A 54-year-old man presents with a 3-month history of progressive chest pain. He describes a band-like retrosternal heaviness that is brought on by walking more than 2 blocks. The discomfort lasts less than 20 minutes and is relieved with rest. His past medical history is significant for hypertension. He is a nonsmoker and has no history of diabetes. His baseline Seattle Angina Questionnaire (SAQ) frequency score is 50, suggesting almost daily angina. In addition to lisinopril, his family physician has recently maximized the patient on optimally tolerated doses of metoprolol, nitroglycerin, and rosuvastatin (20 mg). At a visit with his primary care physician 12 months ago, his high-density lipoprotein cholesterol was 50 mg/dL, his total cholesterol was 170 mg/dL, and his blood pressure (while on lisinopril) was 135 mm Hg. Physical examination reveals a body mass index of 29 kg/m², blood pressure of 145/75 mm Hg, and pulse of 58 bpm. His neck veins are not distended. There is no organomegaly and no peripheral edema, the apex is not displaced, he has normal S₁ and S₂ sounds, and no pathologic murmurs are identified.

Baseline electrocardiogram shows normal sinus rhythm without ischemia, infarction, or chamber enlargement. During the exercise stress test, the patient is able to exercise for 7 minutes with 2 mm of horizontal ST-segment depression 5 minutes after initiation of exercise lasting 2 minutes into recovery. He develops nonlimiting angina during exercise. Subsequent cardiac catheterization shows a proximal left anterior descending artery lesion of borderline significance. Fractional flow reserve decreased from 0.92 at rest to 0.80 after 150 μg of intracoronary adenosine.

Chest pain is a highly heterogeneous clinical entity with a wide array of possible etiologies ranging from relatively benign to life-threatening conditions.^1,2 The diagnostic evaluation of chest pain should be performed in parallel with management of symptoms and initiation of nonpharmacologic and pharmacologic preventive therapies.^1-3 In the outpatient setting, the most common causes are musculoskeletal and gastrointestinal conditions. Chronic chest pain attributable to atherosclerotic coronary artery disease is denoted angina pectoris, which constitutes the most common manifestation of ischemic heart disease (IHD). Other causes of chest pain that have to be considered in the differential diagnosis include pulmonary causes (eg, pleuritis, pulmonary embolism, pneumonia), gastrointestinal causes (eg, biliary disease, peptic ulcer disease, esophagitis), chest wall disorders (eg, costochondritis or herpes zoster), psychiatric causes (eg, anxiety disorders, chronic pain syndrome, factitious disorders), noncoronary cardiac causes (eg, pericarditis or aortic dissection), and nonatherosclerotic coronary causes (eg, vasculitis, coronary spasm, coronary microvascular disease). Of note, a comprehensive diagnostic approach to angina pectoris should include the assessment of concomitant secondary pathologies that may trigger or exacerbate ischemic chest pain, including thyroid disorders, valvular diseases, anemia, hypoxemia, metabolic acidosis, uremia, hypertrophic cardiomyopathy, medication toxicity, and drug abuse.

IHD is a generic term used to identify a group of pathophysiologically related syndromes in which the common denominator is myocardial ischemia.³ In more than 90% of cases, the pathologic substrate of myocardial ischemia is characterized by the presence of a hemodynamic obstructive atherosclerotic lesion that induces an imbalance between the myocardial supply (perfusion) and the myocardial demand (metabolic consumption) of oxygen and metabolites.

Angina pectoris can be defined as a clinical syndrome characterized paroxysmal or recurrent attacks of precordial chest discomfort caused by transient (generally between 15 seconds and 15 minutes) imbalance in myocardial supply and demand. At least 3 forms of angina pectoris can be described: (1) stable angina, (2) unstable angina, and (3) variant or Prinzmetal angina. The common denominator of these forms of chest discomfort is myocardial ischemia, caused by pathophysiologic changes in myocardial perfusion or myocardial demand, with or without coronary artery pathology (Figure 10-1).³

Stable angina is the most common form of angina pectoris.^1-3 The main pathologic substrate of stable angina is coronary atherosclerosis in which an obstructive atherosclerotic plaque locally reduces the coronary blood flow and downstream myocardial perfusion. In this case, myocardial ischemia and subsequent chest discomfort are triggered by an increase in myocardial demand (produced by increase in physical activity, emotional reactions, hormonal stimulation, or any other cause of increased myocardial workload). A graded increase in the severity, frequency, or threshold of chest pain can be observed in stable angina as the fixed coronary artery atherosclerotic narrowing increases, thereby progressively reducing local myocardial arterial blood supply. A typical feature of stable angina is that it is usually relieved by rest (which decreases myocardial demand) or by administering a vasodilator agent (which increases myocardial blood perfusion). Measures to either improve myocardial perfusion (through pharmacologic vasodilation or invasive revascularization) or reduce myocardial metabolic demand (through pharmacologic physiological or metabolic inhibition) can relieve the chest discomfort and pain.

Unstable angina is differentiated from stable angina by more frequent episodes of chest discomfort, more commonly of prolonged duration, that are precipitated by lower levels of myocardial workload or that even occur at rest. The pathologic substrate of unstable angina is constituted by acute plaque changes with exposure of plaque components to the coronary blood flow and local formation of nonocclusive thrombus. Various degrees of local vasospasm with or without distal embolization of plaque components generally occur and contribute to the different and more severe patterns of chest discomfort observed in stable angina.^1-3

Variant angina is the least common pattern of angina, being characterized by paroxysmal and transitory episodes of myocardial ischemia triggered by coronary artery vasospasm (with subsequent decrease in local myocardial blood supply). Of note, the anginal attacks are often not related to physical activity, emotional stressors, or changes in heart rate or blood pressure. A certain degree of coronary atherosclerosis may be present, and in this case, anginal attacks tend to be more severe and possibly associated with myocardial infarction with cardiac biomarker elevation. Characteristically, variant angina is more prevalent in women and occurs more often at night.^1-3

A comprehensive algorithm for the diagnostic workup of IHD is illustrated in Figure 10-2. The first step for evaluation and diagnosis of stable angina is the clinical examination, which consists of careful characterization of the chest pain and assessment of concomitant cardiovascular risk factors.^1-3 Symptom characterization should include the quality, location, severity, duration, associated symptoms, and provocative or alleviating factors. After a detailed characterization of chest pain, the presence of risk factors for IHD should be determined. These include cigarette smoking, hyperlipidemia, diabetes mellitus, hypertension, obesity or metabolic syndrome, peripheral artery disease, cerebrovascular disease, and family history of premature IHD.^4-9 After the characterization of the past medical history and physical examination, an electrocardiogram (ECG) at rest is recommended in patients with chest pain. Patients with chest pain who present with ECG abnormalities at rest (including evidence of prior myocardial infarction, ST or T-wave inversions, left bundle branch block, and ventricular hypertrophy, among others) are at higher risk of primary or secondary cardiovascular events.³ Then, the pretest likelihood determines whether or not a patient is suitable for noninvasive testing for IHD.

Currently, functional cardiac testing to detect inducible myocardial ischemia constitutes the gold standard for detection of IHD.^1-3 All functional tests rely on the principle of the “ischemic cascade,” in which progressively greater ischemia (determined by the imbalance between myocardial oxygen supply and demand) produces sequential pathophysiologic myocardial changes (including changes in perfusion, wall motion changes, and electrical abnormalities) detectable with the various testing modalities.^1-3 The severity of the induced myocardial ischemia (and therefore of the subsequent pathophysiologic changes) is influenced by the severity of the hemodynamic obstruction and concomitant clinical or anatomic factors that may increase myocardial oxygen demand or decrease oxygen supply. Functional, noninvasive cardiac tests include exercise ECG, exercise myocardial perfusion imaging or echocardiography, and pharmacologic stress with myocardial perfusion imaging, echocardiography, or cardiac magnetic resonance.^1-3 Current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines gave a Class I recommendation to standard exercise ECG and to exercise stress test with myocardial perfusion imaging or echocardiography in patients able to exercise.^1-3 In patients unable to exercise or with disabling comorbidities, pharmacologic stress with myocardial perfusion imaging or echocardiography has a Class I recommendation for the initial diagnosis of IHD.^1-3 Cardiac computed tomography angiography (CCTA) has emerged as an important noninvasive anatomic diagnostic tool for IHD.¹⁰ CCTA allows for the anatomic characterization of the coronary vasculature.¹⁰ In addition, CCTA allows for estimation of the coronary artery calcium score, which can provide meaningful prognostic information for future atherothrombotic events.¹⁰ Currently, for the initial diagnosis of IHD, CCTA has a Class IIb recommendation in patients able to exercise and a Class IIa recommendation in patients unable to exercise, patients with prior inconclusive diagnostic results, or patients unable to undergo nuclear myocardial perfusion imaging or echocardiography. The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial randomly assigned 10,003 symptomatic patients to a strategy of anatomic assessment with CCTA versus functional evaluation with exercise ECG, nuclear stress testing, or stress echocardiography. This study showed no significant differences in the primary patient-oriented end point of death, myocardial infarction, hospitalization for unstable angina, or major procedural complication at 2 years between the 2 diagnostic strategies, suggesting that an initial diagnostic strategy with CCTA does not improve clinical outcomes in these settings.¹¹

Coronary angiography (CA) constitutes the gold standard for the diagnosis of coronary artery disease.^1-3 The main goals of CA are (1) to characterize the presence and extent of obstructive coronary lesions and (2) to guide the decision making between invasive revascularization strategies (percutaneous coronary intervention [PCI] versus coronary artery bypass graft [CABG]). CA detects the presence, location, extent, severity, and morphology of the coronary obstructive lesion. The extent of coronary artery disease (CAD; number of diseased vessels), location of stenotic lesions (proximal versus distal), and severity of obstruction (percent stenosis), as assessed with CA, strongly correlate with long-term survival and risk for major cardiovascular events.^1-3 Per the ACC/AHA 2012 guidelines, in the setting of stable angina, CA has a Class I recommendation in patients with suspected IHD with high likelihood of CAD based on clinical and functional testing, as well as in patients with presumed IHD who have persistent anginal symptoms despite optimal medical therapy. In patients with inconclusive prognostic information after functional testing, CA carries a Class IIa recommendation in order to improve risk stratification.^1-3 In addition, when coupled with fractional flow reserve (FFR), testing improves the diagnostic discrimination of coronary lesions suitable for revascularization to improve symptoms and survival.^1-3 FFR is the ratio between the pressure distal to a coronary stenosis and the central aortic pressure during maximum coronary hyperemia after intracoronary administration of adenosine. FFR values ≤0.80 have been established as the cutoff to consider a coronary lesion as hemodynamically significant. In the Deferral of Percutaneous Coronary Intervention (DEFER) trial, non-revascularization of lesions with FFR values ≥0.75 was not associated with increased risk of death or myocardial infarction compared with immediate stenting.¹²