Definition and Epidemiology
Sustained myocardial ischemia, regardless of its cause, can result in myocardial necrosis, which underlies the clinical syndrome of MI. MI represents a spectrum of myocardial necrosis, from relatively small amounts of muscle in the case of demand ischemia, to more extensive subendocardial MI that characterizes NSTEMI, to typically large trans- mural MIs commonly manifesting as STEMI. The current accepted definition of acute MI accounts for clinical setting and mechanism.
STEMI represents the range of large MIs that are almost always caused by total occlusion of an epicardial coronary artery resulting in exten- sive transmural myonecrosis (Fig. 8.8). In contrast, NSTEMI reflects subtotal coronary occlusion leading to subendocardial myonecrosis.
Whereas both NSTEMI and STEMI are life-threatening, their different underlying mechanisms mandate different therapeutic strategies and affect the urgency with which they are applied.
One half of all deaths in the United States and developed countries are related to cardiovascular disease. In the United States, there are over one million nonfatal or fatal MIs each year. CAD plays a role in 360,000 deaths each year, and 110,000 deaths are caused by acute MI.
One half of patients with acute MI at presentation die within 1 hour of onset, before therapy can be instituted. Of the 5 million patients who come to emergency rooms with chest pain, 1.3 million are admitted to hospital with ACS. In this group of patients, the presence of ST ele- vation on ECG or an LBBB indicates the diagnosis of STEMI and the need for prompt intervention to open an occluded coronary artery.
STEMI accounts for 30% of all MIs, but this mechanism of MI is asso- ciated with the highest immediate mortality risk, prompting the need for urgent therapeutic intervention.
Pathology
Lipid-rich coronary plaques are subject to inflammation incited by the response to oxidation of LDL-cholesterol within the plaque. A sequence of inflammatory events leads to macrophage accumulation and the elaboration of metalloproteinases that degrade collagen in the fibrous cap of the plaque. Thinning of the fibrous cap makes the plaque vulnerable to rupture and exposure of blood to thrombogenic stim- uli, resulting in platelet aggregation and activation, thrombin gener- ation, and the evolution of fibrin-based thrombus. If the occlusion is total, transmural myocardial ischemia and necrosis ensue and the ECG demonstrates ST elevation. In contrast, partially occlusive thrombus can result in unstable angina or NSTEMI (subendocardial MI). The presence of coronary collaterals can limit the extent of ischemia and necrosis in either scenario. Both STEMI and NSTEMI can set the stage for arrhythmias and LV dysfunction. Whereas coronary thrombosis is the cause of most MIs, there are patients who develop MI related to coronary embolization, coronary vasospasm, vasculitis, coronary anomalies, dissection of the aorta or a coronary artery, or trauma.
One key feature of the pathology of MI is its time-dependent nature. Experimental and clinical studies have documented that cor- onary occlusion leads to ischemia and myonecrosis in a wavefront manner, from endocardium to epicardium. Restoration of flow to the vessel within 6 hours after occlusion is associated with limitation of infarct size and a favorable effect on mortality risk. The principle of time dependency of MI drives the need to aggressively reperfuse occluded coronary arteries, and this is the cornerstone of contempo- rary therapy for STEMI.
Clinical Presentation
Patients with acute MI usually have a combination of chest discomfort, ECG changes (ST elevation in contiguous leads or LBBB), and eleva- tion in biomarkers such as CK-MB and troponin. The high sensitivity and high specificity of troponin have made it the preferred biomarker in the diagnosis of MI. The chest discomfort associated with MI is sim- ilar to angina pectoris but more severe in nature. It is usually described as substernal pressure, tightness, or fullness. Patients may have symp- toms of discomfort that radiate to the neck, jaw, one or both arms, or the back. Not uncommonly, patients with symptoms of acute MI also experience nausea, vomiting, diaphoresis, apprehension, dyspnea, or weakness. In contrast to angina pectoris associated with stable CAD, acute MI symptoms last longer than 20 to 30 minutes (up to hours).
Occasionally, patients only have symptoms in the non-chest areas usually associated with radiation. Up to 20% of patients, par- ticularly the elderly and diabetics, do not have typical chest discom- fort at presentation. The index of suspicion for acute MI should be high in these groups if the patient exhibits profound weakness, acute dyspnea or pulmonary edema, nausea, vomiting, ventricular arrhyth- mias, or hypotension. The differential diagnosis for patients with chest
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discomfort suspicious for acute MI includes aortic dissection, pulmo- nary embolism, chest wall pain, esophageal reflux, acute pericarditis, pleuritis, and panic attacks. Given the life-threatening nature of aortic dissection and pulmonary embolism, these diagnoses should always be paramount, along with acute MI, in patients presenting with chest discomfort.
Physical examination. A comprehensive examination should be undertaken if acute MI is suspected. Attention must be paid to vital signs, because patients may be either hypertensive or hypotensive during the course of an MI. In some cases, such as inferior MI, profound bradycardia may be present. Auscultation of the heart may reveal an S4. In the case of a large MI, the patient may have symptoms and signs of heart failure such as dyspnea, rales, elevated central venous pressure, and an S3. Severe heart failure may lead to cardiogenic shock with hypotension and vasoconstriction causing the extremities to be cool to touch. Patients with acute MI are also subject to mechanical problems such as mitral regurgitation due to papillary muscle dysfunction.
Electrocardiogram. The ECG is an important tool in the diagnosis of acute MI. ST elevation of 1 mm or greater in contiguous leads is seen in most patients with acute MI. The initial ECG may be nondiagnostic, so it is important to obtain serial tracings no more than 20 minutes apart to detect the evolutionary changes characteristic of STEMI. The first stage of ECG presentation is ST elevation that subtends the region of the heart affected by transmural ischemia. ST depression may be present in opposing leads, and these are termed reciprocal changes (see Chapter 64, “ST Elevation Acute Myocardial Infarction and Complications of Myocardial Infarction,” in Goldman-Cecil Medicine, 26th Edition). The presence of reciprocal changes may indicate a larger and more threatening MI. As the MI progresses, ST elevation gives way to T wave inversion. Varying degrees of resolution of ST and T wave changes occur over time, but patients with transmural MI develop pathologic Q waves in the leads subtending the infarcted muscle. Other causes of ST elevation include pericarditis and a chronic repolarization finding of “early repolarization.” The presence of either cause of ST elevation can confound the early ECG diagnosis of acute MI.
Approximately 30% of acute MIs originate from the circumflex cor- onary artery on the posterior wall of the heart. This type of MI appears on the ECG as precordial ST depression. The presence of precordial ST depression should raise suspicion of the presence of “true poste- rior MI,” and additional leads placed through the axilla to the back may reveal the presence of posterior ST elevation. Echocardiography
demonstrating posterior hypokinesis is also useful in discriminating true posterior MI. Acute inferior MI due to occlusion of the right cor- onary artery can also be associated with right ventricular infarction if the right coronary artery’s acute marginal branch is compromised.
Right ventricular infarction can lead to some challenging management issues, and its diagnosis is aided by the use of right precordial leads to detect ST elevation.
LBBB or ventricular pacing can mask ST elevation due to acute MI.
Patients with clinical features of acute MI who have an LBBB (partic- ularly a new LBBB) should be presumed to have STEMI and treated appropriately. Right bundle branch block (RBBB) does not mask the ST elevation of STEMI.
Differential Diagnosis
The diagnosis of STEMI is usually straightforward based on symptoms and ECG findings, but a number of conditions can mimic the ST eleva- tion of STEMI and confound the diagnosis. The ECG changes of early repolarization, takotsubo syndrome, acute myocarditis, or pericarditis can be difficult or impossible to distinguish from those of STEMI. In the face of ST elevation and chest discomfort, it may be necessary to perform coronary angiography in patients who ultimately are diag- nosed with a condition other than STEMI so as to not miss this critical diagnosis.
Diagnostic testing. Cardiac troponins (cTnI and cTnT) are sarcomere proteins that, when measured in blood, are specific for myocardial injury. The troponin level becomes elevated 2 to 4 hours after the onset of injury, and the abnormal elevation can persist for up to 2 weeks after the event. The CK-MB isomer is not as specific for heart injury as troponin, but it can still be useful in documenting the presence of MI. CK-MB is found elevated within 4 hours after an acute MI, but it clears more rapidly than troponin. In the case of persistently elevated troponin, a measurable increase in CK-MB may herald another episode of myocardial necrosis. Chronic renal insufficiency is associated with false-positive elevations of troponin T, more so than troponin I. In addition to biomarkers of myocardial injury, other laboratory studies obtained in patients with acute MI include a complete blood count, blood chemistries, lipid panel, prothrombin time (PT), and partial thromboplastin time (PTT). Leukocytosis is a common finding in acute MI, reflecting the inflammatory nature of myocardial necrosis.
At the time of admission, chest radiographs are obtained to assess for the presence of pulmonary edema or mediastinal widening Fig. 8.8 Right coronary artery angiogram in a patient with acute inferior myocardial infarction. The left panel
demonstrates total occlusion of the right coronary artery. The right panel depicts restoration of flow 90 min- utes after the intravenous administration of tissue-type plasminogen activator.
suspicious for dissection. Echocardiography is important in delineat- ing the extent of MI and assessing EF. In cases of diagnostic ambi- guity, early use of echocardiography can demonstrate the presence of regional wall motion abnormalities consistent with acute MI.
Echocardiography with color Doppler is also helpful in diagnosing complications of acute MI such as infarct-related mitral regurgitation or ventricular septal defect (VSD), pericardial effusion, or evidence of pseudoaneurysm as a result of myocardial rupture. Follow-up echo- cardiography in the months after acute MI can also reveal recovery of LV function. Radionuclide tracer studies are not useful in diagnosing acute MI. CT, cardiac MRI, and transesophageal echocardiography are all useful in diagnosing aortic dissection when there is an increased index of suspicion. Cardiac MRI can also distinguish myopericarditis.
Treatment
Acute STEMI is caused by occlusion of the epicardial coronary artery by thrombus after rupture of a vulnerable plaque. The process of myocar- dial necrosis is time dependent, so diagnosis and treatment of STEMI to preserve myocardium must occur as quickly as possible. More than half of deaths occur within 1 hour after onset of symptoms, before the patient can be reached for emergency care. Patients often delay seeking care for symptoms of acute MI despite efforts to alert the public to the risk of ignoring symptoms of chest discomfort. Emergency medi- cal personnel who respond to patients with possible MI begin to insti- tute initial therapy in the field. Patients are monitored with ECG for rhythm disturbances such as ventricular tachycardia (VT) or ventric- ular fibrillation (VF) that require prompt cardioversion or defibrilla- tion. Oxygen is administered via nasal cannula, and intravenous access is established. Aspirin (162 to 325 mg) is administered to the patient, and sublingual nitroglycerin may also be given in an attempt to relieve chest discomfort. Some emergency response systems perform 12-lead ECGs and telemeter the results to the emergency department, allow- ing for early diagnosis of STEMI and early decision making regarding revascularization strategies.
Once the patient arrives in the emergency department, an ECG, if not already available, will be performed within 5 minutes. If the ECG is nondiagnostic, a second study is obtained no more than 20 min- utes after presentation. A diagnosis of STEMI triggers decision making regarding reperfusion strategies that are used by the particular institu- tion (see Chapter 64, “ST Elevation Acute Myocardial Infarction and Complications of Myocardial Infarction,” in Goldman-Cecil Medicine, 26th Edition). Hospitals that are capable of performing emergency cardiac catheterization for the purpose of reperfusion therapy have an established rapid response system to activate the catheterization labo- ratory for this urgent therapy. There is evidence that primary PCI ther- apy for STEMI is superior to fibrinolytic therapy, but its use depends on the timely availability of a well-trained catheterization team. The quality of primary PCI is signified by a so-called door-to-balloon time of less than 90 minutes. Likewise, the standard for fibrinolytic ther- apy is a door-to-needle time of less than 30 minutes. Regardless of the means of reperfusion, it is important for the hospital treating patients with STEMI to have a structured protocol for timely diagnosis, deci- sion making, and initiation of therapy.
In addition to aspirin, the patient should be given a loading dose of a P2Y12 inhibitor (ticagrelor 180 mg, clopidogrel 600 mg or pra- sugrel 60 mg), assuming he or she will be treated with primary PCI.
Unfractionated heparin in a dose of 60 IU/kg should be administered (no more than 4000 IU bolus) with a drip rate of 12 IU/kg/hour (max- imum dose, 1000 IU/hour). LMW heparin may also be used (enoxa- parin 30 mg IV bolus with 1 mg/kg subcutaneously every 12 hours for patients younger than 75 years of age who have normal renal function).
Other agents such as glycoprotein IIb/IIIa inhibitors or bivalirudin
are administered depending on the protocols of the catheterization laboratory.
Patients are commonly given sublingual nitroglycerin 0.4 mg (repeat every 5 minutes for no more than three total doses), which often helps to diminish chest discomfort. Intravenous nitroglycerin may be helpful for control of both persistent pain and hypertension if present.
Intravenous morphine (2 to 4 mg, repeated every 5 to 15 minutes as needed) is also frequently used for pain control. Although there has been no consensus statement on the use of morphine in ACS, recently there have been several studies that have suggested an increased risk of in-hospital mortality associated with its use presumed secondary to reduced antiplatelet activity of P2Y12 inhibitors. Intravenous β-block- ers such as metoprolol (5-mg bolus every 10 minutes for a total dose of 15 mg) are indicated in the treatment of STEMI but should be avoided in the face of heart failure, severe COPD, hypotension, or bradycar- dia. β-Blockers (metoprolol, propranolol, atenolol, timolol, and carve- dilol) have been shown to significantly reduce the risk of future MI and cardiovascular mortality. Statin therapy, as mentioned for NSTEMI, is recommended for all patients with STEMI as a presenting symptom regardless of their history of hypercholesterolemia. Other adjunctive measures include bedrest for the first 12 hours, ongoing oxygen by nasal cannula with pulse oximeter monitoring, continuous rhythm monitoring, anxiolytic agents as needed, and stool softeners. Atropine is kept in reserve for the treatment of hemodynamically significant brad ycardia, which may occur with inferior MI.
ACE-inhibitor therapy also plays an important role in the long- term survival of patients after STEMI. ACE-inhibitor therapy has been shown to reduce the incidence of heart failure, recurrent MI, and long- term mortality after STEMI. ACE inhibitors commonly used for this purpose include lisinopril, captopril, enalapril, and ramipril. The deci- sion to initiate ACE-inhibitor therapy is directed by the patient’s tol- erance. Care is warranted early after STEMI, because the patient may be prone to hypotension related to ACE-inhibitor therapy. A low dose should be administered first, with gradual upward titration.
Aldosterone receptor blockade with eplerenone (25 to 50 mg/day) reduces cardiovascular mortality after MI in patients with heart failure and a reduced EF of less than 40% or diabetes. Spironolactone also reduces mortality in patients with heart failure and a history of remote MI.
Reperfusion therapy. Timely reperfusion therapy, either thrombolytic therapy or primary PCI, is critical to limiting the extent of MI and reducing the risks of future morbidity and mortality. Primary PCI has been shown to have advantages over thrombolytic therapy, with higher immediate and long-term vessel patency. Primary PCI depends on the availability of cardiac catheterization facilities and staff to conduct the reperfusion procedure quickly (see earlier discussion).
If the patient has not had access to a catheterization facility for longer than 2 hours after presentation, thrombolytic therapy is a reasonable alternative.
In the randomized, placebo-controlled Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto (GISSI) study, thrombolytic therapy with intravenous streptokinase was shown to reduce the risk of mortality in patients with STEMI if it was administered early after presentation. The time-dependent nature of therapy was also demon- strated, in that patients treated more than 12 hours after the onset of symptoms had no measurable benefit from thrombolysis. The next gen- eration of thrombolytic agents, recombinant tissue-type plasminogen activators (rt-PA), improved on mortality reduction when compared with streptokinase (30-day mortality rate, 7.3% with streptokinase vs.
6.3% with rt-PA). The advantage of rt-PA appeared to be related to enhanced vessel patency at 90 minutes after administration (80% with rt-PA vs. 53% to 60% with streptokinase). Subsequent forms of rt-PA,
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although easier to administer, did not further reduce mortality. The major attribute of thrombolytic therapy is its ease of administration, but there is a significant risk (0.5% to 1%) of catastrophic bleeding complications in the form of intracerebral hemorrhage. Age older than 75 years, female gender, hypertension, and concomitant use of heparin increase the risk of this complication. In the case of failed thrombolytic therapy, rescue PCI may be pursued.
Primary PCI has been shown to be superior to thrombolytic ther- apy based on lower overall mortality rates and reduced risk of recur- rent nonfatal MI. It is also associated with higher vessel patency rates and a low risk of intracranial hemorrhage. Primary PCI is frequently performed by mechanical aspiration of thrombus and placement of a coronary stent. Balloon angioplasty may or may not be needed during this procedure. Patients should receive preprocedure P2Y12 inhibitor (ticagrelor 180 mg, clopidogrel 600 mg or prasugrel 60 mg).
For patients who are not able to take oral medications, whose platelet inhibition may not be at therapeutic levels at the time of stent place- ment, or who are at high risk for life-threatening bleeding requiring cessation of antiplatelet therapy, cangrelor (an intravenous P2Y12 inhibitor given at 30 mcg/kg bolus followed by infusion of 4 mcg/kg/
minute) may be considered given its rapid onset and offset of platelet inhibition.
Bivalirudin was shown in a clinical trial of primary PCI to be supe- rior to both heparin- and glycoprotein IIb/IIIa–based anticoagula- tion with lower post-MI mortality and fewer bleeding complications.
Centers that are dedicated to primary PCI as the preferred therapy are likely to have the best outcomes when operators are sufficiently skilled and the institution cares for this patient population on a regular basis. Primary PCI is the best option for patients in cardiogenic shock (within 18 hours after onset of shock), for patients with prior CABG (graft occlusion is not amenable to thrombolysis), and for patients older than 70 years of age (conferring a reduced risk of intracerebral hemorrhage compared with thrombolysis).