Acute Myocardial Infarction

The diagnosis of AMI relies on criteria established by a committee grouping the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA), and the World Heart Federation (WHF). Indeed, according to the Third Universal Definition, AMI is a clinical event consequent to the death of cardiac myocytes (myocardial necrosis) that is caused by ischemia (as opposed to other etiologies) (7). According to this definition, spontaneous myocardial infarction—also known as type 1—occurs in cases of detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin) with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following: symptoms of ischemia, ischemic ECG changes, identification of an intracoronary thrombus by angiography, or imaging evidence of new loss of viable myocardium or a new regional wall motion abnormality.

ECG findings consistent with STEMI are: new ST elevation at the J point in two anatomically contiguous leads using the following diagnostic thresholds: 0.1 mV (1 mm) or more in all leads other than V2–V3. In V2-V3 leads the following diagnostic thresholds apply: 0.2 mV (2 mm) or more in men 40 years or older; 0.25 mV (2.5 mm) or more in men under 40 years; or 0.15 mV (1.5 mm) or more in women.

Findings consistent with NSTEMI are: new horizontal or down-sloping ST depression 0.05 mV (0.5 mm) or more in two anatomically contiguous leads and/or T inversion 0.1 mV (1 mm) or more in two anatomically contiguous leads with prominent R wave or R/S ratio greater than 1.

The other types of myocardial infarction identified according to the Third Universal Definition are as follows: type 2, myocardial infarction due to ischemic blood supply/demand imbalance; type 3, cardiac death presumed to be caused by myocardial infarction when markers of myocardial injury are unavailable; type 4a, myocardial infarction associated with percutaneous coronary intervention (arbitrary defined by elevation of biomarker values higher than five times 99th percentile URL in patients with normal baseline values or a rise of values over 20% if the baseline values are elevated but stable or falling); type 4b, myocardial infarction related to stent thrombosis; and type 5, myocardial infarction associated to coronary artery bypass grafting (arbitrary defined by elevation of biomarker values over 10 times the 99th percentile URL in patients with normal baseline values) (7).

Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy starts abruptly and unpredictably, with symptoms of chest pain and, often, shortness of breath, usually triggered by an emotionally or physically stressful event (stress cardiomyopathy), especially in postmenopausal women. Typically, ECG changes mimic an anterior wall myocardial infarction whereas coronary arteries lack significant obstructions. During the evaluation of the patient, generally a bulging out of the left ventricular apex is found associated with preserved function of the bases. This apical ballooning is the hallmark of the syndrome that has been termed Takotsubo after a resemblance with the traditional Japanese octopus pot (8). For the final diagnosis, coronary angiography is needed.

Pericarditis

Typically, in this disorder, chest pain changes with the person’s position. The physical examination may reveal a pericardial friction rub, and ECG abnormalities include diffuse ST-segment elevation, PR depression, and peaked T waves. Generally, ECG signs are out of proportion to the clinical scenario; an ECG clue of the diagnosis of pericarditis is that ST-segment elevation is often concave whereas it is typically convex in STEMI. Also, reciprocal ST depression does not occur in pericarditis. Markers of myocardial injury may be elevated when the inflammatory process spreads toward the contiguous myocardium (epimyocarditis). Echocardiography is useful to evaluate pericardial effusion—which can, however, occur in AMI—and in assessing left ventricle wall motion, which is typically normal in pericarditis despite persisting ongoing pain and electrocardiographic abnormalities.

Myocarditis

Symptoms and ECG findings, frequently, are similar to those of AMI. Physical examination and echocardiography may point toward left ventricle dysfunction. Clinical history will generally reveal insidious onset and recent viral syndrome. Frequently coronary angiography is needed to rule out coronary artery disease.

Acute Aortic Dissection

Sharp, tearing chest pain radiating through the chest to the back is the typical presentation of aortic dissection. Typically, the maximal intensity of pain is reached immediately. Pulse and/or blood pressure often generally diminished in the left arm and/or in the legs. Proximal extension of the dissection to the coronary arteries can result in compression of the proximal coronary arteries and AMI. Chest radiography may reveal an enlarged mediastinum and echocardiography may show a dissection flap in the proximal ascending aorta; definitive diagnosis is obtained by computed tomography.

Pulmonary Embolism

Tachycardia and tachypnea associated with diffuse chest pain but without evidence of pulmonary edema suggests pulmonary embolism. Cough may be present. Echocardiography helps to rule out left ventricle wall motion abnormalities and identify right ventricular strain (enlargement, wall motion abnormalities, tricuspid regurgitation). The most frequent ECG finding is sinus tachycardia with nonspecific ST-segment and T-wave changes; the S₁Q₃T₃ pattern (a large S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III) is classic, although rarely seen. Final diagnosis is achieved with ventilation–perfusion lung scan, pulmonary angiogram, or with the computed tomographic angiography.

Pneumothorax

Pain is usually sharp, sudden, and accompanied by dyspnea. Pneumothorax can also have a significant impact on oxygenation and hemodynamics. Auscultation and percussion of the chest often reveal decreased breath sounds and hyperresonance of the affected side. Tracheal deviation, jugular venous distention, hypotension, and shock are indicators of an immediate life-threatening process (tension pneumothorax). Chest radiographs are usually diagnostic when the lung parenchyma is normal, whereas in patients with severe underlying pulmonary disease, a computed tomography scan of the chest often is necessary to make the diagnosis.

Esophageal Disorders

Gastroesophageal reflux disease (GERD), esophageal motility disorders, and esophageal hyperalgesia can cause chest pain very similar to cardiac ischemic pain. Notably, esophageal pain is frequently relieved with nitroglycerin, which is also frequently administered to relieve myocardial ischemic pain. Moreover, both disorders can coexist, thus complicating the diagnosis. Workup for coronary artery disease should always be completed before attributing the pain to GERD. Characteristics suggestive of an esophageal origin of chest pain are postprandial symptoms, relief with antacids or with standing, and lack of pain radiation.

Less obvious causes of chest pain related to esophageal injury include mucosal damage by ingested pills. Occasionally, nasogastric tubes have been found to be the culprit of significant esophageal trauma with resultant chest pain. Moreover, acute increases in intra-abdominal pressure have been associated with esophageal wall rents and rupture. The presence of subcutaneous emphysema, pleural effusion, or mediastinal air on chest radiograph is suggestive of esophageal perforation.

Acute Cholecystitis

This disorder can sometimes mimic the symptoms and ECG findings of inferior wall myocardial infarction. Tenderness in the right upper abdominal quadrant, fever, and elevated leukocyte count favor cholecystitis.

Costochondritis

Inflammation of the costochondral joints frequently results in chest wall pain. This pain is exacerbated by applying pressure over the affected area, by deep breathing, or by coughing. Often, patients can point to the exact area of inflammation.

Tietze syndrome is similar to costochondritis but is differentiated by notable swelling of the costal cartilage that is commonly palpable on examination.

Risk Assessment

Risk stratification using clinical and laboratory markers allows for rapid estimation of the risk of an adverse outcome and provides optimal guidance of treatment to prevent both ischemic and bleeding events. Evolving risk assessment can similarly be used to determine the most appropriate level of care and monitoring.

Killip Classification. This is not a rigorous risk score, but a very rapid and effective system of risk assessment of patients with myocardial infarction. Class I includes individual with no clinical signs of heart failure, Class II includes those with rales or crackles in the lungs, a third heart sound, and elevated jugular venous pressure, Class III are patients with frank, acute pulmonary edema, and Class IV are those with cardiogenic shock or severe hypotension.

Thrombolysis in Myocardial Infarction Risk Scores. The thrombolysis in myocardial infarction (TIMI) risk score is a well-validated scoring system used to predict the 14-day risk of death, myocardial infarction, or urgent revascularization in patients with NSTEMI (9). It is composed of seven independent predictors: age, cardiovascular risk factors, previous coronary artery disease, aspirin use within the prior week, two or more angina episodes in the prior 24 hours, ST-segment deviation greater than 0.5 mm, and elevation of markers of myocardial injury.

A TIMI risk score predicting 30-day adverse events in patients with STEMI has been developed as well, and includes different variables: Killip class, age, cardiovascular risk factors, low systolic blood pressure, high heart rate, low weight, anterior ST elevation or left bundle branch block, time to treatment longer than 4 hours (10). In both cases, the probability of an adverse event proportionally rises with the TIMI risk score.

Global Registry of Acute Coronary Events Score. The Global Registry of Acute Coronary Events (GRACE) score was developed from an international registry with a population of patients across the entire spectrum of ACS (11). It is composed of the following items: age, heart rate, systolic blood pressure, serum creatinine, Killip class, cardiac arrest at admission, elevation of markers of myocardial injury, ST-segment deviation. Patients with GRACE score over 140 have high risk of in-hospital mortality, whereas values between 109 and 140 identify those with an intermediate risk.

Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Bleeding Score. The CRUSADE score has relatively high accuracy for estimating bleeding risk by incorporating admission and treatment variables: baseline hematocrit, creatinine clearance, heart rate, gender, signs of heart failure at presentation, prior vascular disease, diabetes mellitus, systolic blood pressure (12). The risk of bleeding increases progressively with the CRUSADE score.

Oxygen

Supplemental oxygen should be administered to all patients whose saturation is over 90% or in respiratory distress. In patients with normal oxygen saturation, supplemental oxygen may be harmful and is not recommended (13).

Analgesics

Effective analgesia is important to reduce sympathetic stimulation caused by pain and anxiety, thereby decreasing cardiac workload and risks associated with excess catecholamines. Opioids are particularly helpful: Morphine sulfate (2–5 mg IV, every 10–30 minutes) is a very effective analgesic and has additional venodilatory effects that may reduce preload, lower the end-diastolic pressure, and improve hemodynamics. Moreover, morphine has been suggested to help with reducing reperfusion injury and myocardial preconditioning (an increased capacity of myocardium to resist to the ischemic insult) (14). Fentanyl (25–50 µg IV, every 5–30 minutes) is another effective analgesic drug. Care must be taken to avoid respiratory depression with cumulative doses of opioid. Moreover, a retrospective study showed that morphine use is associated with a slight increase of death in patients with NSTEMI (15), probably because of an interference with the antiplatelet effect of P2Y₁₂ receptors blockers (16).

Nitroglycerin

Nitroglycerin acts by reducing preload through venodilation and afterload by arteriolar dilation, promoting coronary vasodilation, relieving coronary vasospasm or vasoconstriction, and by putative effects upon platelet aggregability. These effects act synergically to improve myocardial blood flow and relieve ischemia. Nitroglycerin may be administered sublingually with close monitoring of hemodynamics, and additional doses may be given as long as they are tolerated hemodynamically. For more accurate control, IV nitroglycerin may be initiated and titrated until symptoms are controlled. Extreme care should also be taken before giving nitrates to patients with profound hemodynamic compromise such as those with right ventricle infarction and those with severe aortic stenosis. In this setting, patients are dependent upon preload to maintain cardiac output, and nitrates can cause severe hypotension. In addition, nitroglycerin is contraindicated in patients who have taken a phosphodiesterase inhibitor (sildenafil, vardenafil, tadalafil) for erectile dysfunction or pulmonary hypertension within the previous 24 hours (or perhaps as long as 36 hours with tadalafil).

β-Blockers

β-Blockers act by reducing heart rate, blood pressure, and left ventricle contractility, thereby reducing myocardial oxygen demand. Additionally the reduction of heart rate increases diastolic time resulting in improved coronary blood flow and oxygen supply. The main contraindications include low output state, high risk for cardiogenic shock, bradycardia, atrioventricular conduction defects, and reactive airway disease. Some β-blockers have β₁-selective properties that minimize the risk of bronchospasm (e.g., metoprolol) and/or membrane-stabilizing activity, a kind of type I antidysrhythmic effect, which is valuable for the prevention of ischemia-induced ventricular dysrhythmias (e.g., propranolol). In a polled analysis on 2,537 patients enrolled in primary angioplasty trials, those who received β-blocker therapy before primary angioplasty, compared to those who did not, had lower adjusted in-hospital mortality (OR 0.41, 95% CI 0.20–0.84) and nonsignificantly lower 1-year mortality (OR 0.72, 95% CI 0.47–1.08). Moreover, in a recent study on 270 patients with anterior STEMI undergoing primary percutaneous coronary intervention, early intravenous metoprolol (5 mg IV, every 2 minutes up to three times) before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours (17).

Calcium Channel Antagonists

These agents are effective antianginal drugs but, given their adverse effects and the mortality benefit of β-blockers, they should be considered for only second-line therapy, with the notable exception of ACS in the setting of variant angina where they represent the mainstay of therapy.

Aspirin

Aspirin acts by irreversibly inhibiting cyclooxygenase-1, thus reducing the generation of thromboxane A_2, a potent vasoconstrictor and mediator of platelet aggregation. In an analysis of pooled data from nearly 200,000 patients, aspirin produced a 30% reduction of the combined end point of subsequent nonfatal myocardial infarction, nonfatal stroke, or vascular death in patients with AMI (18). The study also outlined that there was no significant difference in efficacy between lower and higher daily doses and that the addition of a second antiplatelet agent significantly improved the combined end point. Unless there are specific contraindications, such as intolerance or allergy, active bleeding or high hemorrhagic risk, aspirin should be given to all patients with ACS as soon as possible and continued indefinitely. Low-dose aspirin (75–100 mg daily) should be preferred due to increased risk of gastrointestinal bleeding in patients on higher dose (300–325 mg daily) (19).

Clopidogrel

Clopidogrel blocks the binding of adenosine diphosphate (ADP) to the platelet receptor P2Y₁₂, thereby inhibiting activation of the glycoprotein (GP) IIb/IIIa complex and platelet aggregation. In the CURE trial, the addition of clopidogrel to aspirin in patients with NSTEMI has shown to significantly reduce the risk of myocardial infarction, stroke, or cardiovascular death both in patients treated medically and in those undergoing percutaneous coronary intervention (20,21), thus establishing a sound basis for dual antiplatelet therapy in ACS.

Clopidogrel should be administered as an initial loading dose of 300 or 600 mg followed by 75 mg daily. A 600-mg loading dose is indicated in patients undergoing urgent percutaneous coronary intervention as it achieves platelet inhibition more rapidly (22). Contraindications to clopidogrel are the same as for aspirin. Clopidogrel is a prodrug and has to be converted to its active form by the CYP2C19 isoform of the hepatic cytochrome P450. Genetic polymorphisms may be present, with certain patients having reduced CYP2C19 function and consequently lower plasma levels of the active metabolite. In addition, several drugs may interfere with CYP2C19 function. Tests for genetic polymorphisms and clinical assays for assessment of platelet inhibition are currently available although their role in clinical practice is uncertain (23).

Prasugrel

Prasugrel has a more rapid onset of action and is able to achieve higher degrees of platelet inhibition than clopidogrel. Furthermore, prasugrel does not require conversion by CYP2C19 and effectively suppresses platelet activity in a larger numbers of patients than clopidogrel. Prasugrel was compared to clopidogrel in the TRITON-TIMI 38 trial of 13,608 moderate- to high-risk ACS patients undergoing percutaneous coronary intervention, including 3,534 with STEMI (24). Prasugrel was given with a loading dose of 60 mg and maintenance dose of 10 mg/day, while clopidogrel was given with a 300-mg loading dose and a 75-mg/day maintenance dose. For patients with NSTEMI, the coronary anatomy had to be known before randomization (clopidogrel and prasugrel were given after coronary angiography). At 15-month follow-up, the primary efficacy end point (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred significantly less often in patients treated with prasugrel (HR 0.81, 95% CI 0.73–0.90). The safety end point of a major bleeding event not associated with coronary artery bypass graft surgery occurred significantly more often in patients treated with prasugrel (HR 1.32, 95% CI 1.03–1.68). Post hoc analysis identified three predictors of bleeding with prasugrel: a history of stroke or transient ischemic attack, at least 75 years of age, and body weight no more than 60 kg.

In the TRILOGY ACS trial, prasugrel was compared to clopidogrel in 9,326 patients treated with aspirin with ACS in whom percutaneous coronary intervention was not performed (25). Prasugrel was given with a loading dose of 30 mg and a maintenance dose of 10 mg/day in patients under 75 years or 5 mg/day for those at least 75 years or weighed no more than 60 kg; clopidogrel was given with a 300-mg loading dose and a 75-mg/day maintenance dose. There was no statistically significant difference in the rate of the primary end point in the 7,243 patients under 75 years between those who received prasugrel and those who received clopidogrel (HR 0.91, 95% CI 0.79–1.05). The rates of severe and intracranial bleeding were not statistically significantly different. In a separate analysis of the 2,083 individuals at least 75 years of age, the risks of the primary end point and TIMI major bleeding increased progressively with age (26).

Ticagrelor

Ticagrelor differs from the thienopyridines (clopidogrel and prasugrel) in that it binds reversibly rather than irreversibly to P2Y₁₂ platelet receptor, is a direct drug and has a more rapid onset of action than clopidogrel. It belongs to a new chemical class of antiplatelet agents, the cyclopentyltriazolopyrimidines. Similar to prasugrel, treatment with ticagrelor leads to more intense platelet inhibition than clopidogrel. The efficacy and safety of ticagrelor were evaluated in the PLATO trial in which 18,624 patients with ACS were randomly assigned to either ticagrelor (180-mg loading dose followed by 90 mg twice daily) or clopidogrel (300–600 mg loading dose followed by 75 mg daily). In this trial, 38% of patients had STEMI with intended percutaneous coronary intervention. Treatment was started as soon as possible after hospital admission (27,28). At 12 months, the composite primary end point (first event of death from vascular causes, myocardial infarction, or stroke) occurred significantly less often in patients receiving ticagrelor (HR 0.84, 95% CI 0.77–0.92). There was no significant difference in the rates of major bleeding between the ticagrelor and clopidogrel groups (11.6% vs. 11.2%). The primary outcome was similar to the entire study population in three prespecified subgroups: patients with chronic kidney disease (HR 0.77, 95% CI 0.65–0.90) (29), patients who underwent coronary artery bypass graft surgery and were receiving study drug treatment less than 7 days before surgery (HR 0.84, 95% CI 0.60–1.16) (30), and patients with planned noninvasive management (12.0% vs. 14.3%; HR 0.85, 95% CI 0.73–1.00) (31). Of note, another prespecified subgroup analysis found a potentially clinically important interaction between treatment and region: the composite primary end point occurred more often with ticagrelor for patients enrolled in the United States (32). Among 37 baseline and postrandomization factors, only aspirin dose explained a substantial fraction (80%–100%) of the interaction (p = 0.00006). Therefore, aspirin should be administered only at a daily dose of no more than 100 mg when used in conjunction with ticagrelor.

Glycoprotein IIb/IIIa Inhibitors

GP IIb/IIIa inhibitors—abciximab, eptifibatide, and tirofiban—act on the final common pathway of platelet aggregation by preventing fibrinogen-mediated platelet cross-linking via GP IIb/IIIa receptors. Conclusions from early trials are of limited applicability to patients treated today with the routine use of P2Y₁₂ receptor blockers and percutaneous coronary intervention, however these agents may still be considered in high-risk patients (especially high troponin increase) as adjunctive antiplatelet therapy (33). Two large trials of similar but not identical design did not demonstrate a significant benefit of early compared with delayed use of GP IIb/IIIa inhibitor, even in high-risk patients with NSTEMI who are scheduled to undergo early percutaneous coronary intervention (34,35). Moreover, the early use of GP IIb/IIIa use was associated with a significantly increased risk of bleeding. In the ISAR-REACT 4 trial, which compared bivalirudin to heparin plus GP IIb/IIIa inhibitor in STEMI patients receiving aspirin and clopidogrel, the rate of death, recurrent MI, or urgent target-vessel revascularization was similar between the two groups, but bleeding occurred significantly more often in those receiving heparin plus GP IIb/IIIa inhibitor (36). In STEMI patients, the HEAT-PPCI trial called into question the need for the routine use of GP IIb/IIIa inhibitor in patients receiving heparin plus a potent oral antiplatelet agent such as prasugrel or ticagrelor (37).

Gp IIb/IIIa inhibitors can be associated with thrombocytopenia, which is sudden and severe. Therefore, the platelet count should be monitored frequently in patients receiving GP IIb/IIIa inhibitors. If the platelet count falls below 100,000 cells/µL, or to less than 25% of its pretreatment level, the possibility of pseudothrombocytopenia, a laboratory artifact of no clinical concern, should be eliminated by examination of a blood smear for the presence of platelet clumping. The platelet count should be repeated using a tube containing sodium citrate and heparin rather than EDTA as a preservative, if platelet clumping is observed. If pseudothrombocytopenia is ruled out by the above procedures, the GP IIb/IIIa inhibitor should be discontinued.

Heparins

In combination with aspirin, either unfractioned heparin or low–molecular-weight heparin has been shown to reduce the risk of death or myocardial infarction as compared to aspirin alone (38). Trials comparing a low–molecular-weight heparin, usually enoxaparin, to unfractionated heparin in ACS found that enoxaparin leads to better outcomes in patients managed with a conservative strategy (39,40). On the other hand, for patients undergoing an early invasive strategy, unfractioned heparin may be preferable in patients at high bleeding risk due to the increased risk of bleeding seen with enoxaparin (41). There is no evidence to support the use of other low–molecular-weight heparin in preference to enoxaparin. Indeed, these drugs appear to have equivalent efficacy to unfractioned heparin, may be less effective than enoxaparin, and may be associated with higher rates of major bleeding.

Intravenous unfractioned heparin is best administered on a weight basis starting with a bolus of 60 units/kg followed by continuous infusion at a rate of 12 units/kg/hr. Heparin requirement are however variables and optimal therapeutic benefit with minimization of bleeding is best accomplished with activated partial thromboplastin time (aPTT) maintenance at 50 to 70 seconds.

Like unfractioned heparin, enoxaparin inactivates factor Xa, but has a lesser effect on thrombin. Enoxaparin has several advantages over unfractioned heparin, including a more predictable anticoagulant effect, a reduced likelihood of inducing immune-mediated thrombocytopenia, subcutaneous administration, and does not require laboratory monitoring. On the other hand, reversal with protamine sulfate is possible for unfractioned heparin but not for enoxaparin. All heparins require dose adjustment in patients with renal insufficiency.

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