Part 6: Acute Coronary Syndromes

Acute coronary syndromes (ACSs) are life-threatening conditions that form a continuum ranging from an unstable pattern of angina pectoris to the development of a large acute myocardial infarction (MI), a condition of irreversible necrosis of myocardium.

Within the first year after a MI, 19% of men and 26% of women will die. Despite these daunting statistics, mortality associated with ACS has actually substantially and continuously declined in recent decades as a result of major therapeutic advances.

Normal coagulation

When a normal blood vessel is injured, the endothelial surface gets 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 sub-endothelium and aggregate to form a platelet plug.

While the primary hemostatic plug forms, the exposure of subendothelial 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 hemorrhage 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. The thrombus in ACS is generated by interactions among the atherosclerotic plaque, coronary endothelium, circulating platelets, and the vasomotor tone of the vessel wall, which overwhelm the natural antithrombotic mechanisms.

Physiological antithrombotic mechanisms

Several natural inhibitors tightly regulate the coagulation process to oppose thrombosis and maintain blood viscosity. 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. The effectiveness of antithrombin is increased 1,000-fold by binding to heparan sulfate, which is normally present on the luminal surface of endothelial cells.

Protein C, protein S, and 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 inactive form. Thrombomodulin is a thrombin-binding receptor normally present on endothelial cells. Thrombin bound to thrombomodulin cannot convert fibrinogen to fibrin. Instead, the thrombin–thrombomodulin complex activates protein C, which then degrades factors Va and VIIIa, 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 factor Xa–TFPI complex inactivates the binding of factor VIIa with tissue factor, which normally triggers the extrinsic coagulation pathway.

Another anticoagulant measure normally present is tissue plasminogen activator (tPA), which is a protein secreted by endothelial cells. It cleaves the protein plasminogen to form active plasmin, which in turn enzymatically degrades fibrin clots.

Another anticoagulant system normally present is prostacyclin and NO that are normally secreted by endothelial cells as described previously when talking about atherosclerosis. These directly inhibit platelet activation but also indirectly inhibit coagulation via their potent vasodilating properties.

Etiology of ACSs

More than 90% of ACSs result from disruption of an atherosclerotic plaque with subsequent formation of an intracoronary thrombus. The thrombus transforms a region of plaque stenosis to one of severe or complete occlusion, and the impaired blood flow causes a marked imbalance between myocardial oxygen supply and demand. The disease that results from ACS depends on the degree of coronary obstruction and associated ischemia.

A partially occlusive thrombus is the typical cause of unstable angina (UA) and non–ST-elevation myocardial infarction (NSTEMI), with the latter being distinguished from the former by the presence of myocardial necrosis. 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).

Normally, the mechanisms described above serve to prevent spontaneous intravascular thrombosis. However, abnormalities associated with atherosclerotic lesions may overwhelm these natural defenses and result in coronary thrombosis and vessel occlusion. Atherosclerosis contributes to thrombus formation by plaque rupture, which exposes the circulating blood elements to thrombogenic substances, and endothelial dysfunction, causing the loss of normal protective antithrombotic and vasodilatory properties.

Atherosclerotic plaque rupture is considered the major trigger o coronary thrombosis. As described previously in the part about atherosclerosis, atherosclerotic plaques consist of a lipid-laden core surrounded by a fibrous cap. Substances released from inflammatory cells within the plaque can compromise the integrity of the fibrous cap. For example, T cells release interferon-$\gamma$ (IFN-$\gamma$), which inhibits collagen synthesis by smooth muscles and thereby interferes with the usual strength of the cap. Additionally, cells within atherosclerotic lesions produce enzymes like metalloproteinases that degrade the interstitial matrix, further compromising plaque integrity. 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).

ACSs 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 ventricular contractility—actions that may stress the atherosclerotic lesion, causing plaque rupture.

While rupture of the fibrous cap is responsible for the majority of ACSs, superficial erosion without rupture is a less common but important mechanism for thrombus formation. Eroded plaques often do not have a substantial lipid burden but have been associated with smoking and are also frequently the cause of ACS in premenopausal women.

Following plaque disruption, thrombus formation is provoked via mechanisms. For example, during plaque rupture, the exposure of tissue factor from the atheromatous core triggers the coagulation pathway, while subendothelial collagen activates platelets. Activated platelets release their contents, which include facilitators of platelet aggregation (e.g. ADP), activators of the coagulation cascade (e.g. factor Va), and vasoconstrictors (e.g., thromboxane and serotonin). These factors 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. This is because endothelial dysfunction reduces the amount of vasodilators (e.g., NO and prostacyclin) released. 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 vasoconstricting products of platelets. During thrombus formation, vasoconstriction is promoted both by platelet products (thromboxane and serotonin) and by thrombin within the developing clot. Vasoconstriction causes rotational stress that can contribute to plaque rupture or can transiently occlude the stenotic vessel. The reduction in coronary blood flow caused by vasoconstriction also reduces the washout of coagulation proteins, thereby enhancing thrombogenicity.

Fate of coronary thrombosis

The formation of an intracoronary thrombus results in one of the several potential outcomes. For example, plaque rupture is sometimes minor and self-limited such that only a small, non-occlusive 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.

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, prolonged ischemia will occur, and an MI (usually an ST-elevation MI) will result. Conversely, if the thrombus partially occludes the vessel (or it totally occludes the vessel but only transiently because of spontaneous recanalization), the severity and duration of ischemia will be less, and a less severe NSTEMI or UA is the more likely outcome. The distinction between NSTEMI and UA is based on whether the thrombotic event is severe enough to cause necrosis.

Nonatherosclerotic Causes of ACS

Rarely, mechanisms other than acute coronary thrombosis can precipitate ACS. These should be suspected when an ACS occurs in a young patient or a person without atherosclerotic risk factors. These are important to recognize as their management differs from that of typical ACSs due to plaque rupture with coronary thrombosis. These include:

• Coronary emboli from mechanical or infected heart valves
• Inflammation from acute vasculitis
• Patients with connective tissue disorders
• Peripartum women

Occasionally, intense transient coronary spasm can sufficiently reduce myocardial blood supply to result in ACS.

Cocaine abuse can also lead to an ACS. Cocaine increases sympathetic tone by blocking the presynaptic reuptake of norepinephrine and by enhancing the release of adrenal catecholamines, which can lead to intense vasospasm. Moreover, an ACS may ensue because of increased myocardial oxygen demand resulting from cocaine-induced sympathetic myocardial stimulation (increased heart rate and blood pressure).

Pathology

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 myocardial wall and result from total, prolonged occlusion of an epicardial coronary artery.

Subendocardial infarcts exclusively involve the innermost layers of the myocardium. The subendocardium is particularly susceptible to ischemia because it is the zone subjected to the highest pressure from the ventricular chamber, has few collateral connections, and is perfused by vessels that must pass through layers of contracting myocardium.

Myocardium supplied directly by an occluded vessel may necrose quickly. The adjacent tissue may not die immediately because it may be sufficiently perfused by nearby patent vessels. However, the neighboring cells may become increasingly ischemic over time, as demand for oxygen continues in the face of reduced oxygen supply. Thus, the region of infarction may subsequently extend outward.

The amount of tissue that ultimately succumbs to infarction relates to:

• The mass of myocardium perfused by the occluded vessel
• The magnitude and duration of impaired coronary blood flow
• The oxygen demand of the affected myocardium
• The adequacy of collateral circulation

Early Changes in Infarction

As ischemia starts in the myocardium supplied by an occluded coronary vessel, there is a rapid shift from aerobic to anaerobic metabolism. Because mitochondria can no longer oxidize fats or products of glycolysis, ATP production drops dramatically and anaerobic glycolysis leads to the accumulation of lactic acid, resulting in lactic acidosis.

The decreased ATP levels also interferes with transmembrane Na+/K+-ATPase, resulting in elevation in the concentrations of intracellular Na+ and extracellular K+ . High intracellular Na+ contributes to cellular edema. Membrane leak and rising extracellular K+ concentration alter the transmembrane electrical potential, predisposing the myocardium to lethal arrhythmias. Intracellular calcium also accumulates, which is thought to contribute to the final common pathway of cell apoptosis through the activation of degradative lipases and proteases.

Collectively, these metabolic changes decrease myocardial function as early as 2 minutes following occlusive thrombosis. Without intervention, irreversible cell injury ensues in 20 minutes and is marked by the development of membrane defects. Proteolytic enzymes leak across the myocyte’s altered membrane, damaging adjacent myocardium, and the release of certain macromolecules into the circulation serves as a clinical marker of infarction.

Early histological changes include myocardial edema, wavy myofibers, and the presence of contraction bands. Edema of the myocardium develops within 4 to 12 hours, as vascular permeability increases and interstitial oncotic pressure rises (because of the leak of intracellular proteins). Wavy myofibers appear as intercellular edema separates the myocardial cells that are pulled about by the surrounding functional myocardium. Contraction bands can often be seen near the borders of the infarct: sarcomeres are contracted and consolidated and appear as bright eosinophilic belts.

An acute inflammatory response, with infiltration of neutrophils, begins after approximately 4 hours and incites further tissue damage. Within 18 to 24 hours, coagulation necrosis is evident on light microscopy with pyknotic nuclei and eosinophilic cytoplasm. Gross morphologic changes (dark, mottled discoloration of infarcted tissue) do not appear until 18 to 24 hours after coronary occlusion, although special stains (e.g., tetrazolium) allow the pathologist to identify regions of infarction earlier.

The following is a summary of the early pathological changes in MI:

• 1–2 minutes: ATP levels fall, resulting in cessation of contractility

• 10 minutes: cellular edema, decreased membrane potential, and susceptibility to arrhythmias.

• 20–24 minutes: Irreversible cell injury

• 1–3 hours: Wavy myofibers

• 18–24 hours: Coagulative necrosis (pyknotic nuclei with eosinophilic cytoplasm)

• 2–4 days: Total coagulative necrosis (no nuclei or striations with a hyperemic tissue rim);

The following flow chart summarizes the causes of cell necrosis in ACS:

Late Changes in Infarction

Five to seven days after the infarction, the process of wound healing begins. Necrotic myocytes do not regenerate; rather, the cells are removed and replaced by fibrous tissue, a process carried out by the infiltrating macrophages. This period of tissue resorption is termed yellow softening because connective tissue is destroyed and removed along with dead myocardial cells. The phagocytic clearing combined with thinning of the infarcted zone results in structural weakness of the ventricular wall and the possibility of myocardial wall rupture at this stage.

Approximately 1 week after infarction, granulation tissue appears, representing the start of the scarring process. This can be seen grossly as a red border at the edge of the infarct. Fibrosis subsequently ensues, and scarring is complete by 7 weeks after infarction.

Histology slides

Here are two views of very early ischemic changes, with beginning loss of cross-striations within myocardial fibers, but the cardiac fiber nuclei are still present and there is not yet an inflammatory infiltrate. This represents an evolving infarction less than 12 hours old:

This is an early acute MI. There is increasing loss of cross striations, some contraction bands are apparent, and the nuclei are undergoing karyolysis. Some neutrophils are beginning to infiltrate the myocardium:

This is an acute myocardial infarction. There is loss of cross striations, and the nuclei are not present. There is extensive hemorrhage at the border of the infarction, which accounts for the grossly apparent hyperemic border:

This is an acute myocardial infarction of several days’ duration. There is a more extensive neutrophilic infiltrate along with the prominent necrosis and hemorrhage.

Toward the end of the first week, healing of a MI becomes more prominent. Seen here is ingrowth of capillaries, fibroblasts and macrophages filled with hemosiderin, and granulation tissue:

This shows a remote MI evidenced by a collagenous scar with some residual red surviving myocardial fibers. This stage is reached about 2 months following the initial ischemic event. This scar tissue is nonfunctional, and the reduction in ejection fraction is related to the extent of scarring:

Functional alterations

The destruction of functional myocardial cells in infarction quickly leads to impaired ventricular contraction (systolic dysfunction). Cardiac output further diminishes because synchronous contraction of myocytes is lost.

A localized region of reduced contraction is termed hypokinetic, a segment that does not contract at all is called akinetic, and a dyskinetic region bulges outward during contraction of the remaining functional regions of the ventricle.

During an ACS, the left ventricle also undergoes diastolic dysfunction as diastolic relaxation is impaired by the infarcted myocardium (since diastolic relaxation is an energy-dependent process), which reduces ventricular compliance and contributes to elevated ventricular filling pressures.

Sometimes transient myocardial ischemia can result in a prolonged but reversible period of contractile dysfunction. For example, as described in Part 5, stunned myocardium is tissue that demonstrates prolonged systolic dysfunction after an episode of severe ischemia, despite restoration of adequate blood flow, and gradually regains contractile function over days to weeks.

Brief ischemic episodes to a region of myocardium may render that tissue more resistant to subsequent episodes, a phenomenon termed ischemic preconditioning. The clinical relevance is that a patient who sustains an MI in the context of recent angina experience less morbidity and mortality than those without preceding ischemic episodes. The mechanism of this phenomenon is not fully understood but appears to involve multiple signaling pathways. Substances released during ischemia like adenosine and bradykinin are believed to be key triggers of these pathways.

Following an MI, changes occur in the geometry of both infarcted and non-infarcted ventricular muscles. Such alterations in chamber size and wall thickness affect long-term cardiac function. In the early post-MI period, infarct expansion may occur, in which the affected ventricular segment enlarges. Infarct expansion represents thinning and dilatation of the infarcted tissue, resulting in a decreased volume o myocytes in the region. This expansion can be detrimental because it increases ventricular size, which increases wall stress, impairs systolic contractile function, and increases the risk for ventricular aneurysm.

In addition to expansion of the infarcted territory, remodeling of the ventricle may also involve dilatation of the overworked non-infarcted regions, beginning in the early post-infarct period and continues over the ensuing weeks and months. Initially, chamber dilatation serves a compensatory role because it increases cardiac output via the Frank–Starling mechanism, but progressive enlargement may ultimately lead to heart failure and predisposes to ventricular arrhythmias.

Clinical features of ACSs

Unstable Angina

UA presents in one of the ollowing three ways:

• A patient with chronic stable angina experiences a sudden increase in the frequency, duration, and/ or intensity of ischemic episodes

• Episodes of angina that unexpectedly occur at rest

• New onset of anginal episodes, described as severe, in a patient without previous symptoms of coronary artery disease.

These presentations are different from the pattern of chronic stable angina, in which instances of chest discomfort are predictable, brief, and non-progressive, occurring only during physical exertion or emotional stress. Patients with UA may progress further along the continuum of ACS and develop evidence of necrosis (i.e. acute NSTEMI or STEMI) unless the condition is recognized and promptly treated.

Acute Myocardial Infarction

The discomfort experienced during an MI resembles angina pectoris qualitatively but is usually more severe, lasts longer, and may radiate more widely. Like angina, the sensation may result from the release of mediators such as adenosine and lactate from ischemic myocardial cells onto local nerve endings.

Because ischemia in acute MI persists and proceeds to necrosis, these provocative substances continue to accumulate and activate afferent nerves for longer periods. The discomfort is often referred to other regions of the C7 through T4 dermatomes, including the neck, shoulders, and arms.

Symptoms are usually rapid in onset and increase in intensity to leave the patient with a profound “feeling of doom.” Unlike a transient attack of angina, the pain does not wane with rest, and there may be little response to the administration of sublingual nitroglycerin.

The chest discomfort associated with an acute MI may not always be severe. In fact, up to 25% of patients who sustain an MI are asymptomatic during the acute event. This is particularly common among diabetic patients who may not adequately sense pain because of associated neuropathy.

The combination of intense discomfort and baroreceptor response to hypotension (if present) may trigger a dramatic sympathetic nervous system response, presenting with diaphoresis (sweating), tachycardia, and cool and clammy skin caused by vasoconstriction.

If the ischemia affects a sufficiently large amount of myocardium, left ventricular contractility can be reduced (systolic dysfunction), thereby decreasing the stroke volume and causing the diastolic volume and pressure within the LV to rise. The increase in LV pressure, compounded by the ischemia-induced stiffness of the chamber (diastolic dysfunction), is conveyed to the left atrium and pulmonary veins. The resultant pulmonary congestion decreases lung compliance and stimulates juxtacapillary receptors. These J receptors exert a reflex that results in rapid, shallow breathing and evokes the subjective feeling of dyspnea.

Physical findings during an acute MI depend on the location and extent of the infarct. The S4 sound, indicative of atrial contraction into a noncompliant left ventricle, is frequently present. An S3 sound, indicative of volume overload in the presence of ailing LV systolic function, may also be heard.

A systolic murmur may appear if the ischemia affects papillary muscles, causing mitral valvular insufficiency or if the infarct ruptures through the interventricular septum to create a ventricular septal defect.

Diagnosis of ACSs

The diagnosis of ACSs is made on the basis of (1) the patient’s presenting symptoms, (2) acute ECG abnormalities, and (3) detection of specific serum markers for myocardial necrosis.

Specifically, UA is a clinical diagnosis supported by the patient’s symptoms, transient ST abnormalities on the ECG (usually ST depression and/ or T-wave inversion), and the absence of serum biomarkers of myocardial necrosis. Non–ST-segment elevation MI is distinguished from UA by the detection of serum markers of necrosis and often more persistent ST or T-wave abnormalities.

ECG

In UA or NSTEMI, ST-segment depression and/ or T-wave inversions may occur. These abnormalities may be transient, occurring just during chest pain episodes in UA, or they may persist in patients with NSTEMI.

In contrast, STEMI presents with a temporal sequence of abnormalities: initial ST-segment elevation followed by inversion of the T wave and the appearance of pathologic Q waves. These characteristic patterns of ECG abnormalities in ACS can be minimized or prevented by early therapeutic interventions.

Historically, MIs had been classified as “Q-wave” or “non–Q-wave” infarctions before the advent of the terms “STEMI” and “NSTEMI,” respectively. The older terminology reflected the fact that transmural infarctions typically produce pathologic Q waves (after an initial period of ST elevation), whereas subendocardial infarctions do not. However, it is now known that the development of pathological Q waves does not reliably correlate with pathologic findings. Currently, the finding of new pathologic Q waves to classify ACSs has little therapeutic relevance because Q waves, when they occur, take hours to develop and thus are not helpful in making acute treatment decisions.

Serum Markers for Infarction

Necrosis of myocardial tissue causes disruption of the sarcolemma, so that intracellular macromolecules leak into the cardiac interstitium and ultimately into the bloodstream. Detection of such molecules in the serum, particularly cardiac-specific troponins, serves important diagnostic and prognostic roles.

Troponin is a regulatory protein in muscle cells that controls interactions between myosin and actin. It consists of three subunits: TnC, TnI, and TnT. Although these subunits are found in both skeletal and cardiac muscles, the cardiac forms of troponin I (cTnI) and troponin T (cTnT) are structurally unique, and highly sensitive and specific for MI. The presence of even minor elevations of these serum biomarkers serve as evidence of cardiomyocyte necrosis and conveys powerful prognostic information.

However, as new generations of these assays have become ever more sensitive, small serum elevations can also be detected in conditions other than MI, related to acute cardiac strain or inflammation (e.g. in heart failure, myocarditis, hypertensive crises, or pulmonary embolism).

In the case of MI, cardiac troponin serum levels begin to rise 3-4 hours after the onset of chest discomfort, achieve a peak level between 18 and 36 hours, and then decline slowly, remaining detectable for 10 days or more after a large MI.

Creatine kinase

The enzyme creatine kinase (CK) is found in the heart, skeletal muscle, brain, and other organs. Injury to any of these tissues may lead to elevation in serum concentrations of the enzyme.

There are three isoenzymes of CK that improve diagnostic specificity of its origin: CK-MM (found mainly in skeletal muscle), CK-BB (mainly in the brain), and CK-MB (mainly in the heart). Elevation of CK-MB is highly suggestive of myocardial injury.

To facilitate the diagnosis of MI using this marker, it is common to calculate the ratio of CK-MB to total CK. The ratio is usually greater than 2.5% in the setting of myocardial injury and less than that when CK-MB elevation is from another source.

The serum level of CK-MB starts to rise 3-8 hours following infarction, peaks at 24 hours, and returns to normal within 48 to 72 hours.

As CK-MB is not as sensitive or specific for detection of myocardial injury as is cardiac troponin, the latter is the preferred diagnostic biomarker in clinical use. Because troponin and CK-MB levels do not become elevated in the serum until at least a few hours after the onset of MI symptoms, a single normal value drawn early in the course of evaluation does not rule out an acute MI. As a result, early decision making in patients with ACS often relies most heavily on the patient’s history and ECG findings.

Treatment of ACSs

Successful management of ACS requires rapid initiation of therapy to limit myocardial damage and minimize complications. Therapy must address the intracoronary thrombus that incited the syndrome and provide anti-ischemic measures to restore the balance between myocardial oxygen supply and demand.

Although certain therapeutic aspects are common to all ACS, there is a critical difference in the approach to patients who present with STEMI compared with those without ST-segment elevation (UA and NSTEMI).

Patients with STEMI typically have total occlusion of a coronary artery and for optimal therapy require very rapid reperfusion therapy (mechanical or pharmacologic), whereas patients without ST elevation generally do not.

General in-hospital measures for any patient with ACS include admission to the ICU where continuous ECG monitoring for arrhythmias is undertaken. The patient is initially maintained at bed rest to minimize myocardial oxygen demand, while supplemental oxygen is provided if there is any degree of hypoxemia. Analgesics, such as morphine, may be administered to reduce chest pain and associated anxiety.

Treatment of UA and NSTEMI

The primary focus of treatment for UA and NSTEMI consists of anti-ischemic medications to restore the balance between myocardial oxygen supply and demand, and anti-thrombotic therapy to prevent progression and to facilitate resolution of the underlying coronary thrombus.

The same pharmacologic agents used to decrease myocardial oxygen demand in chronic stable angina are appropriate in UA and NSTEMI but are often administered more aggressively. These include β-Blockers, nitrates, and calcium channel blockers as we talked about in Part 5.

β-Blockers reduce the likelihood of progression from UA to MI and lowers mortality rates in patients with infarction. In the absence of contraindications (e.g., marked bradycardia, bronchospasm, decompensated heart failure, or hypotension), a β-blocker is usually initiated in the first 24 hours to achieve a target heart rate of approximately 60 beats/min. Such therapy is usually continued indefinitely after hospitalization because of proven long-term mortality benefits following an MI.

In UA or NSTEMI, nitroglycerin is often initially administered by the sublingual route, followed by a continuous IV infusion. In addition to providing symptomatic relief, IV nitroglycerin is useful as a vasodilator in patients with ACS accompanied by heart failure or severe hypertension.

Non-dihydropyridine calcium channel antagonists (i.e., verapamil and diltiazem) do not show mortality benefit in ACS and are reserved for those with persistent ischemia despite β-blocker and nitrate therapy or for those with contraindications to β-blocker use. They should not be prescribed to patients with LV systolic dysfunction, because clinical trials have shown adverse outcomes in that case.

Anti-thrombotic therapy

The majority of patients with UA or NSTEMI should receive at least 2 forms of antiplatelet therapy, typically aspirin and an inhibitor of the platelet P2Y12 ADP receptor (e.g. clopidogrel, prasugrel, and ticagrelor). Aspirin inhibits platelet synthesis of thromboxane A2, a potent mediator of platelet activation and is one of the most important interventions to reduce mortality in patients with all forms of ACS. It should be administered immediately on presentation and continued indefinitely in patients without contraindications to its use.

Clopidogrel is an oral thienopyridine derivative that further reduces cardiovascular death, recurrent MI, and stroke rates in patients with UA or NSTEMI who are treated with aspirin. However, not all patients respond to clopidogrel with similar benefit as it is a prodrug that requires cytochrome P-450–mediated biotransformation to its active metabolite. Patients with reduced function of the CYP2C19 gene produce lower concentrations of clopidogrel’s activate metabolite and attenuated clinical benefits. Thus, newer P2Y12 ADP receptor blockers have been developed that do not have this metabolic shortcoming, have more rapid onsets of action, and achieve greater degrees of platelet inhibition than clopidogrel. For example, prasugrel is also a thienopyridine derivative that is more potent than clopidogrel and doesn’t require cytochrome P-450 for activation (though it may increase the risk of bleeding complications).

Both clopidogrel and prasugrel are irreversible platelet inhibitors. Ticagrelor is a non-thienopyridine drug that is a reversible P2Y12 ADP receptor blocker. Compared to clopidogrel, it has been shown to further decrease major cardiovascular events and mortality, without an increased risk of bleeding complications. Minor bleeding, however, is more common than with clopidogrel.

In some circumstances, even more powerful antiplatelet agents are utilized in ACSs. The glycoprotein (GP) IIb/ IIIa receptor antagonists (which include the monoclonal antibody abciximab and the small molecules eptifibatide and tirofiban) are potent antiplatelet agents that block the final common pathway of platelet aggregation. These agents are effective in reducing adverse coronary events in patients undergoing PCI. In patients with UA or NSTEMI, their benefit is primarily in those at the highest risk of complications (e.g. the presence of elevated serum troponin levels or recurrent episodes of chest pain). When used, GP IIb/ IIIa receptor antagonists are most commonly initiated in the cardiac catheterization laboratory at the time of PCI.

IV unfractionated heparin (UFH) has long been standard anticoagulant therapy for UA and NSTEMI. It binds to anti-thrombin, which greatly increases its potency for the inactivation of clot-forming thrombin. UFH additionally inhibits coagulation factor Xa, slowing thrombin formation and thereby further impeding clot development. In patients with UA or NSTEMI, UFH improves cardiovascular outcomes and reduces the risk of progression from UA to MI. Because of a high degree of pharmacodynamic variability, its effect must be monitored and the dose should be adjusted through serial measurements of the serum activated partial thromboplastin time (aPTT).

To overcome the pharmacologic shortcomings of UFH, low molecular weight heparins (LMWHs) were developed. Like UFH, LMWHs interact with anti-thrombin but preferentially inhibit coagulation factor Xa. They provide a more predictable pharmacologic response than UFH. As a result, LMWHs are easier to use, prescribed as one or two daily injections based on the patient’s weight. Unlike UFH, repeated monitoring of plasma coagulation profile and dosage adjustments are not generally required. In clinical trials in patients with UA or NSTEMI, the LMWH enoxaparin has demonstrated reduced death and ischemic event rates compared with UFH.

Two other types of anticoagulants have also been shown to benefit UA and NSTEMI patients and are sometimes used in place of UFH or LMWH. Bivalirudin is an IV direct thrombin inhibitor, which is equivalent to UFH plus a GP IIb/ IIIa inhibitor in preventing adverse ischemic outcomes, with less associated bleeding complications. Fondaparinux is a subcutaneously administered agent that is a very specific inhibitor of factor Xa inhibitor. Its effect is similar to the enoxaparin at reducing cardiac adverse events but with fewer bleeding complications.

With all of these choices, the decision of which anticoagulant to prescribe to an individual patient often depends on whether an initial conservative versus invasive approach is followed.

Conservative versus Invasive Management of UA and NSTEMI

Many patients with UA or NSTEMI stabilize following institution of the therapies described above, while others have recurrent ischemic events. Currently, there is no definitive way to predict which direction a patient will take. This uncertainty has led to 2 therapeutic strategies in UA/ NSTEMI:

• An early invasive approach, in which urgent cardiac catheterization is performed and coronary revascularization undertaken

• A conservative approach, in which the patient is managed with medications and undergoes angiography only if ischemic episodes spontaneously recur or if the results of a subsequent stress test indicate substantial residual inducible ischemia.

The conservative approach offers the advantage of avoiding costly and potentially risky invasive procedures. Conversely, an early invasive strategy allows rapid identification and definitive treatment for those with critical coronary disease.

Risk assessment algorithms consider some features and help identify patients at high likelihood of poor outcomes. One commonly used tool is the Thrombolysis in Myocardial Infarction (TIMI) risk score that employs seven variables to predict a patient’s risk level:

1. Age $>65$ years old

2. $\geq 3$ risk factors for coronary artery disease

3. Known coronary stenosis of $\geq 50\%$ by prior angiography

4. ST-segment deviations on ECG at presentation

5. At least 2 anginal episodes in prior 24 hours

6. Use of aspirin in prior 7 days (i.e. implying resistance to aspirin’s effect)

7. Elevated serum troponin or CK-MB

Clinical studies have confirmed that a patient’s TIMI risk score predicts the likelihood of death or subsequent ischemic events, such that an early invasive strategy is recommended in patients with higher scores ($\geq 3$). If an early invasive approach is adopted, the patient should undergo angiography within 72 hours, or within 24 hours for patients at especially high risk.

Acute Treatment of STEMI

In contrast to UA and NSTEMI, the involved artery in STEMI is typically completely occluded. Thus, to limit myocardial damage, the major focus of acute management is to achieve very rapid reperfusion using either percutaneous revascularization or fibrinolytic drugs. These approaches reduce the extent of myocardial necrosis and greatly improve survival. To be effective, they must be undertaken as soon as possible; the earlier the intervention is given, the greater the amount of myocardium that can be saved.

Decisions about therapy must be made within minutes of a patient’s assessment, based on the history and ECG findings, often before serum markers of necrosis would be expected to rise.

In addition, as is the case in UA and NSTEMI, specific medications should be initiated promptly to prevent further thrombosis and to restore the balance between myocardial oxygen supply and demand. For example, antiplatelet therapy with aspirin decreases mortality rates and rates of reinfarction after STEMI. It should be administered immediately on presentation and continued daily thereafter. An anticoagulant is typically initiated to help maintain patency of the coronary vessel and is an important adjuvant to PCI and fibrinolytic regimens. In the absence of contraindications, an oral β-blocker should also be administered to achieve a heart rate of 50-60 bpm. Nitrate therapy, usually intravenous nitroglycerin, is also used to help control ischemic pain and also serves as a beneficial vasodilator in patients with heart failure or severe hypertension.

Primary PCI

The preferred method of reperfusion in acute STEMI is immediate cardiac catheterization and PCI of the lesion responsible for the infarction. This approach, termed primary PCI, is very effective at reestablishing coronary perfusion and, in clinical trials performed at highly experienced medical centers, has achieved optimal flow in the infarct-related artery in more than 95% of patients. The procedure was described in more details in Part 5.

In order to salvage as much myocardium as possible, the goal is that the time from first medical contact to PCI be less than 90 minutes. At medical centers without PCI availability, the decision to transfer a patient to a PCI-capable hospital or to treat with fibrinolytic therapy must be made rapidly. A delay in reperfusion leads to worse outcomes regardless of the mechanism chosen, and the longer the delay, the less benefit primary PCI has over fibrinolytic therapy. Generally, transfer to a PCI-capable hospital is recommended if the procedure can be performed within 120 minutes of first medical contact.

To reduce thrombotic complications, patients undergoing primary PCI receive a combination of medications. Aspirin and a P2Y12 receptor inhibitor (e.g., ticagrelor, prasugrel, or clopidogrel) are the antiplatelet agents typically administered prior to the procedure. A more potent GP IIb/ IIIa platelet inhibitor is also sometimes used. Anticoagulation therapy consists of either UFH or bivalirudin as the primary choices. Recent evidence shows that bivalirudin results in lower rates of bleeding in STEMI when compared to UFH plus a GP IIb/ IIIa inhibitor. However, it is also associated with a higher rate of acute stent thrombosis in this setting.

After primary PCI, aspirin is continued indefinitely. For patients who receive coronary stents during PCI, a prolonged course of a P2Y12 receptor inhibitor reduces the risk of ischemic complications and stent thrombosis.

Fibrinolytic Therapy

Primary PCI is preferred over fibrinolytic therapy in acute STEMI, as it leads to greater survival with lower rates of reinfarction. However, if PCI is not available or is likely to be delayed, fibrinolytic therapy is the alternative.

Currently used fibrinolytic agents include recombinant tissue–type plasminogen activator (alteplase, tPA), reteplase (rPA), and tenecteplase (TNK-tPA). These act by stimulating the natural fibrinolytic system, transforming the inactive precursor plasminogen into the active protease plasmin, which lyses fibrin clots. Although the intracoronary thrombus is the target, plasmin has poor substrate specificity and can degrade other proteins, including fibrin’s precursor fibrinogen. As a result, bleeding is the most common complication of these drugs.

Administration of fibrinolytic agents in the early hours of an acute STEMI restores blood flow in most (70-80%) cases and significantly reduces the extent of tissue damage, substantially increasing the survival rates.

The rapid initiation of fibrinolysis is crucial; patients who receive therapy within 2 hours of the onset of symptoms have half the mortality rate of those who receive it 6 hours after.

To prevent immediate re-occlusion after successful thrombolysis, anticoagulants (UFH or LMWHs) and antiplatelet therapy are administered.

For those treated with fibrinolytic therapy who do not demonstrate an adequate acute response, transfer to a hospital capable of performing a “rescue” PCI is recommended as soon as possible.

The major risk of thrombolysis is bleeding, thus contraindications to such therapy include situations in which necessary fibrin clots within the circulation would be jeopardized (e.g. active peptic ulcer disease, an underlying bleeding disorder, recent stroke, or patients recovering from recent surgery). Consequently, approximately 30% of patients may not be suitable candidates for thrombolysis.

Adjunctive Therapies

Angiotensin-converting enzyme (ACE) inhibitors limit adverse ventricular remodeling and reduce the incidence of heart failure, recurrent ischemic events, and mortality following an MI.

Cholesterol-lowering statins (statins) reduce mortality rates of patients with coronary artery disease. Clinical trials of patients with ACS have demonstrated that it is safe to begin statin therapy early during hospitalization and that a high-intensity statin regimen designed to reduce LDL levels by greater than 50% (ideally to <70 mg/ dL), provides greater protection against subsequent cardiovascular events and death than less intense regimens. Additional LDL lowering with the cholesterol absorption inhibitor ezetimibe after an ACS was recently shown to further reduce subsequent cardiovascular event rates.

Impaired ventricular contractility after MI can lead to heart failure. Patients with a left ventricular ejection fraction less than 40% and symptoms of heart failure after STEMI should be considered for therapy with an aldosterone antagonist (spironolactone or eplerenone) in addition to an ACE inhibitor and β-blocker. Aldosterone increases sodium reabsorption from the distal convoluted tubules of the nephron, contributing to fluid retention (an undesired effect in heart failure) and also promotes inflammation and myocardial fibrosis. Chronic administration of an aldosterone antagonist mitigates these effects and has been shown to decrease mortality following MI in patients with left ventricular dysfunction.

Complications

To identify patients at high risk for complications who may benefit from cardiac catheterization and revascularization, stress ECG testing is often performed (unless the patient has already undergone catheterization and corrective percutaneous revascularization for the presenting ACS). Patients with significantly abnormal results or those who demonstrate an early recurrence of angina are referred or cardiac catheterization.

Patients who have an LV ejection fraction $\leq 30\%$ post-MI are at high risk of sudden cardiac death and are candidates for prophylactic placement of an implantable defibrillator.

Recurrent ischemia

Post-infarction angina has been reported in 20-30% of patients following an MI. This rate has not been reduced by the use of fibrinolytic therapy, but it is lower in those who went primary PCI. Indicative of inadequate residual coronary blood flow, it is a poor prognostic sign and correlates with an increased risk of reinfarction. Such patients usually require urgent cardiac catheterization, often followed by revascularization by percutaneous techniques or coronary artery bypass surgery.

Arrhythmias

Arrhythmias occur frequently during acute MI and are a major source of mortality prior to hospital arrival. Fortunately, modern coronary care units are highly attuned to the detection and treatment of arrhythmias; thus, once a patient is hospitalized, arrhythmia-associated deaths are uncommon.

Mechanisms that contribute to arrhythmogenesis after MI include:

1. Anatomic interruption of blood flow to the electro-conductive system (e.g. SA node, AV node, and bundle branches)

2. Accumulation of toxic metabolites (e.g. cellular acidosis) and abnormal transcellular ion concentrations owing to membrane leaks.

3. Autonomic stimulation (sympathetic and parasympathetic).

4. Enhanced automaticity of surviving ventricular cells.

5. Reentrant circuits that loop around infarcted myocardium.

6. Administration of potentially arrhythmogenic drugs (e.g., dopamine)

Ventricular fibrillation is largely responsible for sudden cardiac death during the course of acute MI. Episodes that occur during the first 48 hours of MI are often related to transient electrical instability, and the long-term prognosis of survivors of such events is not adversely affected. However, ventricular fibrillation occurring later than 48 hours after an MI usually reflects severe LV dysfunction and is associated with high subsequent mortality rates.

Ventricular ectopic beats are common and usually not treated unless the beats become consecutive, multifocal, or frequent. Cardiac care unit personnel are proficient at arrhythmia detection and proper management should more malignant ventricular arrhythmias develop.

Supraventricular arrhythmias are also common in acute MI. Sinus bradycardia results from either excessive vagal stimulation or SA ischemia, usually in the setting of an inferior wall MI. Sinus tachycardia occurs frequently and may result from pain, anxiety, heart failure, drug administration, or intravascular volume depletion (baroreceptor reflex). Because sinus tachycardia increases myocardial oxygen demand and could exacerbate ischemia, identifying and treating its cause are important. Atrial fibrillation may also result from atrial ischemia or atrial distention secondary to LV failure.

Conduction blocks (AV nodal block and bundle branch blocks) develop commonly in acute MI. They may result from ischemia or necrosis of conduction tracts, or in the case of AV blocks, they may develop because of increased vagal tone. Vagal activity may be increased because of stimulation of afferent fibers by the inflamed myocardium or as a result of generalized autonomic activation in association with the discomfort.

Myocardial Dysfunction

Acute cardiac ischemia results in impaired ventricular contractility (systolic dysfunction) and increased myocardial stiffness (diastolic dysfunction), both of which may lead to symptoms of heart failure. Signs and symptoms of such decompensation include dyspnea, pulmonary rales, and a third heart sound (S3). Treatment consists of standard heart failure therapy, which typically includes diuretics for volume overload, ACE inhibitor and β-blocker therapies for long-term mortality. As noted earlier, for patients with an ejection fraction less than 40%, an aldosterone antagonist should be considered.

Cardiogenic shock can also occur, a condition in which severely decreased cardiac output and hypotension causing inadequate perfusion of peripheral tissues develops when more than 40% of the LV mass has infarcted. It may also follow certain severe mechanical complications of MI. Cardiogenic shock starts a positive feedback cycle as hypotension leads to decreased coronary perfusion, which exacerbates ischemic damage. Cardiogenic shock occurs in up to 10% of patients after MI, and the mortality rate is greater than 70%. Early cardiac catheterization and revascularization can improve the prognosis.

Patients in cardiogenic shock require IV inotropic agents (e.g. dobutamine) to increase cardiac output and, once the blood pressure has improved, arterial vasodilators to reduce the peripheral resistance the LV pushes against. Patients may also be stabilized by the placement of an intra-aortic balloon pump. Inserted through a femoral artery, the pump consists of an inflatable chamber that expands during diastole to increase intra-aortic pressure, increasing perfusion of the coronary arteries. During systole, it deflates to create a “vacuum” that serves to reduce the LV, improving cardiac output and peripheral tissue perfusion. If more extensive and prolonged hemodynamic support is required, a percutaneous left ventricular assist device (LVAD) can be placed through a femoral vessel canula. A motor then pumps oxygenated blood from the LA or the LV (depending on the model) to the aorta, bypassing or “assisting” the LV.

Right Ventricular Infarction

Approximately one third of patients with infarction of the LV inferior wall also develop necrosis of portions of the right ventricle, because the same coronary artery (usually the RCA) perfuses both regions in most individuals.

The resulting systolic and diastolic failure of the right ventricle leads to signs of right-sided heart failure out of proportion to signs of left-sided failure. In addition, profound hypotension may result when the right ventricular dysfunction impairs blood flow through the lungs, leading to the left ventricle becoming underfilled. In this setting, IV volume infusion serves to correct hypotension.

Ventricular wall rupture

Ischemic necrosis and rupture of papillary muscles may be rapidly fatal because of acute severe mitral regurgitation, as the valve leaflets lose their anchoring attachments. Partial rupture, with more moderate regurgitation, is not immediately lethal but may result in symptoms of heart failure. Because of the nature of its blood supply, the posteromedial LV papillary muscle is most susceptible to infarction.

An infrequent but deadly complication, rupture of the LV free wall through a tear in the necrotic myocardium may occur within the first 2 weeks following MI. This is more common among women and patients with a history of hypertension. Hemorrhage into the pericardial space following the LV free wall rupture results in rapid cardiac tamponade, severely restricting ventricular filling. In such cases, survival is rare.

On occasion, a ventricular pseudoaneurysm results if rupture of the wall is incomplete and held in check by thrombus formation that “plugs” the hole in the myocardium. This is a very urgent situation as subsequent complete rupture and cardiac tamponade could follow. If detected (usually via imaging like echocardiography), surgical repair may prevent an otherwise disastrous outcome.

Ventricular septal wall rupture is analogous to LV free wall rupture, but the abnormal flow of blood is not directed across into the pericardium. Rather, blood is shunted from the left ventricle to the right ventricle, usually precipitating congestive heart failure because of subsequent volume overload of the pulmonary circulation. This condition mimics ventricular septal defects (VSDs), and a loud harsh holosystolic murmur at the left sternal border is usually heard.

Although each results in a systolic murmur, ventricular septal rupture can be differentiated from acute mitral regurgitation by the location of the murmur, by Doppler echocardiography, or by measuring the O2 saturation of blood in the right-sided heart chambers through a venous catheter. The O2 content in the right ventricle is abnormally higher than that in the right atrium if there is shunting of oxygenated blood from the left ventricle across the septal defect.

True Ventricular Aneurysm

A late complication of MI is a true ventricular aneurysm, which may present weeks to months after the acute infarction. It develops as the ventricular wall is weakened, but not perforated, by the granulation tissue replacing the necrotic tissue. It results in a localized outward bulge (dyskinesis) when the residual viable heart muscle contracts. Unlike pseudoaneurysms, a true aneurysm does not involve communication between the LV cavity and the pericardium, so that rupture and tamponade do not develop.

Potential complications include:

• Thrombus formation within the bulging region (due to stagnant blood flow), serving as a source of emboli to peripheral organs.

• Ventricular arrhythmias associated with the stretched myofibers.

• Heart failure as some of the LV stroke volume is “wasted” by filling the aneurysm cavity during systole.

Clues to the presence o an LV aneurysm include persistent ST-segment elevations on ECG weeks after an acute STEMI and a bulge at the LV border on chest radiography. Definitive diagnosis requires echocardiography or other imaging modalities.

Pericarditis

Acute pericarditis may occur in the early post-MI period as inflammation extends from the myocardium to the adjacent pericardium. Sharp pain, fever, and a pericardial friction rub are typically present in this situation and help distinguish pericarditis from the discomfort of recurrent myocardial ischemia.

The frequency of MI-associated pericarditis has declined since the introduction of acute reperfusion strategies, because those approaches limit the extent of myocardial damage and inflammation.

Dressler syndrome is now a rare form of post-MI pericarditis. The cause is unclear, but an immune process directed against damaged myocardial tissue is suspected to play a role. The syndrome presents with symptoms of pericarditis, typically accompanied by leukocytosis; elevated ESR; and a pericardial effusion.

The symptoms usually promptly respond to aspirin therapy or other nonsteroidal anti-inflammatory drugs. Anticoagulants are relatively contraindicated in MI complicated by pericarditis to avoid hemorrhage from the inflamed pericardial lining.

See also

• Part 5: Ischemic Heart Disease
• Part 7: Valvular Heart Disease

References

• Young, J. L., & Libby, P. (2016). Acute Coronary Syndromes. In L. S. Lilly (Ed.), Pathophysiology of heart disease: A collaborative project of medical students and faculty (6th ed., pp. 162–192). Wolters Kluwer.
• Klatt, E. C. (n.d.). Myocardial Infarction Tutorial. WebPath: The Internet Pathology Laboratory for Medical Education. University of Utah Spencer S. Eccles Health Sciences Library. Retrieved July 23, 2026, from https://webpath.med.utah.edu/TUTORIAL/MYOCARD/MYOCARD.html

Additional Reading

• Giugliano RP, Braunwald E. The year in non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol. 2014;63:201–214.
• Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e426.
• Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/ AHA Focused update of the guideline for the management of patients with unstable angina/ non-ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2012;126:875–910.
• Mega JL, Simon T, Collet JP, et al. Reduced function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominately for PCI: a meta-analysis. JAMA. 2010;304:1821–1830.
• O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/ AHA Guideline for the management of ST-elevation myocardial infarction: Executive summary: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:529–555.
• Stone GW, Clayton T, Deliargyris EN, et al. Reduction in cardiac mortality with bivalirudin in patients with and without major bleeding: The HORIZONS-AMI trial (harmonizing outcomes with revascularization and stents in acute myocardial infarction). J Am Coll Cardiol. 2014;63:15–20.
• Cavender MA and Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet. 2014;384:599-606.
• Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report on the American College of Cardiology/ American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;63:2889–934