6. 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. Vasodilatation helps guard against thrombosis by augmenting blood flow (which minimizes contact between procoagulant factors) and by reducing shear stress (an inducer of platelet activation).
Nitric oxide (NO) is similarly secreted by endothelial cells, as described in Chapter 6. It acts locally to inhibit platelet activation, and it too serves as a potent vasodilator.
Pathogenesis of Coronary Thrombosis
Normally, the mechanisms shown in Figure 7.2 serve to prevent spontaneous intravascular thrombus formation. However, abnormalities associated with atherosclerotic lesions may overwhelm these defenses and result in coronary thrombosis and vessel occlusion ( Fig. 7.3). Atherosclerosis contributes to thrombus formation by (1) plaque rupture, which exposes the circulating blood elements to thrombogenic substances, and (2) endothelial dysfunction with the loss of normal protective antithrombotic and vasodilatory properties.
Figure 7.3. Mechanisms of coronary thrombus formation.
Factors that contribute to this process include plaque disruption (e.g., rupture) and inappropriate vasoconstriction and loss of normal antithrombotic defenses because of dysfunctional endothelium.
Atherosclerotic plaque rupture is considered the major trigger of coronary thrombosis. The underlying causes of plaque disruption are (1) chemical factors that destabilize atherosclerotic lesions and (2) physical stresses to which the lesions are subjected. As described in Chapter 5, atherosclerotic plaques consist of a lipid-laden core surrounded by a fibrous external cap. Substances released from inflammatory cells within the plaque can compromise the integrity of the fibrous cap.
For example, T lymphocytes elaborate ?-interferon, which inhibits collagen synthesis by smooth muscle cells and thereby interferes with the usual strength of the cap. Additionally, cells within atherosclerotic lesions produce enzymes (e.g., metalloproteinases) 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 sympathetic 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 that time of day, and these factors subject vulnerable plaques to rupture.
Following plaque rupture, thrombus formation is provoked via the mechanisms shown in Figure 7.3. The exposure of tissue factor from the atheromatous core triggers the coagulation pathway, while the exposure of subendothelial collagen activates platelets. Activated platelets release the contents of their granules, which include facilitators of platelet aggregation (e.g., adenosine diphosphate [ADP] and fibrinogen), activators of the coagulation cascade (e.g., factor Va), and vasoconstrictors (e.g., thromboxane and serotonin). The developing intra-coronary thrombus, intraplaque hemorrhage, and vasoconstriction all contribute to narrowing the vessel lumen, creating turbulent blood flow that contributes to shear stress and further platelet activation.
Dysfunctional endothelium, which is apparent even in mild atherosclerotic coronary disease, also increases the likelihood of thrombus formation. In the setting of endothelial dysfunction, reduced amounts of vasodilators (e.g., NO and prostacyclin) are released and inhibition of platelet aggregation by these factors is impaired, resulting in the loss of a key defense against thrombosis.
Not only is dysfunctional endothelium less equipped to prevent platelet aggregation, but also is less able to counteract the vasoconstrict-ing products of platelets. During thrombus formation, vasoconstriction 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 prostacyclin release, the influences of which predominate over direct platelet-derived vasoconstrictors (see Fig. 6.4).
However, reduced secretion of endothelial vasodilators in atherosclerosis allows vasoconstriction to proceed unchecked. Similarly, thrombin in a forming clot is a potent vascular smooth muscle constrictor in the setting of dysfunctional endothelium. Vaso-constriction causes torsional stresses that can contribute to plaque rupture or can transiently occlude the stenotic vessel 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 the several potential outcomes ( Fig. 7.4). For example, plaque rupture is sometimes superficial, minor, and self-limited, such that only a small, nonocclusive 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 mechanisms. Recurrent asymptomatic plaque ruptures of this type may cause gradual progressive enlargement of the coronary stenosis.
However, deeper plaque rupture may result in greater exposure of subendothelial collagen and tissue factor, with formation of a larger thrombus that more substantially occludes the vessel’s lumen. Such obstruction may cause prolonged severe ischemia and the development of an ACS. If the intraluminal thrombus at the site of plaque disruption totally occludes the vessel, blood flow beyond the obstruction will cease, prolonged ischemia will occur, 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 duration of ischemia will be less, and a smaller NSTEMI or UA is the more likely outcome. The distinction between NSTEMI and UA is based on the degree of the ischemia and whether the event is severe enough to cause necrosis, indicated by the presence of certain serum biomarkers (see Fig. 7.4). Nonetheless, NSTEMI and UA act quite alike, and the management of these entities is similar.
Figure 7.4. Consequences of coronary thrombosis.
A small thrombus formed on superficial plaque rupture may not result in symptoms or electrocardiogram (ECG) abnormalities, but healing and fibrous organization may incorporate the thrombus into the plaque, causing the atherosclerotic lesion to enlarge. A partially occlusive thrombus (with or without superimposed vasospasm) narrows the arterial lumen, restricts blood flow, and can cause unstable angina or a non–ST-elevation MI, either of which may result in ST segment depression and/or T wave inversion on the ECG. A totally occlusive thrombus with prolonged ischemia is the most common cause of ST-elevation MI, in which the ECG initially shows ST segment elevation, followed by Q wave development. An occlusive thrombus that recanalizes, or one that develops in a region served by adequate collateral blood flow, may result in less prolonged ischemia and a non–ST-elevation MI instead. Markers of myocardial necrosis include cardiac-specific troponins and creatine kinase MB isoenzyme.
Occasionally, a non–ST-elevation infarct may result from total coronary occlusion. In this case, it is likely that a substantial collateral blood supply (see Chapter 1) limits the extent of necrosis, such that a larger ST-elevation MI is prevented.
Nonatherosclerotic Causes of Acute Coronary Syndromes
Infrequently, mechanisms other than acute thrombus formation can precipitate an ACS ( Table 7.1). These should be suspected when an ACS occurs in a young patient or a person with no coronary risk factors. For example, coronary emboli from mechanical or infected cardiac valves may lodge in the coronary circulation, inflammation from acute vasculitis can initiate coronary occlusion, or patients with connective tissue disorders, or peripar-tum women, can rarely experience a spontaneous coronary artery dissection (a tear in the vessel wall, described in Chapter 15). Occasionally, intense transient coronary spasm can sufficiently reduce myocardial blood supply to result in UA or infarction.
Table 7.1. Causes of Acute Coronary Syndromes
Atherosclerotic plaque rupture with superimposed thrombus
- Vasculitic syndromes (see Chapter 15)
- Coronary embolism (e.g., from endocarditis, artificial heart valves)
- Congenital anomalies of the coronary arteries
- Coronary trauma or aneurysm
- Severe coronary artery spasm (primary or cocaine-induced)
- Increased blood viscosity (e.g., polycythemia vera, thrombocytosis)
- Spontaneous coronary artery dissection
- Markedly increased myocardial oxygen demand (e.g., severe aortic stenosis)
Another cause of ACS is cocaine abuse. Cocaine increases sympathetic tone by blocking the presynaptic reuptake of norepinephrine and by enhancing the release of adrenal cat-echolamines, which can lead to vasospasm and therefore decreased myocardial oxygen supply. An ACS 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.