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Mohamad Kenaan

, and Kim Eagle

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date: 03 July 2022

  1. A. Introduction

    1. a. Definition. Myocardial ischemia results when the oxygen supply is inadequate to meet the oxygen demands of the cardiac muscle. Although other diseases may reduce oxygen supply (e.g., coronary artery spasm, valve disease, hypoxemia, anemia) or increase the oxygen demand (e.g., tachycardia as a result of infection or arrhythmia, thyrotoxicosis), the most common cause of myocardial ischemia is coronary artery disease due to atherosclerosis.

    2. b. Risk factors for atherosclerosis include:

      1. i. Age and gender: men older than 45 years and women older than 55 years

      2. ii. Hypertension

      3. iii. Diabetes mellitus

      4. iv. Smoking

      5. v. Dyslipidemia: elevated low-density lipoprotein (LDL) cholesterol and low high-density lipoprotein (HDL) cholesterol

      6. vi. Family history of premature atherosclerosis (first-degree male relative before the age of 55 years or female relative before the age of 65 years)

  2. B. Clinical Manifestations of Coronary Artery Disease

    1. a. Symptoms

      1. i. Angina pectoris is the typical symptom associated with myocardial ischemia. It is described as a diffuse pressure or heaviness beneath or to the left of the midsternum that increases with physical exertion or mental stress, typically lasts from a few minutes up to 20–30 minutes, and subsides gradually with rest or nitroglycerin.

        1. 1. Additional features. If chest pain radiates to the neck or left arm or is accompanied by dyspnea, diaphoresis, or lightheadedness, the likelihood of myocardial ischemia is increased. However, keep in mind that these features need not be present.

        2. 2. Classification. Angina may be stable or unstable:

          • a. Stable angina usually results from a fixed atherosclerotic plaque that limits oxygen delivery to the cardiac tissue. It is usually caused by stenosis involving 70% or more of the diameter of a coronary vessel. Limitation to blood flow can also be affected by length of the stenotic segment and presence of multiple areas (e.g., tandem) stenosis. The oxygen mismatch that results causes a predictable and stable pattern of chest pain during exertion.

          • b. Unstable angina usually results when an atherosclerotic plaque ruptures with the development of superimposed thrombus. As a result, oxygen supply becomes acutely inadequate at lower activity levels or at rest. This often presents as an abrupt change in the pattern of angina, including more severe/intense chest pain, more frequent episodes or longer duration of pain, lower level of exertion needed to induce symptoms, or pain at rest. Unstable angina can also present as new-onset symptoms occurring at mild levels of exertion within the past 4–6 weeks (discussed more in Chapter 11).

        3. 3. “Anginal equivalents.” Other symptoms unaccompanied by chest pain (e.g., dyspnea) may actually represent “anginal equivalents.” Examples of anginal equivalents include exertional dyspnea, exercise intolerance or fatigue, jaw/left arm pain, diaphoresis, nausea/vomiting, midepigastric pain, and lightheadedness. Women and older adults are more likely to present with atypical symptoms.

    2. b. Physical examination findings. A normal physical examination does not rule out the possibility of ischemic heart disease. Transient signs may occur during ischemic episodes, including hypertension or, less commonly, hypotension; ventricular or supraventricular arrhythmias; a third or fourth heart sound (S3 or S4); or a holosystolic murmur over the apex (representative of mitral regurgitation as a result of papillary muscle ischemia). The presence of elevated jugular venous pressure, pulmonary edema, a gallop rhythm, pathologic murmurs, or signs of cardiac risk factors (e.g., peripheral vascular disease from diabetes) should increase suspicion of coronary artery disease. On the other hand, pain reproduced by palpation of the chest wall with similar character/quality of chest discomfort suggests a musculoskeletal etiology.

  3. C. Approach to the Patient. Angina and ischemic heart disease need to be differentiated from the many other causes of chest pain (see Chapter 9).

    1. a. Patient history. The history can be used to classify the symptoms of chest pain as typical, atypical, or noncardiac chest pain. Substernal chest pain with characteristic quality and duration that is induced by exertional or emotional stress and relieved by rest or sublingual nitroglycerin is said to be “typical,” whereas chest pain lacking all three characteristics is considered “noncardiac.” In patients with classic symptoms, the diagnosis of stable or unstable angina can be made on the basis of history alone. An assessment of a patient’s atherosclerotic risk profile is critical for determining suspicion for ischemic heart disease.

    2. b. Resting electrocardiography. Chronic ischemic heart disease can be diagnosed in asymptomatic patients by finding evidence of old myocardial infarctions (e.g., q waves) or active ischemia (e.g., ST segment depression, T wave inversion) on a resting electrocardiogram (EKG). Although up to 50% of patients with stable coronary artery disease can have a normal EKG, a resting EKG is recommended for all patients. Resting EKG can be helpful if obtained during an episode of active symptoms because findings can corroborate clinical symptoms.

    3. c. Patients with episodes of prolonged chest pain or rapidly accelerating angina should have cardiac biomarkers (i.e., creatine kinase [CK] or troponin) evaluated to rule out recent myocardial infarction.

    4. d. Stress tests may be helpful both diagnostically in patients with atypical chest pain and prognostically in patients with typical angina. When selecting a stress test, consideration should be given to the type of stress (exercise vs. pharmacologic) as well as the modality of evaluating for ischemia (EKG, echocardiogram, nuclear myocardial imaging, or cardiac magnetic resonance imaging [MRI]). For diagnostic purposes, a stress test is most helpful if the pretest probability of coronary artery disease is intermediate. If a patient is able to perform routine activities without difficulties, exercise testing is preferred because it provides added functional and prognostic information. Some stress testing modalities (MRI or positron emission tomography [PET] scan) can only be performed with pharmacologic stressors.

      1. i. Types of stress test

        1. 1. Exercise EKG. This type of stress test should be considered in patients without known coronary artery disease and with intermediate pretest probability, who have an interpretable EKG and are able to exercise. Baseline EKG abnormalities such as left bundle branch block, ventricular pacing, preexcitation (Wolff-Parkinson-White syndrome), or baseline ST segment depressions exceeding 1 mm preclude accurate assessment of ischemia. The presence of at least 1 mm of downsloping or horizontal ST segment depression on EKG with exercise is generally considered a positive test for ischemia. Advantages of exercise testing include the ability to obtain prognostic information. Disadvantages include a lower sensitivity compared with stress imaging and lower specificity in patients with abnormal resting EKGs (e.g., ST changes with left ventricular hypertrophy) and in patients taking some medications (digoxin, hydrochlorothiazide, oral contraceptives). Moreover, exercise stress testing rarely allows for localization of ischemic territory (only with ST segment elevations).

        2. 2. Myocardial perfusion scintigraphy (single-photon emission computed tomography [SPECT] or PET scans) is performed in conjunction with stress electrocardiography and involves the injection of a radioactive tracer (thallium-201 [201Tl]- or technetium-99m [99mTc]-based agents [sestamibi] for SPECT, or rubidium for PET) into the peripheral venous blood. Cardiac muscle cells that are ischemic or infarcted do not take up these tracers well compared with normally perfused, living cells.

          • a. Reversible defects, areas that lack tracer uptake on stress images but “fill in” on rest images, indicate noninfarcted, ischemic tissue. Fixed defects are present similarly on both stress and rest imaging and usually denote prior infarction.

          • b. In patients unable to exercise, vasodilators, such as dipyridamole, adenosine, or regadenoson, produce vasodilation in normal coronary arteries out of proportion to that produced in atherosclerotic vessels and therefore decrease blood flow and radioactive tracer delivery to cardiac regions served by diseased vessels. Dipyridamole and adenosine are contraindicated in patients with significant reversible airway disease because they may precipitate bronchospasm. However, regadenoson can be used safely in patients with a history of obstructive lung disease in the absence of active exacerbation or wheezing. Regadenoson is contraindicated in patients with high-grade atrioventricular (AV) node block.

        3. 3. Exercise or dobutamine stress echocardiography. If stress results in a decrease in ejection fraction or new/worsening segmental wall motion abnormalities, cardiac ischemia is presumed. Intravenous dobutamine increases oxygen demand by increasing heart rate and contractility and may be used as an alternative to exercise.

        4. 4. Pharmacologic stress cardiac MRI provides data about stress-induced wall-motion abnormalities (similar to stress echocardiography), whereas contrast images provide data about perfusion abnormalities.

      2. ii. Choosing a test. Although one stress test cannot be universally recommended over the others, certain caveats apply:

        1. 1. Patients with EKG abnormalities may not be evaluated appropriately with standard exercise electrocardiography alone. Imaging is frequently added to increase sensitivity and specificity.

        2. 2. Echocardiography is more likely to be inadequate in obese patients and patients with chronic obstructive pulmonary disease (COPD) because of poor images. The use of echo contrast can help improve image quality.

        3. 3. Patients who cannot be still for the longer duration of a nuclear stress test or have significant claustrophobia might do better with echocardiography than with nuclear testing.

          Hot Key

          For the more commonly used imaging stress testing (echocardiography and nuclear), the sensitivity and specificity are generally in the mid-80% range.

    5. e. Cardiac computed tomography (CT) angiography can be useful in intermediate-risk patients who are unable to exercise, have uninterpretable EKG, or have equivocal stress testing results. The sensitivity of cardiac CT angiography approaches 97%, with specificity in the mid-80% range. It has an excellent negative predictive value (99%) but may be subject to overestimation of the degree of stenosis (especially in the setting of calcification) and is less validated in providing functional data.

    6. f. Cardiac catheterization with coronary angiography is the gold standard for diagnosing obstructive coronary artery disease. It should be considered in patients with presumed stable ischemic heart disease (SIHD) with continued severe symptoms despite optimal medical therapy, in patients with clinical and imaging evidence of high-risk SIHD, or in patients with high pretest probability with an equivocal or negative stress test. If catheterization demonstrates severe coronary artery disease, revascularization with coronary artery bypass surgery or percutaneous coronary intervention (PCI) may be indicated.

  4. D. Treatment

    1. a. Goals of treatment are improving mortality, reducing future risk for cardiovascular events, eliminating or minimizing symptoms, as well as controlling factors that can trigger or worsen ischemia with the least possible adverse effects.

    2. b. General measures. Because angina is most often a symptom of atherosclerosis and coronary artery disease, an essential part of treatment is aimed at identifying and treating cardiac risk factors.

      1. i. Smoking cessation

      2. ii. Control of dyslipidemia. The use of high-intensity statin therapy is recommended in the absence of contraindications to treating with statins. Patients older than 75 years may be treated with moderate-intensity statin therapy.

      3. iii. Control of hypertension (at least systolic <140 mm Hg and diastolic <90 mm Hg)

      4. iv. Control of diabetes mellitus

      5. v. Regular exercise (e.g., moderate aerobic exercise such as brisk walking for 30 minutes, five times weekly)

      6. vi. Weight loss (maintain a body mass index [BMI] of 19–25 kg/m2 and waist circumference of less than 40 inches in men and 35 inches in women).

      7. vii. Treatment of other factors that may aggravate angina (e.g., anemia, hypoxemia, thyrotoxicosis)

      8. viii. Dietary modifications (reduce intake of saturated fats, trans-fatty acids, and cholesterol, switching to a heart-healthy Mediterranean diet).

      9. ix. Screening for stress and depression

    3. c. Specific measures for the relief of angina

      1. i. Pharmacologic therapy is generally aimed at increasing myocardial oxygen supply (by coronary vasodilation), decreasing oxygen demand (by decreasing heart rate, contractility, preload, or afterload), and preventing acute thrombotic events. Most patients are initially given an aspirin, β‎-blocker, and short-acting nitrates, unless there are contraindications.

        1. 1. Aspirin (usually 81–162 mg/day) inhibits platelet aggregation and coronary thrombosis and therefore prevents acute coronary syndromes. For patients allergic to aspirin, clopidogrel may be used as an alternative or aspirin desensitization considered.

        2. 2. Nitrates lower oxygen demand by decreasing preload and afterload and increase oxygen supply by vasodilating coronary arteries.

          • a. Short-acting nitrates. Nitroglycerin 0.3–0.6 mg sublingually or by aerosol (0.4-mg metered dose spray) may be used for angina prophylaxis (the dose is taken 5 minutes before an activity known to result in angina) or immediate therapy (the dose is administered every 3–5 minutes until the pain is relieved; if pain is not relieved in 15–20 minutes, the patient should seek immediate medical attention.

          • b. Long-acting nitrates (e.g., isosorbide dinitrate, isosorbide mononitrate, transdermal nitroglycerin patches) are recommended for the treatment of angina when optimization of β‎-blockers does not provide adequate symptom control or when β‎-blockers are contraindicated. An interval of approximately 10 hours per day without nitrate therapy is needed to prevent tachyphylaxis, so the last dose is often given after dinner, and patches are removed overnight. Headaches may occur with the initiation of nitrate therapy; if they can be managed conservatively, they frequently resolve after 1–2 weeks. Counseling to avoid use of nitrates with phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) is important.

        3. 3. β‎-Blockers decrease heart rate and myocardial contractility, resulting in symptomatic control of angina by lowering oxygen demands. In addition, unlike other antianginal agents, they have been shown to have a mortality benefit in patients with coronary artery disease who have already experienced myocardial infarction.

          • a. In the absence of left ventricular systolic dysfunction, all β‎-blockers can be used with equal effectiveness. Frequently used agents include metoprolol (50–100 mg orally twice daily) and atenolol (50–100 mg orally once daily).

          • b. Gradually, the dose of β‎-blockers may be increased until symptoms are controlled, side effects develop, blood pressure falls below approximately 100/60 mm Hg, resting heart rate falls below approximately 55 beats/min, or maximal dose is reached. If symptoms are still not controlled, long-acting nitrates or calcium channel blockers may be added and increased as needed with attention to symptoms, side effects, and blood pressure.

          • c. β‎-Blockers are contraindicated in patients with significant bradyarrhythmias. In patients with COPD, a β‎1-selective agent (e.g., metoprolol or atenolol) should be used; these agents may need to be avoided in patients with severe COPD. Similarly, care should be practiced when using β‎-blockers in patients who have severe peripheral artery disease. While patients with impaired left ventricular function benefit from β‎-blockers, these must be started with at a low dose (e.g., 12.5 mg metoprolol or 3.125 mg carvedilol) and titrated up gradually with frequent patient monitoring. β‎-Blockers that are of proven mortality benefit in heart failure with reduced ejection fraction include metoprolol succinate, carvedilol, and bisoprolol.

          • d. Abrupt withdrawal of β‎-blocker therapy should be avoided because cessation is associated with increased risk for acute myocardial infarction and sudden cardiac death).

        4. 4. Calcium channel blockers lower oxygen demand (by decreasing heart rate, contractility, and afterload) and may increase oxygen supply (by inducing vasodilation of the coronary arteries).

          • a. Agents include nondihydropyridines (verapamil, diltiazem) and dihydropyridines (nifedipine, felodipine, amlodipine), in order of increased effect on lowering systemic vascular resistance and decreased effect on myocardial inotropy and chronotropy. Verapamil and diltiazem are usually preferred for angina but should be used carefully with β‎-blockers. If acute coronary syndrome is suspected, avoid the use of nifedipine (see Chapter 11).

          • b. Calcium channel blockers have not been associated with improved survival after myocardial infarction and may lead to a worse outcome; therefore, they are not the initial drugs of choice for most patients with coronary artery disease, particularly if left ventricular dysfunction is present. Amlodipine alone has been shown to be safe in those with ejection fractions less than 40%.

        5. 5. Ranolazine is an agent that can reduce the frequency of angina and improve exercise performance. It may be considered in patients who experience continued symptoms despite optimal medical therapy with β‎-blockers as well as long-acting nitrates/calcium channel blockers. Ranolazine can cause QT prolongation, and careful monitoring is necessary. It is never used as first-line treatment of angina.

        6. 6. Angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor blockers) do not acutely improve angina symptoms. However, tissue-based ACE inhibitors (i.e., ramipril) reduce mortality rates in patients with ischemic heart disease, likely because of coronary plaque stabilization. These agents should be used in all patients with stable ischemic heart disease with reduced left ventricular systolic function (left ventricular ejection fraction <40%), chronic kidney disease, diabetes mellitus, or hypertension unless contraindicated.

      2. ii. Revascularization. The indications for medical therapy versus coronary revascularization in addition to optimal medical therapy should be evaluated on a case-by-case basis with cardiology consultation.

        1. 1. Medical therapy versus PCI. The COURAGE trial consisted of 2287 patients with stable angina who were randomized to aggressive medical therapy (β‎-blockers, calcium channel blockers, antiplatelet agents, nitrates, and aggressive statin therapy) versus aggressive medical therapy with PCI. At more than 4 years of follow-up, there was no significant difference in mortality or hospitalizations between the two groups. A higher percentage of those in the PCI group were angina free at 3 years, but there was no significant difference after 5 years between groups. Therefore, all patients should receive aggressive medical therapy with the decision for PCI made on an individual basis. In general PCI is reserved for high-risk patients or those who experience continued symptoms despite optimal medical therapy.

        2. 2. Coronary artery bypass surgery is generally considered superior in the treatment of patients with left main coronary artery disease (>50% diameter occlusion) or three-vessel disease (>70% diameter occlusion) associated with decreased left ventricular function (<50%). Diabetic patients also benefit more from bypass surgery compared with PCI.

          • a. Bypass surgery may also benefit patients with three-vessel disease and severe angina (class III or IV) and patients with proximal left anterior descending occlusion associated with two-vessel disease; nevertheless, there is less consensus on whether bypass surgery, angioplasty, or medical therapy is appropriate in these instances.

        3. 3. Often the final choice between bypass or PCI depends on the suitability of the coronary anatomy for revascularization (i.e., good “targets” for bypass surgery, approachable lesions for PCI). This is often assessed during angiography and in consultation with interventional cardiology and cardiovascular surgery.

Suggested Further Readings

Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16.Find this resource:

Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;64:1929–49.Find this resource:

Lee TH, Boucher CA. Clinical practice. Noninvasive tests in patients with stable coronary artery disease. N Engl J Med 2001;344:1840–5. (Classic Article.)Find this resource:

Ohman EM. Clinical practice. Chronic stable angina. N Engl J Med 2016;374:1167–76.Find this resource: