Definition
Asymptomatic CAD or chronic stable angina may undergo transition to a more aggressive stage of disease called acute coronary syndrome (ACS). ACS comprises a spectrum of clinical presentations, ranging from unstable angina to NSTEMI or STEMI. Unstable angina rep- resents the new onset of angina at rest or on exertion, or an increase in frequency of previously stable anginal symptoms, particularly at rest.
ACS manifesting as MI, either NSTEMI or STEMI, is differentiated from unstable angina on the basis of prolonged symptoms, character- istic ECG changes, and the presence of biomarkers in blood. Unstable angina may be a harbinger of either NSTEMI or STEMI, and the diag- nosis of unstable angina identifies a patient who requires careful assess- ment and treatment.
Epidemiology
The occurrence of ACS represents a significant clinical event in up to 1.3 million Americans annually. One third of those categorized as hav- ing ACS are diagnosed with NSTEMI. More than half of patients with NSTEMI are 65 years of age or older, and approximately one half are women. NSTEMI is more common in patients with diabetes, periph- eral vascular disease, or chronic inflammatory disease (e.g., rheuma- toid arthritis).
Primary ACS is the most common form of the disease and reflects underlying plaque rupture leading to intracoronary thrombus for- mation and limitation of blood flow. This is in contrast to demand ische mia that reflects imbalances in myocardial oxygen supply and demand leading to myocardial ischemia. Examples of decreased oxy- gen supply include profound anemia, systemic hypotension, and hypoxemia. Increased demand occurs in the face of severe systemic hypertension, fever, tachycardia, and thyrotoxicosis. Demand isch- emia not uncommonly unmasks previously asymptomatic obstruc- tive CAD, but it may also occur in the absence of CAD. Treatment of demand ischemia is directed at correcting the underlying medical condition.
Pathology
Most patients who experience NSTEMI do so as a result of plaque rupture with subsequent thrombosis causing subtotal occlusion of the coronary artery. The limitation of coronary blood flow in this situation leads to subendocardial ischemia in the distribution of the affected coronary artery. The same pathology underlies STEMI, although in that case complete vessel occlusion occurs, leading to more extensive MI. It is possible for patients with obstructive CAD to develop collateral support of the affected artery, and in that case plaque rupture with complete vessel occlusion may lead to NSTEMI as opposed to STEMI.
A smaller percentage of patients have ACS due to coronary vaso- spasm, which, if severe and prolonged, can lead to myocardial necrosis.
Vasospasm may occur in regions of endothelial dysfunction induced by atherosclerotic plaque, or it may be triggered by exogenous vaso- constrictors such as cocaine ingestion, the use of serotonin agonists (for migraine therapy), or chemotherapeutic agents (e.g., 5-fluoroura- cil). A less common cause of ACS is coronary vasculitis.
An alternative coronary artery pathology that can lead to MI is spontaneous coronary artery dissection (SCAD). Less is known about the underlying pathology of SCAD in contrast with MI due to plaque rupture, but its recognition is critical to appropriate treatment. SCAD has a predilection for a younger patient population with a strong bias toward females and is associated in particular with pregnancy and in patients with fibromuscular dysplasia. Rapid diagnosis can be chal- lenging given that the patient population is one with few risk factors for CAD, and so a high index of suspicious is critical. Treatment dif- fers from traditional MI in that a conservative approach is more often taken owing to increased complexity of percutaneous coronary inter- vention (PCI) on coronary dissection. Medical therapy for SCAD is similar to plaque rupture MI.
Atherosclerotic plaques rich in LDL are prone to develop inflam- mation, which in turn degrades the collagen-rich fibrous cap, leading to rupture and thrombosis as described previously. Systemic inflam- matory conditions may also play a role in plaque rupture in some patients. It is possible to have multiple sites of plaque ulceration or rupture.
Plaque rupture leads to platelet adherence and subsequent activa- tion at the site of rupture. As platelets aggregate, the thrombosis cas- cade is triggered, leading to progressive accumulation of intravascular thrombus. The severity of myocardial ischemia and MI depends on the degree to which thrombus occludes the vessel. It is also possible for ACS to occur as a result of embolization of platelet aggregates or thrombus.
Clinical Presentation
ACS may manifest as a first symptom of angina pectoris in a previously asymptomatic patient. Alternatively, patients with preexisting angina pectoris experience more frequent angina, angina at lower levels of exertion, or angina at rest. Patients who have developed ACS com- monly experience their typical symptom of angina in terms of loca- tion and radiation but with increased intensity and duration. Patients with subtotal or total occlusion of a coronary artery may be much less responsive or completely unresponsive to the effects of nitroglycerin.
Physical examination during myocardial ischemia may reveal a patient who is clearly anxious and uncomfortable and who may also be experiencing dyspnea, nausea, or vomiting. Sinus tachycardia and hypertension is a common response to the discomfort of ACS, but in some instances sinus bradycardia and varying degrees of heart block may be observed. Bradyarrhythmias may also be associated with hypotension. Auscultation may reveal the presence of an S4, reflecting diminished LV compliance, or an S3 if there is extensive LV dysfunc- tion. In the case of ischemia-induced papillary muscle dysfunction, the systolic murmur of mitral regurgitation can be heard. Patients with large areas of ischemic myocardium develop elevated LV filling pres- sures leading to pulmonary congestion, dyspnea, and the physical find- ing of rales on lung auscultation.
Diagnosis
Patients presenting with ACS require urgent care directed at rapid diagnosis and treatment. The ECG is critically important in early diag- nosis of presumed ACS. The finding of ST elevation in multiple leads (Fig. 8.5) is diagnostic of STEMI and portends a more extensive MI
89 CHAPTER 8 Coronary Heart Disease
and the need for prompt revascularization. The distribution of ST ele- vation reflects the region of myocardium affected by thrombotic cor- onary occlusion. For example, ST elevation in leads II, III, and aVF reflects an inferior MI due to occlusion of the right coronary artery (or circumflex coronary artery in some cases). ST elevation in leads V2 through V6 (see Fig. 8.5) reflects an anterior MI caused by obstruction of the left anterior descending coronary artery.
Unstable angina or NSTEMI is caused by subtotal vessel occlusion by thrombus leading to reduced coronary blood flow. This results in subendocardial ischemia and the characteristic ECG changes of ST depression (Fig. 8.6). It is important to recognize that up to half of patients with acute MI do not have significant ECG abnormali- ties on the initial study. Sequential ECGs are frequently required to establish a diagnosis. If there is a high index of suspicion for MI and ECGs are persistently nondiagnostic, the use of leads extending to the patient’s back (V7 to V9) may demonstrate ST changes related to pos- terior LV ischemia (usually a circumflex coronary artery occlusion).
Echocardiography showing regional wall motion abnormalities can also help to establish the diagnosis of acute MI.
Serum biomarkers also play an important role in the diagnosis of acute MI. Myocardial necrosis leads to the release of biomarkers that can be measured in serial fashion to document the occurrence of MI. The presence of specific biomarkers is definitive evidence of MI, and they are particularly helpful to provide prognostic significance when symptoms are mild and ECG changes are minimal. Common biomarkers include creatine kinase (CK), troponin I, troponin T, lac- tate dehydrogenase (LDH), and aspartate aminotransferase (AST).
Sequential measurement of biomarkers demonstrates their various time courses for abnormal elevation after an acute MI (Fig. 8.7). This information can be helpful in retrospectively timing the occurrence of an event. In contemporary practice, troponin has become the most frequently measured biomarker. LDH, CK, and AST are no longer rou- tinely measured for the diagnosis of MI. Some centers are adopting the “high-sensitivity troponin,” which can detect more subtle degrees of myocardial injury than its predecessors. In principle this allows for more rapid triaging of patients presenting with chest pain while main- taining high sensitivity as the test will pick up on troponin release very early in the course of ACS.
Troponins I and T are the most sensitive and most specific mark- ers of myocardial necrosis, and as a consequence, they have become the standard in the biochemical diagnosis of acute MI. The myocar- dial-specific isozyme CK-MB may be in the normal range while con- comitant measurement of troponin I or T reveals the presence of myocardial necrosis. Troponins I and T begin to rise within 4 hours of myocardial necrosis and remain elevated for 7 to 10 days after the MI event. Confounding elevations of troponin T occur in patients with renal failure and congestive heart failure not related to ACS. Troponin release also occurs in the case of demand ischemia not related to cor- onary thrombosis. This requires careful attention to the entire clinical presentation in discerning the likelihood of underlying ACS due to coronary thrombosis.
In the absence of clear evidence of NSTEMI (i.e., normal exam- ination, ECG findings, and biomarkers), patients who present with the diagnosis of unstable angina should undergo stress testing. A negative exercise stress test is very helpful for distinguishing those patients who require more aggressive diagnostic testing (e.g., cathe- terization) from those who can be monitored as outpatients. Some centers have embraced the use of CT coronary angiography in the assessment of low-risk patients. This technique has a high negative predictive value for ACS by demonstrating the absence of obstruc- tive CAD.
Echocardiography can be helpful in patients with equivocal ECG findings for ischemia and normal biomarkers. The presence of regional wall motion abnormalities, particularly if they correlate with the dis- tribution of ECG abnormalities, raises the risk for underlying CAD as a cause of symptoms. The echocardiogram may also show evidence of other abnormalities as causes of chest discomfort, such as pericarditis, pulmonary embolism, or aortic dissection.
Patients with a high risk for future coronary events should be directed toward coronary angiography. In the absence of contraindi- cations, coronary angiography is indicated for patients with clear evi- dence of NSTEMI based on clinical presentation of symptoms, ECG changes, and positive biomarkers. Patients undergoing evaluation for unstable angina who have significant stress test abnormalities are also candidates for coronary angiography. Some patients who have ambig- uous stress test findings or ongoing symptoms in the absence of other 10 mm/mV 25 mm/s Filter ON
1-11-111 10 mm/mV
V1-V2-V3
aVR aVL aVF V4-V5-V6
Fig. 8.5 Acute anterolateral myocardial infarction. Leads I, aVL, and V2 to V6 demonstrate ST-segment ele- vation. Reciprocal ST-segment depression is seen in leads II, III, and aVF. Deep Q waves have developed in leads V2 and V3.
findings of NSTEMI require coronary angiography to resolve the issue as to whether underlying CAD is present.
Up to 15% of patients undergoing coronary angiography for NSTEMI have no significant obstructive CAD. In a number of patients, there will be a clear “culprit” lesion showing the earmarks of plaque rupture with ulceration, associated thrombus, or reduced coronary
flow. Lesions that may have played a role in symptoms, ECG findings, or biomarker release that are not clearly stenotic may be assessed for physiologic significance with the use of a fractional flow reserve (FFR) study using a pressure wire device.
Patients who have new-onset chest pain require careful monitor- ing in an appropriate care setting that allows for rhythm monitoring as well as repeat evaluations of ECG findings and biomarker mea- surements. Risk assessment is aided by the use of risk scores calcu- lated with either the Thrombolysis in Myocardial Infarction (TIMI) or the Global Registry of Acute Coronary Events (GRACE) algorithms (see Chapter 63, “Acute Coronary Syndrome: Unstable Angina and Non-ST Elevation Myocardial Infarction,” in Goldman-Cecil Medicine, 26th Edition). The overall assessment in cases of new symptoms of chest discomfort aims to triage patients based on risk for coronary events. Low-risk patients can be spared aggressive anticoagulation pro- tocols and coronary angiography, whereas high-risk patients are likely to benefit from these approaches. The use of appropriate therapies in high-risk patients (medical therapy or revascularization or both) leads to a 20% to 40% decrease in recurrent ischemic events and a 10%
reduction in mortality.
Differential Diagnosis
The initial assessment of patients with possible ACS should include consideration of other potentially life-threatening conditions such as pulmonary embolism and aortic dissection. These considerations are particularly important if the patient’s presentation does not entirely fit that of ACS. Pulmonary embolism can be associated with ECG changes and troponin elevation, and such findings lead to early use of coronary angiography. If there is no CAD-related explanation of the patient’s presentation, prompt investigation for pulmonary embolism is war- ranted. If the patient has findings suggestive of aortic dissection, that diagnosis should be aggressively pursued with appropriate imaging techniques, given the high risk of mortality associated with that dis- ease. Valvular heart diseases such as aortic stenosis or regurgitation and hypertrophic cardiomyopathy can manifest with symptoms and ECG findings suggestive of ACS. Physical examination should aid in I
II
III
aVR Boston University Hospital
aVL
aVF
V1
V2
V3
V4
V5
V6
Fig. 8.6 Marked ST-segment depression in a patient with prolonged chest pain resulting from an acute non–
ST segment elevation myocardial infarction. Between 1 and 3 mm of ST-segment depression is seen in leads I, aVL, and V4 to V6. The patient was known to have had a previous inferior myocardial infarction.
Days after infarction
Serum enzyme level
Normal
5 AST
LDH CK
cTnl, cTnT
10 15
Fig. 8.7 Typical time course for the detection of enzymes released after myocardial infarction. AST, Serum aspartate aminotransferase; CK, cre- atine kinase; cTnI, cardiac troponin I; cTnT, cardiac troponin T; LDH, lac- tate dehydrogenase.
91 CHAPTER 8 Coronary Heart Disease
consideration of these conditions. Pericarditis and myopericarditis can also present diagnostic dilemmas related to chest pain, ECG abnormal- ities (ST and T wave changes mimicking ischemia), and positive bio- markers. Stress cardiomyopathy (takotsubo syndrome) also manifests with chest pain, T wave inversion, and positive biomarkers. Patients with this diagnosis frequently undergo urgent catheterization to assess for CAD. The absence of a culprit lesion and findings of characteristic wall motion abnormalities establish the diagnosis.
Treatment
Patients with chest pain suggestive of ACS need urgent evaluation for evidence of ischemia (serial ECGs) and myocardial necrosis (serial bio- markers). Serial biomarker measurements, in the current era usually troponin, establish the diagnosis of MI. Continuous ECG monitoring is important given the risk of ischemia-mediated arrhythmias, and serial ECGs establish a pattern of ST changes consistent with isch- emia. Patients are also placed on activity limitations up to and includ- ing bedrest for patients with particularly difficult to control angina.
Supplemental oxygen is provided to patients who are hypoxemic, but routine administration of supplemental oxygen to patients with ACS has not been shown to provide any benefit. Those with a high index of suspicion for ACS require hospital admission for observa- tion and appropriate diagnostic testing. Chest pain lends itself well to diagnosis and treatment algorithms that guide the clinician through decision trees based on expert opinion and evidence-based medicine (see Chapter 63, “Acute Coronary Syndrome: Unstable Angina and Non-ST Elevation Myocardial Infarction,” in Goldman-Cecil Medicine, 26th Edition). STEMI is typically diagnosed at the time of initial pre- sentation. Those without evidence of ST elevation can be risk stratified, as discussed earlier, using the guidance of recurrent symptoms, ECG changes, or abnormal biomarker levels. Treatment of patients who are categorized as having unstable angina or NSTEMI is directed by their allocation to either low- or high-risk status.
Once recognized as having ACS, patients require antiplatelet ther- apy because plaque rupture and thrombosis is a frequent underlying pathology, and antiplatelet therapy significantly reduces mortality risk in patients with NSTEMI. Patients should be given aspirin (75 to 162 mg per day) and a P2Y12 inhibitor (either clopidogrel or ticagrelor).
Given prasugrel and ticagrelor’s increased strength and rapidity of platelet inhibition compared to clopidogrel they are favored in the ACS setting. Note that prasugrel is reserved for patients undergoing PCI and is contraindicated in patients with a history of stroke or transient ischemic attack.
The use of these more potent antiplatelet agents must be weighed against an increased risk of bleeding that accompanies this effect. The aspirin/P2Y12 inhibitor combination is indicated as ongoing therapy in the year following diagnosis of NSTEMI.
Symptoms of chest discomfort can be treated with nitrates (sublin- gual, topical, or intravenous drip) and β-blockers. The latter therapy slows heart rate and reduces blood pressure, effects that translate into reduced myocardial oxygen demand in the face of limited supply. It is important not to give nitrates to patients who have taken phospho- diesterase-5 inhibitors (sildenafil, tadalafil, or vardenafil) within the previous 24 to 48 hours. Attention to this detail minimizes the risk for nitrate-induced hypotension. Calcium-channel antagonists may be used in lieu of β-blockers, particularly if there is a need for blood pres- sure control, but they should be avoided in patients with reduced EF or overt heart failure. The dihydropyridine calcium-channel blocker nifedipine can be effective in controlling blood pressure and promot- ing coronary vasodilation, but it should be given in conjunction with a β-blocker because of the potential for the drug to induce reflex tachy- cardia and thereby increase myocardial oxygen demand.
Glycoprotein IIb/IIIa inhibitors block platelet aggregation and can reduce ischemic events in patients undergoing PCI as treatment for NSTEMI. These drugs are usually reserved for high-risk patients at the time of PCI. They require intravenous administration and are given for 12 to 24 hours after PCI. The use of this class of drugs for PCI has decreased in light of data suggesting advantages of bivalirudin, a direct thrombin inhibitor, over the glycoprotein IIb/IIIa inhibitors.
Heparin, given in its unfractionated form or as a low-molecu- lar-weight (LMW) preparation, has been shown to reduce the risk of ischemic complications in patients with NSTEMI. Heparin acts by acti- vating antithrombin and thereby inhibiting the formation and activity of thrombin. The anti-ischemic effect of heparin is additive to that of aspirin. Unfractionated heparin is given by continuous intravenous drip for up to 48 hours. It is usually not continued after revasculariza- tion. Heparin may be associated with mild thrombocytopenia, and 1%
to 5% of patients experience profound antibody-mediated thrombo- cytopenia. These patients usually have been exposed to heparin in the past, and a known diagnosis of heparin-induced thrombocytopenia necessitates the use of alternative antithrombin therapy.
LMW heparins are fragments of unfractionated heparin that are more predictable in their antithrombin activity and are associated with reduced risks for thrombocytopenia and bleeding complications. The drug should be avoided in patients who have a history of heparin-in- duced thrombocytopenia. Clinical studies of patients with NSTEMI have shown superiority of LMW heparin over unfractionated heparin in reducing the end point of death or MI during hospitalization. LMW heparin, either enoxaparin or dalteparin, is administered subcutane- ously for up to 8 days after hospitalization. As with unfractionated hep- arin, LMW heparin is not continued after revascularization. Dosing of LMW heparin is based on renal function status, age, and weight. LMW heparin has a long duration of action and cannot be reversed with prot amine. Unfractionated heparin has a shorter duration of action and is reversible with protamine, making unfractionated heparin the preferred anticoagulant for patients who may require CABG.
Fondaparinux is a selective factor Xa inhibitor that does not induce thrombocytopenia. It can reduce ischemic events in patients with NSTEMI and is associated with a lower risk of bleeding than is seen with enoxaparin. There is an increased risk of catheter-related thrombosis in patients treated with fondaparinux who are undergoing coronary angiography. This drug is reserved for cases that will be man- aged noninvasively and where there is a higher risk for heparin-related bleeding.
Bivalirudin, a direct thrombin inhibitor, is an alternative to heparin for patients who are undergoing PCI. It is as effective as the combina- tion of heparin and glycoprotein IIb/IIIa inhibitor in reducing the risk of ischemic complications related to PCI, and it is associated with a reduced risk of postprocedure bleeding. Bivalirudin is used preferen- tially in patients with a history of heparin-induced thrombocytopenia.
Statin therapy is also indicated in patients with NSTEMI at presen- tation. Statins act to stabilize plaque and improve endothelial function.
These drugs should be initiated at the time of admission to the hospital and continued after discharge. There is evidence that high-dose ator- vastatin (80 mg/day) given to patients with NSTEMI reduces the risk of subsequent ischemic events.
Risk stratification is important in appropriately evaluating patients with ACS. Low-risk patients (age <75 years, normal troponin levels, 0 to 2 TIMI risk factors) should be evaluated with noninvasive test- ing, either exercise or pharmacologic stress testing before hospital discharge. Those whose tests are positive for ischemia should be con- sidered for predischarge coronary angiography. This approach leads to selective use of invasive testing and subsequent revascularization.
Patients with high-risk ACS profiles (age >75 years, elevated troponin