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InternalMed_Harrison. additional damage and the poorer the prognosis is. Risk estimation must include age, presenting symptoms, all risk factors, signs of arterial disease, existing cardiac damage, and signs of impending damage (i.e., ischemia).


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InternalMed_Harrison. The greater the number and severity of risk factors for coronary atherosclerosis (advanced age [>75 years], hypertension, dyslipidemia, diabetes, morbid obesity, accompanying peripheral and/or cerebrovascular disease, previous myocardial infarction), the worse the prognosis of an angina patient. Evidence exists that elevated levels of CRP in the plasma, extensive coronary calcification on electron beam CT (see above), and increased carotid intimal thickening on ultrasound examination also indicate an increased risk of coronary events.


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InternalMed_Harrison. Once the diagnosis of IHD has been made, each patient must be evaluated individually with respect to his or her level of understanding, expectations and goals, control of symptoms, and prevention of adverse clinical outcomes such as myocardial infarction and premature death. The degree of disability and the physical and emotional stress that precipitates angina must be recorded carefully to set treatment goals. The management plan should include the following components: (1) explanation of the problem and reassurance about the ability to formulate a treatment plan, (2) identification and treatment of aggravating conditions, (3) recommendations for adaptation of activity as needed, (4) treatment of risk factors that will decrease the occurrence of adverse coronary outcomes, (5) drug therapy for angina, and (6) consideration of revascularization.


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InternalMed_Harrison. Patients with IHD need to understand their condition and realize that a long and productive life is possible even though they have angina pectoris or have experienced and recovered from an acute myocardial infarction. Offering results of clinical trials showing improved outcomes can be of great value in encouraging patients to resume or maintain activity and return to work. A planned program of rehabilitation can encourage patients to lose weight, improve exercise tolerance, and control risk factors with more confidence.


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InternalMed_Harrison. A number of conditions may increase oxygen demand or decrease oxygen supply to the myocardium and may precipitate or exacerbate angina in patients with IHD. Left ventricular hypertrophy, aortic valve disease, and hypertrophic cardiomyopathy may cause or contribute to angina and should be excluded or treated. Obesity, hypertension, and hyperthyroidism should be treated aggressively to reduce the frequency and severity of anginal episodes. Decreased myocardial oxygen supply may be due to reduced oxygenation of the arterial blood (e.g., in pulmonary disease or, when carboxyhemoglobin is present, due to cigarette or cigar smoking) or decreased oxygen-carrying capacity (e.g., in anemia). Correction of these abnormalities, if present, may reduce or even eliminate angina pectoris.


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InternalMed_Harrison. Myocardial ischemia is caused by a discrepancy between the demand of the heart muscle for oxygen and the ability of the coronary circulation to meet that demand. Most patients can be helped to understand this concept and utilize it in the rational programming of activity. Many tasks that ordinarily evoke angina may be accomplished without symptoms simply by reducing the speed at which they are performed. Patients must appreciate the diurnal variation in their tolerance of certain activities and should reduce their energy requirements in the morning, immediately after meals, and in cold or inclement weather. On occasion, it may be necessary to recommend a change in employment or residence to avoid physical stress.


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InternalMed_Harrison. Physical conditioning usually improves the exercise tolerance of patients with angina and has substantial psychological benefits. A regular program of isotonic exercise that is within the limits of the individual patient’s threshold for the development of angina pectoris and that does not exceed 80% of the heart rate associated with ischemia on exercise testing should be strongly encouraged. Based on the results of an exercise test, the number of metabolic equivalent tasks (METs) performed at the onset of ischemia can be estimated (Table 293-2) and a practical exercise prescription can be formulated to permit daily activities that will fall below the ischemic threshold (Table 293-3).


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InternalMed_Harrison. A family history of premature IHD is an important indicator of increased risk and should trigger a search for treatable risk factors such as hyperlipidemia, hypertension, and diabetes mellitus. Obesity impairs the treatment of other risk factors and increases the risk of adverse coronary events. In addition, obesity often is accompanied by three other risk factors: diabetes mellitus, hypertension, and hyperlipidemia. The treatment of obesity and these accompanying risk factors is an important component of any management plan. A diet low in saturated and trans-unsaturated fatty acids and a reduced caloric intake to achieve optimal body weight are a cornerstone in the management of chronic IHD. It is especially important to emphasize weight loss and regular exercise in patients with the metabolic syndrome or overt diabetes mellitus.


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InternalMed_Harrison. Cigarette smoking accelerates coronary atherosclerosis in both sexes and at all ages and increases the risk of thrombosis, plaque instability, myocardial infarction, and death (Chap. 291e). In addition, by increasing myocardial oxygen needs and reducing oxygen supply, it aggravates angina. Smoking cessation studies have demonstrated important benefits with a significant decline in the occurrence of these adverse outcomes. The physician’s message must be clear and strong and supported by programs that achieve and monitor abstinence (Chap. 470). Hypertension (Chap. 298) is associated with an increased risk of adverse clinical events from coronary atherosclerosis as well as stroke. In addition, the left ventricular hypertrophy that results from sustained hypertension aggravates ischemia. There is evidence that long-term effective treatment of hypertension can decrease the occurrence of adverse coronary events.


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InternalMed_Harrison. Diabetes mellitus (Chap. 417) accelerates coronary and peripheral atherosclerosis and is frequently associated with dyslipidemias and increases in the risk of angina, myocardial infarction, and sudden coronary death. Aggressive control of the dyslipidemia (target LDL cholesterol <70 mg/dL) and hypertension (target blood pressure 120/80 mmHg) that are frequently found in diabetic patients is highly effective and therefore essential, as described below. Abbreviation: METs, metabolic equivalent tasks. Source: Modified from WL Haskell: Rehabilitation of the coronary patient, in NK Wenger, HK Hellerstein (eds): Design and Implementation of Cardiac Conditioning Program. New York, Churchill Livingstone, 1978.


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InternalMed_Harrison. 1588 DYSLIPIDEMIA The treatment of dyslipidemia is central in aiming for long-term relief from angina, reduced need for revascularization, and reduction in myocardial infarction and death. The control of lipids can be achieved by the combination of a diet low in saturated and trans-unsaturated fatty acids, exercise, and weight loss. Nearly always, HMG-CoA reductase inhibitors (statins) are required and can lower LDL cholesterol (25–50%), raise HDL cholesterol (5–9%), and lower triglycerides (5–30%). A powerful treatment effect of statins on atherosclerosis, IHD, and outcomes is seen regardless of the pretreatment LDL cholesterol level. Fibrates or niacin can be used to raise HDL cholesterol and lower triglycerides (Chaps. 291e and 421). Controlled trials with lipid-regulating regimens have shown equal proportional benefit for men, women, the elderly, diabetic patients, and smokers. Compliance with the health-promoting behaviors listed above is generally very poor, and a conscientious


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InternalMed_Harrison. shown equal proportional benefit for men, women, the elderly, diabetic patients, and smokers. Compliance with the health-promoting behaviors listed above is generally very poor, and a conscientious physician must not underestimate the major effort required to meet this challenge. Many patients who are discharged from the hospital with proven coronary disease do not receive adequate treatment for dyslipidemia. In light of the proof that treating dyslipidemia brings major benefits, physicians need to establish treatment pathways, monitor compliance, and follow up regularly.


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InternalMed_Harrison. The incidence of clinical IHD in premenopausal women is very low; however, after menopause, the atherogenic risk factors increase (e.g., increased LDL, reduced HDL) and the rate of clinical coronary events accelerates to the levels observed in men. Women have not given up cigarette smoking as effectively as have men. Diabetes mellitus, which is more common in women, greatly increases the occurrence of clinical IHD and amplifies the deleterious effects of hypertension, hyperlipidemia, and smoking. Cardiac catheterization and coronary revascularization are underused in women and are performed at a later and more severe stage of the disease than in men. When cholesterol lowering, beta blockers after myocardial infarction, and coronary artery bypass grafting are applied in the appropriate patient groups, women benefit to the same degree as men.


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InternalMed_Harrison. The commonly used drugs for the treatment of angina pectoris are summarized in Tables 293-4 through 293-6. Pharmacotherapy for IHD is designed to reduce the frequency of anginal episodes, myocardial infarction, and coronary death. There is a wealth of trial Preparation of Agent Dose Schedule aA 10to 12-h nitrate-free interval is recommended. Source: Modified from DA Morrow, WE Boden: Stable ischemic heart disease. In RO Bonow et al (eds): Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th edition. Philadelphia, Saunders, 2012, p. 1224. data to emphasize how important this medical management is when added to the health-promoting behaviors discussed above. To achieve maximum benefit from medical therapy for IHD, it is frequently necessary to combine agents from different classes and titrate the doses as guided by the individual profile of risk factors, symptoms, hemodynamic responses, and side effects.


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InternalMed_Harrison. The organic nitrates are a valuable class of drugs in the management of angina pectoris (Table 293-4). Their major mechanisms of action include systemic venodilation with concomitant reduction in left ventricular end-diastolic volume and pressure, thereby reducing myocardial wall tension and oxygen requirements; dilation of epicardial coronary vessels; and increased blood flow in collateral vessels. When metabolized, organic nitrates release nitric oxide (NO) that binds to guanylyl cyclase in vascular smooth muscle cells, leading to an increase in cyclic guanosine monophosphate, which causes relaxation of vascular smooth muscle. Nitrates also exert antithrombotic activity by NO-dependent activation of platelet guanylyl cyclase, impairment of intraplatelet calcium flux, and platelet activation.


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InternalMed_Harrison. The absorption of these agents is most rapid and complete through the mucous membranes. For this reason, nitroglycerin is most commonly administered sublingually in tablets of 0.4 or 0.6 mg. Patients with angina should be instructed to take the medication both to relieve angina and also approximately 5 min before stress that is likely to induce an episode. The value of this prophylactic use of the drug cannot be overemphasized. Nitrates improve exercise tolerance in patients with chronic angina and relieve ischemia in patients with unstable angina as well as patients with Prinzmetal’s variant angina (Chap. 294). A diary of angina and nitroglycerin use may be valuable for detecting changes in the frequency, severity, or threshold for discomfort that may signify the development of unstable angina pectoris and/or herald an impending myocardial infarction.


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InternalMed_Harrison. Long-Acting Nitrates None of the long-acting nitrates are as effective as sublingual nitroglycerin for the acute relief of angina. These organic nitrate preparations can be swallowed, chewed, or administered as a patch or paste by the transdermal route (Table 293-4). They can provide effective plasma levels for up to 24 h, but the therapeutic response is highly variable. Different preparations and/or administration during the daytime should be tried only to prevent discomfort while avoiding side effects such as headache and dizziness. Individual dose titration is important to prevent side effects. To minimize the effects of tolerance, the minimum effective dose should be used and a minimum of 8 h each day kept free of the drug to restore any useful response(s).


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InternalMed_Harrison. β-Adrenergic Blockers These drugs represent an important component of the pharmacologic treatment of angina pectoris (Table 293-5). They reduce myocardial oxygen demand by inhibiting the increases in heart rate, arterial pressure, and myocardial contractility caused by adrenergic activation. Beta blockade reduces these variables most strikingly during exercise but causes only small reductions at rest. Long-acting beta-blocking drugs or sustained-release formulations offer the advantage of once-daily dosing (Table 293-5). The therapeutic aims include relief of angina and ischemia. These drugs also can reduce mortality and reinfarction rates in patients after myocardial infarction and are moderately effective antihypertensive agents.


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InternalMed_Harrison. Relative contraindications include asthma and reversible airway obstruction in patients with chronic lung disease, atrioventricular conduction disturbances, severe bradycardia, Raynaud’s phenomenon, and a history of mental depression. Side effects include fatigue, reduced exercise tolerance, nightmares, impotence, cold extremities, intermittent claudication, bradycardia (sometimes severe), impaired atrioventricular conduction, left ventricular failure, bronchial asthma, worsening claudication, and intensification of the hypoglycemia produced by oral hypoglycemic agents and insulin.


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InternalMed_Harrison. Acebutolol β1 Yes 200–600 mg twice daily Atenolol β1 No 50–200 mg/d Betaxolol β1 No 10–20 mg/d Bisoprolol β1 No 10 mg/d Esmolol (intravenous)a β1 No 50–300 μg/kg/min Labetalolb None Yes 200–600 mg twice daily Metoprolol β1 No 50–200 mg twice daily Nadolol None No 40–80 mg/d Nebivolol β1 (at low doses) No 5–40 mg/d Pindolol None Yes 2.5–7.5 mg 3 times daily Propranolol None No 80–120 mg twice daily Timolol None No 10 mg twice daily aEsmolol is an ultra-short-acting beta blocker that is administered as a continuous intravenous infusion. Its rapid offset of action makes esmolol an attractive agent to use in patients with relative contraindications to beta blockade. bLabetolol is a combined alpha and beta blocker.


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InternalMed_Harrison. Note: This list of beta blockers that may be used to treat patients with angina pectoris is arranged alphabetically. The agents for which there is the greatest clinical experience include atenolol, metoprolol, and propranolol. It is preferable to use a sustained-release formulation that may be taken once daily to improve the patient’s compliance with the regimen. Source: Modified from RJ Gibbons et al: J Am Coll Cardiol 41:159, 2003. Reducing the dose or even discontinuation may be necessary if these side effects develop and persist. Since sudden discontinuation can intensify ischemia, the doses should be tapered over 2 weeks. Beta blockers with relative β1-receptor specificity such as metoprolol and atenolol may be preferable in patients with mild bronchial obstruction and insulin-requiring diabetes mellitus.


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InternalMed_Harrison. Calcium Channel Blockers Calcium channel blockers (Table 293-6) are coronary vasodilators that produce variable and dose-dependent reductions in myocardial oxygen demand, contractility, and arterial pressure. These combined pharmacologic effects are advantageous and make these agents as effective as beta blockers in the treatment of angina pectoris. They are indicated when beta blockers are contraindicated, poorly tolerated, or ineffective. Because of differences in the dose-response relationship on cardiac electrical activity between the dihydropyridine and nondihydropyridine calcium channel blockers, verapamil and diltiazem may produce symptomatic disturbances in cardiac conduction and bradyarrhythmias. They also exert negative inotropic actions and are more likely to aggravate left ventricular failure, particularly when used in patients with left ventricular dysfunction, especially if the patients are also receiving beta blockers. Although useful effects usually are achieved when


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InternalMed_Harrison. failure, particularly when used in patients with left ventricular dysfunction, especially if the patients are also receiving beta blockers. Although useful effects usually are achieved when calcium channel blockers are combined with beta blockers and nitrates, individual titration of the doses is essential with these combinations. Variant (Prinzmetal’s) angina responds particularly well to calcium channel blockers (especially members of the dihydropyridine class), supplemented when necessary by nitrates (Chap. 294).


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InternalMed_Harrison. Verapamil ordinarily should not be combined with beta blockers because of the combined adverse effects on heart rate and contractility. Diltiazem can be combined with beta blockers in patients with normal ventricular function and no conduction disturbances. Amlodipine and beta blockers have complementary actions on coronary blood supply and myocardial oxygen demands. Whereas the former decreases blood pressure and dilates coronary arteries, the latter slows heart rate and decreases contractility. Amlodipine and the other second-generation dihydropyridine calcium antagonists (nicardipine, isradipine, long-acting nifedipine, and felodipine) are aMay be associated with increased risk of mortality if administered during acute myocardial infarction.


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InternalMed_Harrison. Note: This list of calcium channel blockers that may be used to treat patients with angina pectoris is divided into two broad classes, dihydropyridines and nondihydropyridines, and arranged alphabetically within each class. Among the dihydropyridines, the greatest clinical experience has been obtained with amlodipine and nifedipine. After the initial period of dose titration with a short-acting formulation, it is preferable to switch to a sustained-release formulation that may be taken once daily to improve patient compliance with the regimen. Source: Modified from RJ Gibbons et al: J Am Coll Cardiol 41:159, 2003. 1590 potent vasodilators and are useful in the simultaneous treatment of angina and hypertension. Short-acting dihydropyridines should be avoided because of the risk of precipitating infarction, particularly in the absence of concomitant beta blocker therapy.


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InternalMed_Harrison. Choice Between Beta Blockers and Calcium Channel Blockers for Initial Therapy Since beta blockers have been shown to improve life expectancy after acute myocardial infarction (Chaps. 294 and 295) and calcium channel blockers have not, the former may also be preferable in patients with angina and a damaged left ventricle. However, calcium channel blockers are indicated in patients with the following: (1) inadequate responsiveness to the combination of beta blockers and nitrates; many of these patients do well with a combination of a beta blocker and a dihydropyridine calcium channel blocker; (2) adverse reactions to beta blockers such as depression, sexual disturbances, and fatigue; (3) angina and a history of asthma or chronic obstructive pulmonary disease; (4) sick-sinus syndrome or significant atrioventricular conduction disturbances; (5) Prinzmetal’s angina; or (6) symptomatic peripheral arterial disease.


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InternalMed_Harrison. Antiplatelet Drugs Aspirin is an irreversible inhibitor of platelet cyclooxygenase and thereby interferes with platelet activation. Chronic administration of 75–325 mg orally per day has been shown to reduce coronary events in asymptomatic adult men over age 50, patients with chronic stable angina, and patients who have or have survived unstable angina and myocardial infarction. There is a dose-dependent increase in bleeding when aspirin is used chronically. It is preferable to use an enteric-coated formulation in the range of 81–162 mg/d. Administration of this drug should be considered in all patients with IHD in the absence of gastrointestinal bleeding, allergy, or dyspepsia. Clopidogrel (300–600 mg loading and 75 mg/d) is an oral agent that blocks P2Y12 ADP receptor–mediated platelet aggregation. It provides benefits similar to those of aspirin in patients with stable chronic IHD and may be substituted for aspirin if aspirin causes the side effects listed above. Clopidogrel


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InternalMed_Harrison. aggregation. It provides benefits similar to those of aspirin in patients with stable chronic IHD and may be substituted for aspirin if aspirin causes the side effects listed above. Clopidogrel combined with aspirin reduces death and coronary ischemic events in patients with an acute coronary syndrome (Chap. 294) and also reduces the risk of thrombus formation in patients undergoing implantation of a stent in a coronary artery (Chap. 296e). Alternative antiplatelet agents that block the P2Y12 platelet receptor such as prasugrel and ticagrelor have been shown to be more effective than clopidogrel for prevention of ischemic events after placement of a stent for an acute coronary syndrome but are associated with an increased risk of bleeding. Although combined treatment with clopidogrel and aspirin for at least a year is recommended in patients with an acute coronary syndrome treated with implantation of a drug-eluting stent, studies have not shown any benefit from the routine addition


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InternalMed_Harrison. aspirin for at least a year is recommended in patients with an acute coronary syndrome treated with implantation of a drug-eluting stent, studies have not shown any benefit from the routine addition of clopidogrel to aspirin in patients with chronic stable IHD.


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InternalMed_Harrison. The angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of survivors of myocardial infarction, patients with hypertension or chronic IHD including angina pectoris, and those at high risk of vascular diseases such as diabetes. The benefits of ACE inhibitors are most evident in IHD patients at increased risk, especially if diabetes mellitus or left ventricle dysfunction is present, and those who have not achieved adequate control of blood pressure and LDL cholesterol on beta blockers and statins. However, the routine administration of ACE inhibitors to IHD patients who have normal left ventricular function and have achieved blood pressure and LDL goals on other therapies does not reduce the incidence of events and therefore is not cost-effective.


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InternalMed_Harrison. Despite treatment with nitrates, beta blockers, or calcium channel blockers, some patients with IHD continue to experience angina, and additional medical therapy is now available to alleviate their symptoms. Ranolazine, a piperazine derivative, may be useful for patients with chronic angina despite standard medical therapy. Its antianginal action is believed to occur via inhibition of the late inward sodium current (INa). The benefits of INa inhibition include limitation of the Na overload of ischemic myocytes and prevention of Ca2+ overload via the Na+–Ca2+ exchanger. A dose of 500–1000 mg orally twice daily is usually well tolerated. Ranolazine is contraindicated in patients with hepatic impairment or with conditions or drugs associated with QTc prolongation and when drugs that inhibit the CYP3A metabolic system (e.g., ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and large quantities of grapefruit juice) are being used.


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InternalMed_Harrison. Nonsteroidal anti-inflammatory drug (NSAID) use in patients with IHD may be associated with a small but finite increased risk of myocardial infarction and mortality. For this reason, they generally should be avoided in IHD patients. If they are required for symptom relief, it is advisable to coadminister aspirin and strive to use an NSAID associated with the lowest risk of cardiovascular events, in the lowest dose required, and for the shortest period of time. Another class of agents opens ATP-sensitive potassium channels in myocytes, leading to a reduction of free intracellular calcium ions. The major drug in this class is nicorandil, which typically is administered orally in a dose of 20 mg twice daily for prevention of angina. (Nicorandil is not available for use in the United States but is used in several other countries.)


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InternalMed_Harrison. Angina and Heart Failure Transient left ventricular failure with angina can be controlled by the use of nitrates. For patients with established congestive heart failure, the increased left ventricular wall tension raises myocardial oxygen demand. Treatment of congestive heart failure with an ACE inhibitor, a diuretic, and digoxin (Chap. 279) reduces heart size, wall tension, and myocardial oxygen demand, which helps control angina and ischemia. If the symptoms and signs of heart failure are controlled, an effort should be made to use beta blockers not only for angina but because trials in heart failure have shown significant improvement in survival. A trial of the intravenous ultra-short-acting beta blocker esmolol may be useful to establish the safety of beta blockade in selected patients. Nocturnal angina often can be relieved by the treatment of heart failure.


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InternalMed_Harrison. The combination of congestive heart failure and angina in patients with IHD usually indicates a poor prognosis and warrants serious consideration of cardiac catheterization and coronary revascularization. Clinical trials have confirmed that with the initial diagnosis of stable IHD, it is first appropriate to initiate a thorough medical regimen as described above. Revascularization should be considered in the presence of unstable phases of the disease, intractable symptoms, severe ischemia or high-risk coronary anatomy, diabetes, and impaired left ventricular (LV) function. Revascularization should be employed in conjunction with but not replace the continuing need to modify risk factors and assess medical therapy. An algorithm for integrating medical therapy and revascularization options in patients with IHD is shown in Fig. 293-3.


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InternalMed_Harrison. (See also Chap. 296e) Percutaneous coronary intervention (PCI) involving balloon dilatation usually accompanied by coronary stenting is widely used to achieve revascularization of the myocardium in patients with symptomatic IHD and suitable stenoses of epicardial coronary arteries. Whereas patients with stenosis of the left main coronary artery and those with three-vessel IHD (especially with diabetes and/or impaired LV function) who require revascularization are best treated with CABG, PCI is widely employed in patients with symptoms and evidence of ischemia due to stenoses of one or two vessels and even in selected patients with three-vessel disease (and, perhaps, in some patients with left main disease) and may offer many advantages over surgery.


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InternalMed_Harrison. Indications and Patient Selection The most common clinical indication for PCI is symptom-limiting angina pectoris, despite medical therapy, accompanied by evidence of ischemia during a stress test. PCI is more effective than medical therapy for the relief of angina. PCI improves Initiate medical therapy: 1. Decrease demand ischemia 2. Minimize IHD risk factors 3. ASA (clopidogrel if ASA intolerant) Any high-risk features? Low exercise capacity or ischemia at low workload, large area of ischemic myocardium, EF <40%, ACS presentation No Yes Are exertional symptoms controlled? Refer for coronary arteriography Yes No Yes No Single vessel disease LM +/or multi vessel disease PCI Assess: PCI vs CABG Consider unconventional treatments Continue medical therapy periodic stress assessment (see Fig. 293-2) Anatomy suitable for revascularization?


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InternalMed_Harrison. FIGURE 293-3 Algorithm for management of a patient with ischemic heart disease. All patients should receive the core elements of medical therapy as shown at the top of the algorithm. If high-risk features are present, as established by the clinical history, exercise test data, and imaging studies, the patient should be referred for coronary arteriography. Based on the number and location of the diseased vessels and their suitability for revascularization, the patient is treated with a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery or should be considered for unconventional treatments. See text for further discussion. ACS, acute coronary syndrome; ASA, aspirin; EF, ejection fraction; IHD, ischemic heart disease; LM, left main.


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InternalMed_Harrison. outcomes in patients with unstable angina or when used early in the course of myocardial infarction with and without cardiogenic shock. However, in patients with stable exertional angina, clinical trials have confirmed that PCI does not reduce the occurrence of death or myocardial infarction compared to optimum medical therapy. PCI can be used to treat stenoses in native coronary arteries as well as in bypass grafts in patients who have recurrent angina after CABG.


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InternalMed_Harrison. Risks When coronary stenoses are discrete and symmetric, two and even three vessels can be treated in sequence. However, case selection is essential to avoid a prohibitive risk of complications, which are usually due to dissection or thrombosis with vessel occlusion, uncontrolled ischemia, and ventricular failure (Chap. 296e). Oral aspirin, a P2Y12 antagonist, and an antithrombin agent are given to reduce coronary thrombus formation. Left main coronary artery stenosis generally is regarded as a contraindication to PCI; such patients should be treated with CABG. In selected cases such as patients with prohibitive surgical risks, PCI of an unprotected left main can be considered, but such a procedure should be performed only by a highly skilled operator; importantly, there are regional differences in the use of this 1591 approach internationally.


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InternalMed_Harrison. Efficacy Primary success, i.e., adequate dilation (an increase in luminal diameter >20% to a residual diameter obstruction <50%) with relief of angina, is achieved in >95% of cases. Recurrent stenosis of the dilated vessels occurs in ~20% of cases within 6 months of PCI with bare metal stents, and angina will recur within 6 months in 10% of cases. Restenosis is more common in patients with diabetes mellitus, arteries with small caliber, incomplete dilation of the stenosis, long stents, occluded ves sels, obstructed vein grafts, dilation of the left anterior descending coronary artery, and stenoses containing thrombi. In diseased vein grafts, procedural success has been improved by the use of capture devices or filters that prevent embolization, ischemia, and infarction.


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InternalMed_Harrison. It is usual clinical practice to administer aspirin indefinitely and a P2Y12 antagonist for 1–3 months after the implantation of a bare metal stent. Although aspirin in combination with a thienopyridine may help prevent coronary thrombosis during and shortly after PCI with stenting, there is no evidence that these medications reduce the incidence of restenosis.


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InternalMed_Harrison. The use of drug-eluting stents that locally deliver antiproliferative drugs can reduce restenosis to less than 10%. Advances in PCI, especially the availability of drug-eluting stents, have vastly extended the use of this revascularization option in patients with IHD. Of note, however, the delayed endothelial healing in the region of a drug-eluting stent also extends the period during which the patient is at risk for subacute stent thrombosis. Current recommendations are to administer aspirin indefinitely and a P2Y12 antagonist daily for at least 1 year after implantation of a drug-eluting stent. When a situation arises in which temporary discontinuation of antiplatelet therapy is necessary, the clinical circumstances should be reviewed with the operator who performed the PCI and a coordinated plan should be established for minimizing the risk of late stent thrombus; central to this plan is the discontinuation of antiplatelet therapy for the shortest acceptable period. The risk of


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InternalMed_Harrison. plan should be established for minimizing the risk of late stent thrombus; central to this plan is the discontinuation of antiplatelet therapy for the shortest acceptable period. The risk of stent thrombosis is dependent on stent size and length, complexity of the lesions, age, diabetes, and technique. However, compliance with dual antiplatelet therapy and individual responsiveness to platelet inhibition are very important factors as well.


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InternalMed_Harrison. Successful PCI produces effective relief of angina in >95% of cases. The majority of patients with symptomatic IHD who require revascularization can be treated initially by PCI. Successful PCI is less invasive and expensive than CABG and permits savings in the initial cost of care. Successful PCI avoids the risk of stroke associated with CABG surgery, allows earlier return to work, and allows the resumption of an active life. However, the early health-related and economic benefit of PCI is reduced over time because of the greater need for follow-up and the increased need for repeat procedures. When directly compared in patients with diabetes or three-vessel or left main CAD, CABG was superior to PCI in preventing major adverse cardiac or cerebrovascular events over a 12-month follow-up.


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InternalMed_Harrison. Anastomosis of one or both of the internal mammary arteries or a radial artery to the coronary artery distal to the obstructive lesion is the preferred procedure. For additional obstructions that cannot be bypassed by an artery, a section of a vein (usually the saphenous) is used to form a connection between the aorta and the coronary artery distal to the obstructive lesion. Although some indications for CABG are controversial, certain areas of agreement exist: 1. The operation is relatively safe, with mortality rates <1% in patients without serious comorbid disease and normal LV function and when the procedure is performed by an experienced surgical team. 2. Intraoperative and postoperative mortality rates increase with the severity of ventricular dysfunction, comorbidities, age >80 years, and lack of surgical experience. The effectiveness and risk of CABG vary widely depending on case selection and the skill and experience of the surgical team.


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InternalMed_Harrison. 1592 3. Occlusion of venous grafts is observed in 10–20% of patients during the first postoperative year and in approximately 2% per year during 5to 7-year follow-up and 4% per year thereafter. Long-term patency rates are considerably higher for internal mammary and radial artery implantations than for saphenous vein grafts. In patients with left anterior descending coronary artery obstruction, survival is better when coronary bypass involves the internal mammary artery rather than a saphenous vein. Graft patency and outcomes are improved by meticulous treatment of risk factors, particularly dyslipidemia. 4. Angina is abolished or greatly reduced in ~90% of patients after complete revascularization. Although this usually is associated with graft patency and restoration of blood flow, the pain may also have been alleviated as a result of infarction of the ischemic segment or a placebo effect. Within 3 years, angina recurs in about one-fourth of patients but is rarely severe. 5.


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InternalMed_Harrison. 5. Survival may be improved by operation in patients with stenosis of the left main coronary artery as well as in patients with three-or two-vessel disease with significant obstruction of the proximal left anterior descending coronary artery. The survival benefit is greater in patients with abnormal LV function (ejection fraction <50%). Survival may also be improved in the following patients: (a) patients with obstructive CAD who have survived sudden cardiac death or sustained ventricular tachycardia; (b) patients who have undergone previous CABG and have multiple saphenous vein graft stenoses, especially of a graft supplying the left anterior descending coronary artery; and (c) patients with recurrent stenosis after PCI and high-risk criteria on noninvasive testing. 6.


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InternalMed_Harrison. 6. Minimally invasive CABG through a small thoracotomy and/or off-pump surgery can reduce morbidity and shorten convalescence in suitable patients but does not appear to reduce significantly the risk of neurocognitive dysfunction postoperatively. 7. Among patients with type 2 diabetes mellitus and multivessel coronary disease, CABG surgery plus optimal medical therapy is superior to optimal medical therapy alone in preventing major cardiovascular events, a benefit mediated largely by a significant reduction in nonfatal myocardial infarction. The benefits of CABG are especially evident in diabetic patients treated with an insulin-sensitizing strategy as opposed to an insulin-providing strategy. CABG has also been shown to be superior to PCI (including the use of drug-eluting stents) in preventing death, myocardial infarction, and repeat revascularization in patients with diabetes mellitus and multivessel IHD.


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InternalMed_Harrison. Indications for CABG usually are based on the severity of symptoms, coronary anatomy, and ventricular function. The ideal candidate is male, <80 years of age, has no other complicating disease, and has troublesome or disabling angina that is not adequately controlled by medical therapy or does not tolerate medical therapy. The patient wishes to lead a more active life and has severe stenoses of two or three epicardial coronary arteries with objective evidence of myocardial ischemia as a cause of the chest discomfort. Great symptomatic benefit can be anticipated in such patients. Congestive heart failure and/or LV dysfunction, advanced age (>80 years), reoperation, urgent need for surgery, and the presence of diabetes mellitus are all associated with a higher perioperative mortality rate.


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InternalMed_Harrison. LV dysfunction can be due to noncontractile or hypocontractile segments that are viable but are chronically ischemic (hibernating myocardium). As a consequence of chronic reduction in myocardial blood flow, these segments downregulate their contractile function. They can be detected by using radionuclide scans of myocardial perfusion and metabolism, PET, cardiac MRI, or delayed scanning with thallium-201 or by improvement of regional functional impairment provoked by low-dose dobutamine. In such patients, revascularization improves myocardial blood flow, can return function, and can improve survival.


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InternalMed_Harrison. The Choice Between PCI and CABG All the clinical characteristics of each individual patient must be used to decide on the method of revascularization (e.g., LV function, diabetes, lesion complexity). A number of randomized clinical trials have compared PCI and CABG in patients with multivessel CAD who were suitable technically for both procedures. The redevelopment of angina requiring repeat coronary angiography and repeat revascularization is higher with PCI. This is a result of restenosis in the stented segment (a problem largely solved with drug-eluting stents) and the development of new stenoses in unstented portions of the coronary vasculature. It has been argued that PCI with stenting focuses on culprit lesions, whereas a bypass graft to the target vessel also provides a conduit around future culprit lesions proximal to the anastomosis of the graft to the native vessel (Fig. 293-4). By contrast, stroke rates are lower with PCI.


InternalMed_Harrison

InternalMed_Harrison. Based on available evidence, it is now recommended that patients with an unacceptable level of angina despite optimal medical management be considered for coronary revascularization. Patients with singleor two-vessel disease with normal LV function and anatomically suitable lesions ordinarily are advised to undergo PCI (Chap. 296e). Patients with three-vessel disease (or two-vessel disease that includes the proximal left descending coronary artery) and impaired global LV function (LV ejection fraction <50%) or diabetes mellitus and those with left main CAD or other lesions unsuitable for catheter-based procedures should be considered for CABG as the initial method of revascularization. In light of the complexity of the decision making, it is desirable to have a multidisciplinary team, including a cardiologist and a cardiac surgeon in conjunction with the patient’s primary care physician, provide input along with ascertaining the patient’s preferences before committing to a particular


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InternalMed_Harrison. a cardiologist and a cardiac surgeon in conjunction with the patient’s primary care physician, provide input along with ascertaining the patient’s preferences before committing to a particular revascularization option.


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InternalMed_Harrison. On occasion clinicians will encounter a patient who has persistent disabling angina despite maximally tolerated medical therapy and for whom revascularization is not an option (e.g., small diffusely diseased vessels not amenable to stent implantation or acceptable targets for bypass grafting). In such situations, unconventional treatments should be considered. Enhanced external counterpulsation utilizes pneumatic cuffs on the lower extremities to provide diastolic augmentation and systolic unloading of blood pressure to decrease cardiac work and oxygen consumption while enhancing coronary blood flow. Clinical trials have shown that regular application improves angina, exercise capacity, and regional myocardial perfusion. Experimental approaches such as gene and stem cell therapies are also under active study.


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InternalMed_Harrison. Obstructive CAD, acute myocardial infarction, and transient myocardial ischemia are frequently asymptomatic. During continuous ambulatory ECG monitoring, the majority of ambulatory patients with typical chronic stable angina are found to have objective evidence of myocardial ischemia (ST-segment depression) during episodes of chest discomfort while they are active outside the hospital. In addition, many of these patients also have more frequent episodes of asymptomatic ischemia. Frequent episodes of ischemia (symptomatic and asymptomatic) during daily life appear to be associated with an increased likelihood of adverse coronary events (death and myocardial infarction). In addition, patients with asymptomatic ischemia after a myocardial infarction are at greater risk for a second coronary event. The widespread use of exercise ECG during routine examinations has also identified some of these previously unrecognized patients with asymptomatic CAD. Longitudinal studies have demonstrated


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InternalMed_Harrison. event. The widespread use of exercise ECG during routine examinations has also identified some of these previously unrecognized patients with asymptomatic CAD. Longitudinal studies have demonstrated an increased incidence of coronary events in asymptomatic patients with positive exercise tests.


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InternalMed_Harrison. The management of patients with asymptomatic ischemia must be individualized. When coronary disease has been confirmed, the aggressive treatment of hypertension and dyslipidemia is essential and will decrease the risk of infarction and death. In addition, the


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InternalMed_Harrison. FIGURE 293-4 Difference in the approach to the lesion with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). PCI is targeted at the “culprit” lesion or lesions, whereas CABG is directed at the epicardial vessel, including the culprit lesion or lesions and future culprits, proximal to the insertion of the vein graft, a difference that may account for the superiority of CABG, at least in the intermediate term, in patients with multivessel disease. (Reproduced from BJ Gersh, RL Frye: N Engl J Med 352:2235, 2005.) physician should consider the following: (1) the degree of positivity of the stress test, particularly the stage of exercise at which ECG signs of ischemia appear; the magnitude and number of the ischemic zones of myocardium on imaging; and the change in LV ejection fraction that occurs on radionuclide ventriculography or echocardiography during ischemia and/or during exercise; (2) the ECG leads showing a positive response, with changes in the


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InternalMed_Harrison. in LV ejection fraction that occurs on radionuclide ventriculography or echocardiography during ischemia and/or during exercise; (2) the ECG leads showing a positive response, with changes in the anterior precordial leads indicating a less favorable prognosis than changes in the inferior leads; and (3) the patient’s age, occupation, and general medical condition.


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InternalMed_Harrison. Most would agree that an asymptomatic 45-year-old commercial airline pilot with significant (0.4-mV) ST-segment depression in leads V1 to V4 during mild exercise should undergo coronary arteriography, whereas an asymptomatic, sedentary 85-year-old retiree with 0.1-mV ST-segment depression in leads II and III during maximal activity need not. However, there is no consensus about the most appropriate approach in the large majority of patients for whom the situation is less extreme. Asymptomatic patients with silent ischemia, three-vessel CAD, and impaired LV function may be considered appropriate candidates for CABG.


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InternalMed_Harrison. The treatment of risk factors, particularly lipid lowering and blood pressure control as described above, and the use of aspirin, statins, and beta blockers after infarction have been shown to reduce events and improve outcomes in asymptomatic as well as symptomatic patients with ischemia and proven CAD. Although the incidence of asymptomatic ischemia can be reduced by treatment with beta blockers, calcium channel blockers, and long-acting nitrates, it is not clear whether this is necessary or desirable in patients who have not had a myocardial infarction. 294 Acute Coronary Syndrome (non-ST-Segment Elevation Myocardial infarction and unstable Angina) Christopher P. Cannon, Eugene Braunwald


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InternalMed_Harrison. Patients with ischemic heart disease fall into two large groups: patients with chronic coronary artery disease (CAD) who most commonly present with stable angina (Chap. 293) and patients with acute coronary syndromes (ACSs). These include patients with acute myocardial infarction with ST-segment elevation (STEMI) on their presenting electrocardiogram (Chap. 295) and those with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). The latter include patients with non-ST-segment elevation myocardial infarction (NSTEMI), who, by definition, have evidence of myocyte necrosis, and those with unstable angina (UA), who do not. The relative incidence of NSTEMI compared to STEMI appears to be increasing (Fig. 294-1). Every year in the United States, approximately 1.1 million patients are admitted to hospitals with NSTE-ACS as compared with ~300,000 patients with acute STEMI. Women comprise more than one-third of patients with NSTE-ACS, but less than one-fourth of patients with STEMI.


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InternalMed_Harrison. NSTE-ACS is most commonly caused by an imbalance between oxygen supply and oxygen demand resulting from a partially occluding thrombus forming on a disrupted atherothrombotic coronary plaque 1594 Trends of STEMI and NSTEMI in NRMI Registry (1990–2006) myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) and of frequency of use of troponin assay to diagnose acute myocardial infarction. NRMI, National Registry of Myocardial Infarction. (From N Arora, RG Brindis, CP Cannon: Acute coronary syndrome in North America, in Theroux P [ed]: Acute Coronary Syndromes, 2nd ed. Philadelphia: Elsevier, 2011.) or on eroded coronary artery endothelium. Severe ischemia or myocardial necrosis may occur consequent to the reduction of coronary blood flow caused by the thrombus and by downstream embolization of platelet aggregates and/or atherosclerotic debris. Other causes of NSTE-ACS include: (1) dynamic obstruction (e.g., coronary spasm, as in Prinzmetal’s variant


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InternalMed_Harrison. and by downstream embolization of platelet aggregates and/or atherosclerotic debris. Other causes of NSTE-ACS include: (1) dynamic obstruction (e.g., coronary spasm, as in Prinzmetal’s variant angina [see “Prinzmetal’s Variant Angina” later]); (2) severe mechanical obstruction due to progressive coronary atherosclerosis; and (3) increased myocardial oxygen demand produced by conditions such as fever, tachycardia, and thyrotoxicosis in the presence of fixed epicardial coronary obstruction. More than one of these processes may be involved.


InternalMed_Harrison

InternalMed_Harrison. Among patients with NSTE-ACS studied at angiography, approximately 10% have stenosis of the left main coronary artery, 35% have three-vessel CAD, 20% have two-vessel disease, 20% have single-vessel disease, and 15% have no apparent critical epicardial coronary artery stenosis; some of the latter may have obstruction of the coronary microcirculation and/or spasm. The “culprit lesion” responsible for ischemia may show an eccentric stenosis with scalloped or overhanging edges and a narrow neck on coronary angiography. Optical coherence tomography (an invasive technique) and contrast-enhanced coronary computed tomographic angiography (CCTA), a noninvasive technique (Fig. 294-2), have shown that culprit lesions are composed of a lipid-rich core with a thin fibrous cap. Patients with NSTE-ACS frequently have multiple such plaques that are at risk of disruption (vulnerable plaques).


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InternalMed_Harrison. CLINICAL PRESENTATION Diagnosis The diagnosis of NSTE-ACS is based largely on the clinical presentation. Typically, chest discomfort is severe and has at least one of three features: (1) it occurs at rest (or with minimal exertion), lasting >10 minutes; (2) it is of relatively recent onset (i.e., within the prior 2 weeks); and/or (3) it occurs with a crescendo pattern (i.e., distinctly more severe, prolonged, or frequent than previous episodes). The diagnosis of NSTEMI is established if a patient with these clinical features develops evidence of myocardial necrosis, as reflected in abnormally elevated levels of biomarkers of cardiac necrosis (see below).


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InternalMed_Harrison. History and Physical Examination The chest discomfort, often severe enough to be described as frank pain, is typically located in the sub-sternal region or sometimes in the epigastrium, and radiates to the left arm, left shoulder, and/or neck. Anginal “equivalents” such as dyspnea, epigastric discomfort, nausea, or weakness may occur instead of chest pain and appear to be more frequent in women, the elderly, and patients with diabetes mellitus. The physical examination resembles that in patients with stable angina (Chap. 293) and may be unremarkable. If the patient has a large area of myocardial ischemia or a large NSTEMI, the physical findings can include diaphoresis; pale, cool skin; sinus tachycardia; a third and/or fourth heart sound; basilar rales; and, sometimes, hypotension.


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InternalMed_Harrison. FIGURE 294-2 Coronary computed tomographic angiogram showing an obstructive plaque in the right coronary artery. (From PJ de Feyter, K Nieman. Multislice computed tomography in acute coro-nary syndromes, in Theroux P [ed]: Acute Coronary Syndromes, 2nd ed. Philadelphia: Elsevier, 2011.) Electrocardiogram ST-segment depression occurs in 20 to 25% of patients; it may be transient in patients without biomarker evidence of myocardial necrosis, but may be persistent for several days in NSTEMI. T-wave changes are common but are less specific signs of ischemia, unless they are new and deep T-wave inversions (≥0.3 mV).


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InternalMed_Harrison. Cardiac Biomarkers Patients with NSTEMI have elevated biomarkers of necrosis, such as cardiac troponin I or T, which are specific, sensitive, and the preferred markers of myocardial necrosis. The MB isoform of creatine kinase (CK-MB) is a less sensitive alternative. Elevated levels of these markers distinguish patients with NSTEMI from those with UA. There is a characteristic temporal rise and fall of the plasma concentration of these markers and a direct relationship between the degree of elevation and mortality (see Fig. 294-4B). However, in patients without a clear clinical history of myocardial ischemia, minor cardiac troponin (cTn) elevations have been reported and can be caused by congestive heart failure, myocarditis, or pulmonary embolism, or using high-sensitivity assays, they may occur in ostensibly normal subjects. Thus, in patients with an unclear history, small elevations of cTn, especially if they are persistent, may not be diagnostic of an ACS.


InternalMed_Harrison

InternalMed_Harrison. With more widespread measurement of troponin, especially using high-sensitivity assays, an increasing fraction of patients with NSTEACS are found to have NSTEMI, whereas the fraction of patients with UA is dwindling. In addition to the clinical examination, three major noninvasive tools are used in the evaluation of NSTEMI-ACS: the electrocardiogram (ECG), cardiac biomarkers, and stress testing. CCTA is an additional emerging option (Fig. 294-2). The goals are to: (1) recognize or exclude myocardial infarction (MI) using cardiac biomarkers, preferably cTn;


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InternalMed_Harrison. Definite ACS Possible ACS See Chap. 295 Outpatient follow-up Chronic stable angina See Chap. 293 Noncardiac diagnosis Treatment as indicated by alternative diagnosis Observe 12 h or more from symptom onset Nondiagnostic ECG Normal initial cTn No recurrent pain; negative follow-up studies Recurrent ischemic pain or positive follow-up studies Diagnosis of ACS confirmed Stress study to provoke ischemia consider evaluation of LV function if ischemia is present Negative Potential diagnoses: nonischemic discomfort; low-risk ACS Positive Diagnosis of ACS confirmed or highly likely Admit to hospital Manage via acute ischemia pathway STand/or T-wave changes Ongoing pain or elevated cTn Hemodynamic abnormalities No ST-segment elevation ST-segment elevation Symptoms suggestive of ACS FIGURE 294-3 Algorithm for evaluation and management of patients with suspected acute coronary syndrome (ACS). Follow-up stud-ies refer to ST deviations and elevation of troponin levels. cTn, cardiac troponin; ECG,


InternalMed_Harrison

InternalMed_Harrison. for evaluation and management of patients with suspected acute coronary syndrome (ACS). Follow-up stud-ies refer to ST deviations and elevation of troponin levels. cTn, cardiac troponin; ECG, electrocardiogram; LV, left ventricular. (Modified from JL Anderson et al: J Am Coll Cardiol 61:e179, 2013.) (2) detect rest ischemia (using serial or continuous ECGs); and (3) detect significant coronary obstruction at rest with CCTA and myocardial ischemia using stress testing (Chap 270e).


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InternalMed_Harrison. Patients with a low likelihood of ischemia are usually managed with an emergency department–based critical pathway (which, in some institutions, is carried out in a “chest pain unit”) (Fig. 294-3). Evaluation of such patients includes clinical monitoring for recurrent ischemic discomfort and continuous monitoring of ECGs and cardiac markers, typically obtained at baseline and at 4–6 h and 12 h after presentation. If new elevations in cardiac markers or ST-T-wave changes on the ECG are noted, the patient should be admitted to the hospital. Patients who remain pain free with negative markers may proceed to stress testing to determine the presence of ischemia or CCTA to detect coronary luminal obstruction (Fig. 294-2).


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InternalMed_Harrison. Patients with documented NSTE-ACS exhibit a wide spectrum of early (30 days) risk of death, ranging from 1 to 10%, and a recurrent ACS rate of 5 to 15% during the first year. Assessment of risk can be accomplished by clinical risk scoring systems such as that developed from the Thrombolysis in Myocardial Infarction (TIMI) Trials, which includes seven independent risk factors (Fig. 294-4A). The presence of an abnormally elevated cTn is especially important, as is its peak level, which correlates with the extent of myocardial damage (Fig. 294-4B). Other risk factors include diabetes mellitus, left ventricular dysfunction, renal dysfunction, and elevated levels of B-type natriuretic peptides and C-reactive protein. Multimarker strategies are now gaining favor, both to define more fully the pathophysiologic mechanisms underlying a given patient’s presentation and to stratify the patient’s risk further. Patients with ACS without elevated levels of cTn (infrequently encountered with the new


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InternalMed_Harrison. mechanisms underlying a given patient’s presentation and to stratify the patient’s risk further. Patients with ACS without elevated levels of cTn (infrequently encountered with the new sensitive troponin assays) are considered to have UA and have a more favorable prognosis than those with cTn elevations (NSTEMI).


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InternalMed_Harrison. Early risk assessment is useful both in predicting the risk of recurrent cardiac events and in identifying patients who would derive the greatest benefit from an early invasive strategy. For example, in the TACTICSTIMI 18 Trial, an early invasive strategy conferred a 40% reduction in recurrent cardiac events in patients with an elevated cTn level, whereas no benefit was observed in those without detectable troponin. Patients should be placed at bed rest with continuous ECG monitoring for ST-segment deviation and cardiac arrhythmias. Ambulation is permitted if the patient shows no recurrence of ischemia (symptoms or ECG changes) and does not develop an elevation of a biomarker of necrosis for 12–24 h. Medical therapy involves simultaneous anti-ischemic and antithrombotic treatments and consideration of coronary revascularization.


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InternalMed_Harrison. To provide relief and prevention of recurrence of chest pain, initial treatment should include bed rest, nitrates, beta adrenergic blockers, and inhaled oxygen in the presence of hypoxemia. Nitrates These should first be given sublingually or by buccal spray (0.3–0.6 mg) if the patient is experiencing ischemic pain. If pain persists after three doses given 5 min apart, intravenous nitroglycerin (5–10 μg/min using nonabsorbing tubing) is recommended. The rate of the infusion may be increased by 10 μg/min every 3–5 min until symptoms are relieved, systolic arterial pressure falls to This is the second major cornerstone of treatment. There are two components of antithrombotic therapy: antiplatelet drugs and anticoagulants.


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InternalMed_Harrison. This is the second major cornerstone of treatment. There are two components of antithrombotic therapy: antiplatelet drugs and anticoagulants. Antiplatelet Drugs (See Chap. 143) Initial treatment should begin with the platelet cyclooxygenase inhibitor aspirin. The typical initial 4.7 8.3 13.2 19.9 26.2 40.9 dose is 325 mg/d, with lower doses (75–100 mg/d) recommended thereafter. Contraindications are active bleeding or aspirin intolerance. “Aspirin resistance” has been noted in 2–8% of patients but frequently has been related to noncompliance.


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InternalMed_Harrison. In the absence of a high risk for bleeding, patients with NSTE-ACS, 0/12 3 4 56/7 TIMI risk score UA/NSTEMI % Population 4.3 17.3 32.0 29.3 13.0 3.4 irrespective of whether an invasive or conservative strategy (see below) is selected, should receive a platelet P2Y12 receptor blocker to inhibit platelet activation. The thienopyridine clopidogrel is an inactive prodrug that is converted into an active metabolite that causes irreversible blockade of the platelet P2Y12 receptor. When added to aspirin, so-called dual antiplatelet therapy, it has been shown to confer a 20% relative reduction in cardiovascular death, MI, or stroke, compared to aspirin alone, but to be associated with a moderate (absolute 1%) increase in major bleeding.


InternalMed_Harrison

InternalMed_Harrison. Continued benefit of treatment with the combination of aspirin and clopidogrel has been observed both in patients treated con servatively and in those who underwent PCI. This regimen should continue for at least 1 year in patients with NSTE-ACS, especially those with a drug-eluting stent, to prevent stent thrombosis. Up to one-third of patients have an inadequate response to clopidogrel, and a substantial proportion of these cases are related to a genetic variant of the cytochrome P450 system. A variant of the 2C19 gene leads to reduced conversion of clopidogrel into its active metabo lite, which, in turn, reduces platelet inhibition and is associated 1.0 Mortality at 6 weeks(% of patients)1.7 3.4 3.7 6.0 7.5 0–<0.4 0.4–<1.0 1.0–<2.0 2.0–<5.0 5.0–<9.0 ˜9.0 831 174 148 134 50 67 0 1 2 3 4 5 6 7 8 Risk ratio 1.0 1.8 3.5 3.9 6.2 7.8 95% confidence – 0.5–6.7 1.2–10.6 1.3–11.7 1.7–22.3 2.6–23.0


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InternalMed_Harrison. Risk ratio 1.0 1.8 3.5 3.9 6.2 7.8 95% confidence – 0.5–6.7 1.2–10.6 1.3–11.7 1.7–22.3 2.6–23.0 FIGURE 294-4 A. Death (D), myocardial infarction (MI), or need for urgent revascularization (UR) through 6 weeks by Thrombolysis in Myocardial Infarction (TIMI) Risk Score in the unfractionated heparin arm of the TIMI 11B trial. (From EM Antman et al: JAMA 284:835, 2000.) B. Mortality rate at 42 days by baseline cardiac troponin I levels in the TIMI 3B trial. (From EM Antman et al: N Engl J Med 335:1342, 1996.) <100 mmHg, or the dose reaches 200 μg/min. Topical or oral nitrates (Chap. 293) can be used when the pain has resolved, or they may replace intravenous nitroglycerin when the patient has been pain-free for 12–24 h. The only absolute contraindications to the use of nitrates are hypotension or the use of sildenafil or other phosphodiesterase-5 inhibitors within the previous 24–48 h.


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InternalMed_Harrison. Beta Adrenergic Blockers and Other Agents Beta blockers are the other mainstay of anti-ischemic treatment. They may be started by the intravenous route in patients with severe ischemia, but this is contraindicated in the presence of heart failure. Ordinarily, oral beta blockade targeted to a heart rate of 50–60 beats/min is recommended. Heart rate–slowing calcium channel blockers, e.g., verapamil or diltiazem, are recommended for patients who have persistent symptoms or ECG signs of ischemia after treatment with full-dose nitrates and beta blockers and in patients with contraindications to either class of these agents. Additional medical therapy includes angiotensin-converting enzyme (ACE) inhibitors or, if these are not tolerated, angiotensin receptor blockers. Early administration of intensive HMG-CoA reductase inhibitors (statins), such as atorvastatin 80 mg/d, prior to percutaneous coronary intervention (PCI), and continued thereafter, has been shown to reduce complications of the


InternalMed_Harrison

InternalMed_Harrison. HMG-CoA reductase inhibitors (statins), such as atorvastatin 80 mg/d, prior to percutaneous coronary intervention (PCI), and continued thereafter, has been shown to reduce complications of the procedure and recurrences of ACS.


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InternalMed_Harrison. with increases in the incidence of adverse cardiovascular events. Alternate P2Y12 blockers, such as prasugrel or ticagrelor (see below) used with aspirin, should be considered in patients with NSTE-ACS who develop a coronary event while receiving clopidogrel and aspirin or who are hyporesponsive to clopidogrel as identified by platelet and/or genetic testing, although such testing is not yet widespread.


InternalMed_Harrison

InternalMed_Harrison. A second P2Y12 blocker, prasugrel, also a thienopyridine, achieves a more rapid onset and higher level of platelet inhibition than clopidogrel. It has been approved for ACS patients following angiography in whom PCI is planned. It should be administered at a loading dose of 60 mg followed by 10 mg/d for up to 15 months. The TRITON-TIMI 38 trial showed that relative to clopidogrel, prasugrel reduced the risk of cardiovascular death, MI, or stroke significantly, albeit with an increase in major bleeding. Stent thrombosis was reduced by half. This agent is contraindicated in patients with prior stroke or transient ischemic attack or at high risk for bleeding. It has not been found to be effective in patients treated by a conservative strategy (see below).


InternalMed_Harrison

InternalMed_Harrison. Ticagrelor is a novel, potent, reversible platelet P2Y12 inhibitor. It has been shown in the PLATO trial to reduce the risk of cardiovascular death, MI, or stroke compared with clopidogrel in ACS patients who are treated by either an invasive or a conservative strategy. This agent reduced mortality but increased the risk of bleeding not associated with coronary artery bypass grafting. After a loading dose of 180 mg, 90 mg bid is administered as maintenance.


InternalMed_Harrison

InternalMed_Harrison. Prior to the development of the oral P2Y12 receptor blockers, many trials had shown the benefit of intravenous glycoprotein IIb/ IIIa inhibitors. Their benefit, however, has been small (i.e., only a 10% reduction in death or MI, with a significant increase in major bleeding). Two recent studies failed to show a benefit of routine early initiation of a drug in this class compared with their use only in patients who undergo PCI. The addition of these agents to aspirin and a P2Y12 inhibitor (i.e., triple antiplatelet therapy) should be reserved for unstable patients with recurrent rest pain, elevated cTn, and ECG changes, as well as those who have a coronary thrombus evident on angiography when they undergo PCI.


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InternalMed_Harrison. aAllergy or prior intolerance is a contraindication for all categories of drugs listed in this chart. bChoice of the specific agent is not as important as ensuring that appropriate candidates receive this therapy. If there are concerns about patient intolerance due to existing pulmonary disease, especially asthma, left ventricular dysfunction, risk of hypotension, or severe bradycardia, initial selection should favor a short-acting agent, such as propranolol or metoprolol or the ultra-short-acting agent esmolol. Mild wheezing or a history of chronic obstructive pulmonary disease should prompt a trial of a short-acting agent at a reduced dose (e.g., 2.5 mg IV metoprolol, 12.5 mg oral metoprolol, or 25 μg/kg per min esmolol as initial doses) rather than complete avoidance of beta blocker therapy.


InternalMed_Harrison

InternalMed_Harrison. Note: Some of the recommendations in this guide suggest the use of agents for purposes or in doses other than those specified by the U.S. Food and Drug Administration. Such recommendations are made after consideration of concerns regarding nonapproved indications. Where made, such recommendations are based on more recent clinical trials or expert consensus. 2°, second-degree; 3°, third-degree; ECG, electrocardiogram; IV, intravenous. Source: Modified from J Anderson et al: J Am Coll Cardiol 61:e179, 2013.


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InternalMed_Harrison. Anticoagulants (See Chap. 143) Four options are available for anti-clinical risk factors, ST-segment deviation, and/or positive biomarkcoagulant therapy to be added to antiplatelet agents: (1) unfrac-ers) (Table 294-3). In this strategy, following treatment with antitionated heparin (UFH), long the mainstay of therapy; (2) the ischemic and antithrombotic agents, coronary arteriography is low-molecular-weight heparin (LMWH), enoxaparin, which has been carried out within ~48 h of presentation, followed by coronary shown to be superior to UFH in reducing recurrent cardiac events, revascularization (PCI or coronary artery bypass grafting), depend-especially in patients managed by a conservative strategy but with ing on the coronary anatomy. In low-risk patients, the outcomes some increase in bleeding; (3) bivalirudin, a direct thrombin inhibi-from an invasive strategy are similar to those obtained from a tor that is similar in efficacy to either UFH or LMWH but causes less conservative


InternalMed_Harrison

InternalMed_Harrison. bleeding; (3) bivalirudin, a direct thrombin inhibi-from an invasive strategy are similar to those obtained from a tor that is similar in efficacy to either UFH or LMWH but causes less conservative strategy. The latter consists of anti-ischemic and anti-bleeding and is used just prior to and/or during PCI; and (4) the indi-thrombotic therapy followed by “watchful waiting,” in which the rect factor Xa inhibitor, fondaparinux, which is equivalent in efficacy patient is closely observed and coronary arteriography is carried to enoxaparin but appears to have a lower risk of major bleeding. out only if rest pain or ST-segment changes recur, a biomarker of


InternalMed_Harrison

InternalMed_Harrison. Excessive bleeding is the most important adverse effect of necrosis becomes positive, or there is evidence of severe ischemia all antithrombotic agents, including both antiplatelet agents on a stress test. and anticoagulants. Therefore, attention must be directed to the doses of antithrombotic agents, accounting for body weight, creatinine clearance, and a previous history of excessive bleeding, as The time of hospital discharge is a “teachable moment” for the patient a means of reducing the risk of bleeding. Patients who have experi with NSTE-ACS, when the physician can review and optimize the enced a stroke are at higher risk of intracranial bleeding with potent medical regimen. Risk-factor modification is key, and the caregiver antiplatelet agents and combinations of antithrombotic drugs.


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InternalMed_Harrison. should discuss with the patient the importance of smoking cessa tion, achieving optimal weight, daily exercise, blood-pressure control, INVASIVE VERSUS CONSERVATIVE STRATEGY following an appropriate diet, control of hyperglycemia (in diabetic Multiple clinical trials have demonstrated the benefit of an early patients), and lipid management as recommended for patients with invasive strategy in high-risk patients (i.e., patients with multiple chronic stable angina (Chap. 293). Aspirin Initial dose of 325 mg nonenteric formulation followed by 75–100 mg/d of an enteric or a nonenteric formulation Clopidogrel Loading dose of 300–600 mg followed by 75 mg/d Prasugrel Pre-PCI: Loading dose 60 mg followed by 10 mg/d Ticagrelor Loading dose of 180 mg followed by 90 mg twice daily Abciximab 0.25 mg/kg bolus followed by infusion of 0.125 μg/ kg per min (maximum 10 μg/min) for 12–24 h


InternalMed_Harrison

InternalMed_Harrison. Ticagrelor Loading dose of 180 mg followed by 90 mg twice daily Abciximab 0.25 mg/kg bolus followed by infusion of 0.125 μg/ kg per min (maximum 10 μg/min) for 12–24 h Eptifibatide 180 μg/kg bolus followed 10 min later by second bolus of 180 μg with infusion of 2.0 μg/kg per min for 72–96 h following first bolus Tirofiban 25 μg/kg per min followed by infusion of 0.15 μg/kg per min for 48–96 h Unfractionated hepa-bBolus 70–100 U/kg (maximum 5000 U) IV followed rin (UFH) by infusion of 12–15 U/kg per h (initial maximum 1000 U/h) titrated to ACT 250–300 s Enoxaparin 1 mg/kg SC every 12 h; the first dose may be preceded by a 30-mg IV bolus; renal adjustment to 1 mg/kg once daily if creatine clearance <30 cc/min Fondaparinux 2.5 mg SC qd Bivalirudin Initial IV bolus of 0.75 mg/kg and an infusion of 1.75 mg/kg per h. aOther low-molecular-weight heparins exist beyond those listed. bIf no glycoprotein IIb/IIIa inhibitor planned.


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InternalMed_Harrison. Bivalirudin Initial IV bolus of 0.75 mg/kg and an infusion of 1.75 mg/kg per h. aOther low-molecular-weight heparins exist beyond those listed. bIf no glycoprotein IIb/IIIa inhibitor planned. Abbreviations: ACT, activated clotting time for HemoTec; IV, intravenous; SC, subcutaneously. Source: Modified from J Anderson et al: J Am Coll Cardiol 61:e179, 2013. There is evidence of benefit with long-term therapy with five classes of drugs that are directed at different components of the atherothrombotic process. Beta blockers, statins (at a high dose, e.g., atorvastatin 80 mg/d), and ACE inhibitors or angiotensin receptor blockers are recommended for long-term plaque stabilization. Antiplatelet therapy, Class I (Level of Evidence: A) Indications


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InternalMed_Harrison. Class I (Level of Evidence: A) Indications Recurrent angina at rest/low-level activity despite treatment Elevated TnT or TnI New ST-segment depression CHF symptoms, rales, MR EF <0.40 Sustained VT PCI <6 months, prior CABG High-risk findings from noninvasive testing Hemodynamic instability Mild-to-moderate renal dysfunction Diabetes mellitus High TIMI Risk Score (>3)b aAny one of the high-risk indicators. bSee Antman (JAMA 284:835, 2000). Abbreviations: CABG, coronary artery bypass grafting; CHF, congestive heart failure; EF, ejection fraction; MR, mitral regurgitation; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction; TnI, troponin I; TnT, troponin T; VT, ventricular tachycardia. Source: Modified from J Anderson et al: J Am Coll Cardiol 61:e179, 2013.


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InternalMed_Harrison. Source: Modified from J Anderson et al: J Am Coll Cardiol 61:e179, 2013. now recommended to be the combination of low-dose (75–100 mg/d) aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) for 1 year, with aspirin continued thereafter, prevents or reduces the severity of any thrombosis that would occur if a plaque were to rupture. Registries have shown that women and racial minorities, as well as patients with NSTE-ACS at high risk, including the elderly and patients with diabetes or chronic kidney disease, are less likely to receive evidence-based pharmacologic and interventional therapies with resultant poorer clinical outcomes and quality of life. Special attention should be directed to these groups.


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InternalMed_Harrison. In 1959 Prinzmetal et al. described a syndrome of severe ischemic pain that usually occurs at rest and is associated with transient ST-segment elevation. Prinzmetal’s variant angina (PVA) is caused by focal spasm of an epicardial coronary artery, leading to severe transient myocardial ischemia and occasionally infarction. The cause of the spasm is not well defined, but it may be related to hypercontractility of vascular smooth muscle due to adrenergic vasoconstrictors, leukotrienes, or serotonin. For reasons that are not clear, the prevalence of PVA has decreased substantially during the past few decades.


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InternalMed_Harrison. Clinical and Angiographic Manifestations Patients with PVA are generally younger and have fewer coronary risk factors (with the exception of cigarette smoking) than do patients with NSTE-ACS. Cardiac examination is usually unremarkable in the absence of ischemia. The clinical diagnosis of PVA is made by the detection of transient ST-segment elevation with rest pain. Many patients also exhibit multiple episodes of asymptomatic ST-segment elevation (silent ischemia). Small elevations of troponin may occur in patients with prolonged attacks.


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InternalMed_Harrison. Coronary angiography demonstrates transient coronary spasm as the diagnostic hallmark of PVA. Atherosclerotic plaques in at least one proximal coronary artery occur in about half of patients, and in these patients, spasm usually occurs within 1 cm of the plaque. Focal spasm is most common in the right coronary artery, and it may occur at one or more sites in one artery or in multiple arteries simultaneously. Hyperventilation or intracoronary acetylcholine has been used to provoke focal coronary stenosis on angiography or to provoke rest angina with ST-segment elevation to establish the diagnosis.


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InternalMed_Harrison. Nitrates and calcium channel blockers are the main therapeutic agents. Aspirin may actually increase the severity of ischemic episodes, possibly as a result of the sensitivity of coronary tone to modest changes in the synthesis of prostacyclin. The response to beta blockers is variable. Coronary revascularization may be helpful in patients who also have discrete, flow-limiting, proximal fixed obstructive lesions.


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InternalMed_Harrison. Prognosis Many patients with PVA pass through an acute, active phase, with frequent episodes of angina and cardiac events during the first 6 months after presentation. Survival at 5 years is excellent (~90–95%). Patients with no or mild fixed coronary obstruction tend to experience a more benign course than do patients with associated severe obstructive lesions. Nonfatal MI occurs in up to 20% of patients by 5 years. Patients with PVA who develop serious arrhythmias during spontaneous episodes of pain are at a higher risk for sudden cardiac death. In most patients who survive an infarction or the initial 3to 6-month period of frequent episodes, there is a tendency for symptoms and cardiac events to diminish over time. ST-Segment Elevation Myocardial infarction Elliott M. Antman, Joseph Loscalzo Acute myocardial infarction (AMI) is one of the most common diag-noses in hospitalized patients in industrialized countries. In the United 295


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InternalMed_Harrison. States, approximately 525,000 patients experience a new AMI, and 190,000 experience a recurrent AMI each year. More than half of AMI-related deaths occur before the stricken individual reaches the hospital. The in-hospital mortality rate after admission for AMI has declined from 10% to about 6% over the past decade. The 1-year mortality rate after AMI is about 15%. Mortality is approximately fourfold higher in elderly patients (over age 75) as compared with younger patients.


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InternalMed_Harrison. When patients with prolonged ischemic discomfort at rest are first seen, the working clinical diagnosis is that they are suffering from an acute coronary syndrome (Fig. 295-1). The 12-lead electrocardiogram (ECG) is a pivotal diagnostic and triage tool because it is at the center of the decision pathway for management; it permits distinction of those patients presenting with ST-segment elevation from those presenting without ST-segment elevation. Serum cardiac biomarkers are obtained to distinguish unstable angina (UA) from non-ST-segment elevation myocardial infarction (NSTEMI) and to assess the magnitude of an ST-segment elevation myocardial infarction (STEMI). This chapter focuses on the evaluation and management of patients with STEMI, while Chap. 294 discusses UA/NSTEMI. Acute coronary syndrome Presentation Working Dx ECG Biochem. marker Final Dx Myocardial infarction Unstable angina NQMI Qw MI No ST elevation NSTEMI ST elevation Ischemic Discomfort


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InternalMed_Harrison. FIGURE 295-1 Acute coronary syndromes. Following disruption of a vulnerable plaque, patients experience ischemic discomfort resulting from a reduction of flow through the affected epicardial coronary artery. The flow reduction may be caused by a completely occlusive thrombus (right) or subtotally occlusive thrombus (left). Patients with ischemic discomfort may present with or without ST-segment elevation. Of patients with ST-segment elevation, the majority (wide red arrow) ultimately develop a Q wave on the ECG (Qw MI), while a minority (thin red arrow) do not develop Q wave and, in older literature, were said to have sustained a non-Q-wave MI (NQMI). Patients who present without ST-segment elevation are suffering from either unstable angina or a non-ST-segment elevation MI (NSTEMI) (wide green arrows), a distinction that is ultimately made based on the presence or absence of a serum cardiac marker such as CK-MB or a cardiac troponin detected in the blood. The majority of patients


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InternalMed_Harrison. green arrows), a distinction that is ultimately made based on the presence or absence of a serum cardiac marker such as CK-MB or a cardiac troponin detected in the blood. The majority of patients presenting with NSTEMI do not develop a Q wave on the ECG; a minority develop a Qw MI (thin green arrow). Dx, diagnosis; ECG, electrocardiogram; MI, myocardial infarction. (Adapted from CW Hamm et al: Lancet 358:1533, 2001, and MJ Davies: Heart 83:361, 2000; with permission from the BMJ Publishing Group.)


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InternalMed_Harrison. PATHOPHYSIOLOGY: ROLE OF ACUTE PLAQUE RUPTURE 1599


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InternalMed_Harrison. STEMI usually occurs when coronary blood flow decreases abruptly after a thrombotic occlusion of a coronary artery previously affected by atherosclerosis. Slowly developing, high-grade coronary artery stenoses do not typically precipitate STEMI because of the development of a rich collateral network over time. Instead, STEMI occurs when a coronary artery thrombus develops rapidly at a site of vascular injury. This injury is produced or facilitated by factors such as cigarette smoking, hypertension, and lipid accumulation. In most cases, STEMI occurs when the surface of an atherosclerotic plaque becomes disrupted (exposing its contents to the blood) and conditions (local or systemic) favor thrombogenesis. A mural thrombus forms at the site of plaque disruption, and the involved coronary artery becomes occluded. Histologic studies indicate that the coronary plaques prone to disruption are those with a rich lipid core and a thin fibrous cap (Chap. 291e). After an initial platelet


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InternalMed_Harrison. artery becomes occluded. Histologic studies indicate that the coronary plaques prone to disruption are those with a rich lipid core and a thin fibrous cap (Chap. 291e). After an initial platelet monolayer forms at the site of the disrupted plaque, various agonists (collagen, ADP, epinephrine, serotonin) promote platelet activation. After agonist stimulation of platelets, thromboxane A2 (a potent local vasoconstrictor) is released, further platelet activation occurs, and potential resistance to fibrinolysis develops.


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InternalMed_Harrison. In addition to the generation of thromboxane A2, activation of platelets by agonists promotes a conformational change in the glycoprotein IIb/IIIa receptor (Chap. 140). Once converted to its functional state, this receptor develops a high affinity for soluble adhesive proteins (i.e., integrins) such as fibrinogen. Since fibrinogen is a multivalent molecule, it can bind to two different platelets simultaneously, resulting in platelet cross-linking and aggregation.


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InternalMed_Harrison. The coagulation cascade is activated on exposure of tissue factor in damaged endothelial cells at the site of the disrupted plaque. Factors VII and X are activated, ultimately leading to the conversion of prothrombin to thrombin, which then converts fibrinogen to fibrin (Chap. 141). Fluid-phase and clot-bound thrombin participates in an autoamplification reaction leading to further activation of the coagulation cascade. The culprit coronary artery eventually becomes occluded by a thrombus containing platelet aggregates and fibrin strands.


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InternalMed_Harrison. In rare cases, STEMI may be due to coronary artery occlusion caused by coronary emboli, congenital abnormalities, coronary spasm, and a wide variety of systemic—particularly inflammatory—diseases. The amount of myocardial damage caused by coronary occlusion depends on (1) the territory supplied by the affected vessel, (2) whether or not the vessel becomes totally occluded, (3) the duration of coronary occlusion, (4) the quantity of blood supplied by collateral vessels to the affected tissue, (5) the demand for oxygen of the myocardium whose blood supply has been suddenly limited, (6) endogenous factors that can produce early spontaneous lysis of the occlusive thrombus, and (7) the adequacy of myocardial perfusion in the infarct zone when flow is restored in the occluded epicardial coronary artery.


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InternalMed_Harrison. Patients at increased risk for developing STEMI include those with multiple coronary risk factors (Chap. 291e) and those with UA (Chap. 294). Less common underlying medical conditions predisposing patients to STEMI include hypercoagulability, collagen vascular disease, cocaine abuse, and intracardiac thrombi or masses that can produce coronary emboli. There have been major advances in the management of STEMI with recognition that the “chain of survival” involves a highly integrated system starting with prehospital care and extending to early hospital management so as to provide expeditious implementation of a reperfusion strategy. In up to one-half of cases, a precipitating factor appears to be present before STEMI, such as vigorous physical exercise, emotional stress, or a medical or surgical illness. Although STEMI may commence at any time of the day or night, circadian variations have been reported such that clusters are seen in the morning within a few hours of awakening.


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InternalMed_Harrison. Pain is the most common presenting complaint in patients with STEMI. The pain is deep and visceral; adjectives commonly used to 1600 describe it are heavy, squeezing, and crushing, although, occasionally, it is described as stabbing or burning (Chap. 19). It is similar in character to the discomfort of angina pectoris (Chap. 293) but commonly occurs at rest, is usually more severe, and lasts longer. Typically, the pain involves the central portion of the chest and/or the epigastrium, and, on occasion, it radiates to the arms. Less common sites of radiation include the abdomen, back, lower jaw, and neck. The frequent location of the pain beneath the xiphoid and epigastrium and the patients’ denial that they may be suffering a heart attack are chiefly responsible for the common mistaken impression of indigestion. The pain of STEMI may radiate as high as the occipital area but not below the umbilicus. It is often accompanied by weakness, sweating, nausea, vomiting, anxiety, and a sense


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InternalMed_Harrison. of indigestion. The pain of STEMI may radiate as high as the occipital area but not below the umbilicus. It is often accompanied by weakness, sweating, nausea, vomiting, anxiety, and a sense of impending doom. The pain may commence when the patient is at rest, but when it begins during a period of exertion, it does not usually subside with cessation of activity, in contrast to angina pectoris. The pain of STEMI can simulate pain from acute pericarditis (Chap. 288), pulmonary embolism (Chap. 300), acute aortic dissection (Chap. 301), costochondritis, and gastrointestinal disorders. These conditions should therefore be considered in the differential diagnosis. Radiation of discomfort to the trapezius is not seen in patients with STEMI and may be a useful distinguishing feature that suggests pericarditis is the correct diagnosis. However, pain is not uniformly present in patients with STEMI. The proportion of painless STEMIs is greater in patients with diabetes mellitus, and it increases


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InternalMed_Harrison. pericarditis is the correct diagnosis. However, pain is not uniformly present in patients with STEMI. The proportion of painless STEMIs is greater in patients with diabetes mellitus, and it increases with age. In the elderly, STEMI may present as sudden-onset breathlessness, which may progress to pulmonary edema. Other less common presentations, with or without pain, include sudden loss of consciousness, a confusional state, a sensation of profound weakness, the appearance of an arrhythmia, evidence of peripheral embolism, or merely an unexplained drop in arterial pressure.


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InternalMed_Harrison. Most patients are anxious and restless, attempting unsuccessfully to relieve the pain by moving about in bed, altering their position, and stretching. Pallor associated with perspiration and coolness of the extremities occurs commonly. The combination of substernal chest pain persisting for >30 min and diaphoresis strongly suggests STEMI. Although many patients have a normal pulse rate and blood pressure within the first hour of STEMI, about one-fourth of patients with anterior infarction have manifestations of sympathetic nervous system hyperactivity (tachycardia and/or hypertension), and up to one-half with inferior infarction show evidence of parasympathetic hyperactivity (bradycardia and/or hypotension).


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InternalMed_Harrison. The precordium is usually quiet, and the apical impulse may be difficult to palpate. In patients with anterior wall infarction, an abnormal systolic pulsation caused by dyskinetic bulging of infarcted myocardium may develop in the periapical area within the first days of the illness and then may resolve. Other physical signs of ventricular dysfunction include fourth and third heart sounds, decreased intensity of the first heart sound, and paradoxical splitting of the second heart sound (Chap. 267). A transient midsystolic or late systolic apical systolic murmur due to dysfunction of the mitral valve apparatus may be present. A pericardial friction rub may be heard in patients with transmural STEMI at some time in the course of the disease, if they are examined frequently. The carotid pulse is often decreased in volume, reflecting reduced stroke volume. Temperature elevations up to 38°C may be observed during the first week after STEMI. The arterial pressure is variable; in most


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InternalMed_Harrison. pulse is often decreased in volume, reflecting reduced stroke volume. Temperature elevations up to 38°C may be observed during the first week after STEMI. The arterial pressure is variable; in most patients with transmural infarction, systolic pressure declines by approximately 10–15 mmHg from the preinfarction state.


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InternalMed_Harrison. STEMI progresses through the following temporal stages: (1) acute (first few hours–7 days), (2) healing (7–28 days), and (3) healed (≥29 days). When evaluating the results of diagnostic tests for STEMI, the temporal phase of the infarction must be considered. The laboratory tests of value in confirming the diagnosis may be divided into four groups: (1) ECG, (2) serum cardiac biomarkers, (3) cardiac imaging, and (4) nonspecific indices of tissue necrosis and inflammation.


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InternalMed_Harrison. The electrocardiographic manifestations of STEMI are described in Chap. 268. During the initial stage, total occlusion of an epicardial coronary artery produces ST-segment elevation. Most patients initially presenting with ST-segment elevation ultimately evolve Q waves on the ECG. However, Q waves in the leads overlying the infarct zone may vary in magnitude and even appear only transiently, depending on the reperfusion status of the ischemic myocardium and restoration of transmembrane potentials over time. A small proportion of patients initially presenting with ST-segment elevation will not develop Q waves when the obstructing thrombus is not totally occlusive, obstruction is transient, or if a rich collateral network is present. Among patients presenting with ischemic discomfort but without ST-segment elevation, if a serum cardiac biomarker of necrosis (see below) is detected, the diagnosis of NSTEMI is ultimately made (Fig. 295-1). A minority of patients who present initially


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InternalMed_Harrison. without ST-segment elevation, if a serum cardiac biomarker of necrosis (see below) is detected, the diagnosis of NSTEMI is ultimately made (Fig. 295-1). A minority of patients who present initially without ST-segment elevation may develop a Q-wave MI. Previously, it was believed that transmural myocardial infarction (MI) is present if the ECG demonstrates Q waves or loss of R waves, and nontransmural MI may be present if the ECG shows only transient ST-segment and T-wave changes. However, electrocardiographic-pathologic correlations are far from perfect and terms such as Q-wave MI, non-Q-wave MI, transmural MI, and nontransmural MI, have been replaced by STEMI and NSTEMI (Fig. 295-1). Contemporary studies using magnetic resonance imaging (MRI) suggest that the development of a Q wave on the ECG is more dependent on the volume of infarcted tissue rather than the transmurality of infarction.


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InternalMed_Harrison. Certain proteins, called serum cardiac biomarkers, are released from necrotic heart muscle after STEMI. The rate of liberation of specific proteins differs depending on their intracellular location, their molecular weight, and the local blood and lymphatic flow. Cardiac biomarkers become detectable in the peripheral blood once the capacity of the cardiac lymphatics to clear the interstitium of the infarct zone is exceeded and spillover into the venous circulation occurs. The temporal pattern of protein release is of diagnostic importance. The criteria for AMI require a rise and/or fall in cardiac biomarker values with at least one value above the 99th percentile of the upper reference limit for normal individuals


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InternalMed_Harrison. Cardiac-specific troponin T (cTnT) and cardiac-specific troponin I (cTnI) have amino-acid sequences different from those of the skeletal muscle forms of these proteins. These differences permitted the development of quantitative assays for cTnT and cTnI with highly specific monoclonal antibodies. Since cTnT and cTnI are not normally detectable in the blood of healthy individuals but may increase after STEMI to levels many times higher than the upper reference limit (the highest value seen in 99% of a reference population not suffering from MI), the measurement of cTnT or cTnI is of considerable diagnostic usefulness, and they are now the preferred biochemical markers for MI (Fig. 295-2). With improvements in the assays for the cardiac-specific troponins, it is now possible to detect concentrations <1 ng/L in patients without ischemic-type chest discomfort. The cardiac troponins are particularly valuable when there is clinical suspicion of either skeletal muscle injury or a small MI


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InternalMed_Harrison. <1 ng/L in patients without ischemic-type chest discomfort. The cardiac troponins are particularly valuable when there is clinical suspicion of either skeletal muscle injury or a small MI that may be below the detection limit for creatine phosphokinase (CK) and its MB isoenzyme (CK-MB) measurements, and they are, therefore, of particular value in distinguishing UA from NSTEMI. In practical terms, the high-sensitivity troponin assays are of less immediate value in patients with STEMI. Contemporary urgent reperfusion strategies necessitate making a decision (based largely on a combination of clinical and ECG findings) before the results of blood tests have returned from the laboratory. Levels of cTnI and cTnT may remain elevated for 7–10 days after STEMI.


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InternalMed_Harrison. CK rises within 4–8 h and generally returns to normal by 48–72 h (Fig. 295-2). An important drawback of total CK measurement is its lack of specificity for STEMI, as CK may be elevated with skeletal muscle disease or trauma, including intramuscular injection. The MB isoenzyme of CK has the advantage over total CK that it is not present in significant concentrations in extracardiac tissue and, therefore, Multiples of the AMI cutoff limit Zone of necrosing myocardium Actin Troponin complex bound to actin filament Lymphatic system Venous system Days after onset of AMI


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InternalMed_Harrison. FIGURE 295-2 The zone of necrosing myocardium is shown at the top of the figure, followed in the middle portion of the figure by a diagram of a cardiomyocyte that is in the process of releasing biomarkers. The biomarkers that are released into the interstitium are first cleared by lymphatics followed subsequently by spillover into the venous system. After disruption of the sarcolemmal membrane of the cardiomyocyte, the cytoplasmic pool of biomarkers is released first (left-most arrow in bottom portion of figure). Markers such as myoglobin and CK isoforms are rapidly released, and blood levels rise quickly above the cutoff limit; this is then followed by a more protracted release of biomarkers from the disintegrating myofilaments that may continue for several days. Cardiac troponin levels rise to about 20 to 50 times the upper reference limit (the 99th percentile of values in a reference control group) in patients who have a “classic” acute myocardial infarction (MI) and sustain