This article aims to provide a comprehensive overview outlining current noninvasive diagnostic imaging modalities for coronary artery disease (CAD) in patients presenting with acute chest pain. Traditionally, invasive coronary angiography was used early in diagnosing patients with suspected CAD; however, there is evidence that a large percentage of patients presenting with chest pain do not have significant coronary obstruction.1,2 The unnecessary use of invasive diagnostic modalities may lead to serious complications and additional cost. The 2019 European Society of Cardiology (ESC) guidelines for diagnosis and management of chronic coronary syndromes and the 2021 American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for evaluation and diagnosis of chest pain recommend using either noninvasive functional or noninvasive anatomical imaging as the initial test to diagnose CAD, except for certain situations discussed later. The ESC and the ACC/AHA guidelines also highlight that clinicians should become familiar with each imaging modality as well as when and why to order them.3,4

Figure. No caption available.

Pathophysiology

CAD is a pathologic process characterized by obstructive and nonobstructive atherosclerotic plaque formation, commonly made up of fibrous and fatty tissue, in the coronary arteries. The leading cause of CAD is atherosclerosis, in which foam cells, a specific type of macrophage laden with lipids, accumulate in the tunica intima of vessels forming fatty streaks. The accumulated macrophages also stimulate smooth muscle cell proliferation, causing the formation of a fibrous plaque. As the size of the fibrous plaque increases, the diameter of the vessel lumen decreases, leading to myocardial ischemia.5,6 The process of atherosclerosis, and resultant CAD, can be accelerated by various risk factors such as dyslipidemia, diabetes, hypertension, or smoking.3,7 The narrowing and subsequent myocardial ischemia seen in CAD most commonly presents as angina, localized in the chest; however, the chest discomfort may extend to the lower jaw, back, or arms. Patients may describe angina as chest pressure, tightness, or heaviness.3 Chest pain is classified into categories of typical angina, atypical angina, and nonanginal chest pain.3 For angina to be classified as typical, chest pain should meet three criteria: (i) discomfort in the front of the chest (retrosternal) or the shoulder, arm, neck, or jaw and described as constricting; (ii) discomfort is provoked by physical exertion; and (iii) discomfort is relieved by rest or with nitrates within 5 minutes. An individual would be classified as having atypical angina if they met two of these criteria and would be classified as having nonanginal chest pain if they met one or none of the criteria.3,8,9

The decision of which diagnostic test to use to determine the cause of chest pain relies primarily on whether the chest pain is acute/unstable or stable. The AHA/ACC guideline established that characteristics including onset, location, intensity, and duration of chest pain distinguish acute chest pain due to ACS compared with chest pain secondary to noncardiac causes.4 History taking is substantial in differentiating between chest pain secondary to CAD and chest pain due to bone or muscle disorders. Asking the patient about a history of chest pain is invaluable, especially if the patient is known to have CAD and experienced ACS in the past.4 Stable chest pain is described as chronic with known and persistent precipitating factors.4 The ESC guidelines further described stable chest pain as a condition with a pattern of transient inducible and reversible ischemia.3

The European and American guidelines stipulate their recommendations for diagnosing CAD based on the patient's pre-test probability (PTP) of CAD (see Clinical pre-test probability of obstructive CAD in symptomatic patients).10 The AHA/ACC guideline recommends the use of clinical decision pathways for risk stratification of patients into low-, intermediate-, and high-risk groups.4 The ESC guidelines provide a table of PTP values according to the patient's age, sex, nature of symptoms (that is, typical, atypical, and nonanginal), and presence of dyspnea.3 For example, a 65-year-old male patient presenting with typical angina symptoms would be assigned a PTP of 44% from the ESC table based on their sex (male), age (65 years old), and their presenting chest pain (typical). The same patient presenting with dyspnea as a primary symptom would be assigned a PTP of 27%. Routine testing of patients with a PTP of less than 5% is not recommended. Consideration may be given to pursuing noninvasive diagnostic testing for patients with a PTP of 5% to 15%. Noninvasive testing is recommended for patients with a PTP greater than 15%.3 Proceeding directly to invasive coronary angiography (ICA) without further diagnostic testing is reasonable in patients with a high clinical likelihood of CAD.3 ICA is also recommended in patients with symptoms unresponsive to medical therapy or in patients with typical angina at low levels of exercise.3 In patients where CAD cannot be excluded by clinical assessment alone, noninvasive diagnostic testing to establish a diagnosis and assess the event risk is recommended.11 Noninvasive testing for CAD is divided into two main categories:

1. Functional imaging techniques:

a. stress echocardiography

b. stress cardiac magnetic resonance (CMR)

c. myocardial perfusion imaging (MPI): positron emission tomography (PET) and stress single-photon emission computed tomography (SPECT)

2. Anatomical imaging techniques, which mainly include coronary computed tomography angiography (CCTA) and computed tomography-based fractional flow reserve (FFR_CT)

Anatomical noninvasive tests are key in ruling out CAD by visualizing lesion(s) or plaques in the coronary arteries. On the other hand, functional tests are primarily used to rule in CAD by providing information on hemodynamically relevant CAD (obstructions greater than 50% of the lumen), such as myocardial ischemia.11 There are also techniques, such as FFR_CT, which allow for functional and anatomical imaging. Indications for ordering anatomical imaging include presence of ischemic symptoms (that is, acute chest pain) with high likelihood of normal study findings and the absence of a history of CAD.12,13 Anatomical imaging is useful for making treatment decisions based on the extent of the ischemia, such as whether the ischemia can be treated pharmacologically or if more invasive action must be taken (that is, percutaneous coronary intervention or coronary artery bypass graft surgery).14 Functional imaging is indicated when there is a need to detect the presence and degree of ischemia while also providing useful prognostic information.12,13

Functional noninvasive imaging

Stress echocardiography. Stress echocardiography allows a practitioner to assess wall motion abnormalities (WMAs) under rest and stress conditions, indicating any hemodynamic abnormalities brought about by coronary stenosis.11 The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of echocardiography are 64%, 84%, 70%, and 81%, respectively.15 Advantages of using echocardiography are that the test is widely available and can be performed at the bedside, while not exposing the patient to contrast or radiation, and is also able to evaluate ventricular size and function.11 A potential major disadvantage of echocardiography is that it is operator-dependent and has a limited diagnostic value in patients with poor acoustic windows (such as due to body habitus or pulmonary disease).19 Stress during the test can be induced by either exercise (treadmill or bike) or pharmacologic (for example, dobutamine or atropine) means to increase either the force (inotropic) or speed (chronotropic) of the heart's contractions.11 The AHA/ACC and ESC guidelines and the 2014 Canadian Cardiovascular Society (CCS) Guidelines for the Diagnosis and Management of Stable Ischemic Heart Disease recommend ordering echocardiography for patients who present with acute chest pain and an intermediate PTP who require a rapid bedside test.3,4,20

Cardiac magnetic resonance. CMR imaging is a functional noninvasive testing modality which evaluates myocardial ischemia under conditions of stress and rest.11 A 2019 meta-analysis by Pontone et al. using invasive FFR as a reference standard found the sensitivity, specificity, NPV, and PPV for CMR to be 87%, 88%, 86%, and 86%, respectively.15 The ESC guidelines suggest considering CMR in patients with suspected CAD when echocardiography with I.V. contrast is inconclusive.3 On top of assessing for ischemia, CMR can also assess the dimensions and function of the right and left ventricles as well as assess for regional WMAs.11 Based on the AHA/ACC and ESC guidelines, CMR is indicated in patients who present with intermediate PTP, acute chest pain, and known CAD.3,4 CMR is useful for cardiac risk stratification in patients with suspected or known CAD. A unique feature of CMR is the ability to characterize tissue and depict myocardial edema and fibrosis using late gadolinium enhancement (LGE). Gadolinium is an I.V. contrast agent that has been shown to have delayed washout in areas of increased extracellular space caused by myocardial cell death or deposits of foreign extracellular material.16 Other potential causes of chest pain, such as myocarditis, sarcoidosis, and hypertrophic cardiomyopathy, can be diagnosed based on the pattern of LGE and edema.17 Contraindications for CMR include claustrophobia, inability to lie flat for long periods of time and perform breath holds, and metal prosthetics or non-MR-conditional devices.11 CMR imaging may also take a long time to acquire and is not always widely available.10 (See Overview of different noninvasive anatomical and functional imaging modalities to assess coronary artery disease.)

The Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC 2) was a randomized clinical trial that compared the efficacy and safety of care guided by CMR, MPI, and the United Kingdom National Institute for Health and Care Excellence (NICE) guidelines.18 The CE-MARC 2 included 1,202 participants randomized into three groups: CMR (n = 481), MPI (n = 481), and NICE (n = 240). The study found that using CMR and MPI in patients with a 61% to 90% (n = 389) pretest likelihood of CAD resulted in reduced probability of requiring unnecessary invasive angiography within 12 months compared with those in the NICE group.

Myocardial perfusion imaging: Positron emission tomography and single-photon emission computed tomography. PET and SPECT are well-recognized nuclear cardiac imaging tests, also called MPI, used for functional evaluation of myocardial ischemia.11,21 In comparison to ECG, SPECT offers higher sensitivity and specificity when assessing for myocardial ischemia and scarring while also allowing for ventricular size and function assessment.10,22 A benefit to SPECT usage is the practitioner's ability to combine SPECT with CCTA, allowing comprehensive anatomical and functional evaluation.23,24 Overall, PET is significantly more sensitive than SPECT. PET has a sensitivity of 88%, specificity of 86%, NPV of 88%, and PPV of 85%, compared with 71%, 79%, 70%, and 75% of SPECT in the same order.15

Among all noninvasive diagnostic testing, PET has the highest diagnostic accuracy and is considered the gold standard for accurate quantification of myocardial blood flow.11 In cases where SPECT and CMR may have limited diagnostic accuracy due to balanced ischemia, such as with three-vessel disease, the availability of a PET scan is instrumental.25 In a comparative study by Bateman et al., PET was significantly more sensitive than SPECT when it came to identifying multivessel coronary disease, 71% compared with 48%, respectively.26

A well-known limitation for MPIs is the phenomenon of balanced ischemia where there is homogenous uptake and distribution of the radio tracer/contrast in all segments of the myocardium. Given that the diagnosis of CAD using SPECT and CMR are based around the ability to detect differences in perfusion across the myocardium, balanced ischemia is likely to yield false-negative results due to the uniform distribution of the ischemic burden.27 PET adds an advantage over stress echocardiography by having good image quality in women and individuals with obesity.11 SPECT and PET have certain advantages over CCTA and CMR imaging and are preferred in patients with arrhythmias or severe renal disease as well as in those unable to lie flat for long periods.11 Disadvantages of these imaging modalities are that both SPECT and PET expose patients to radiation; additionally, PET is associated with high costs and cannot be performed with exercise-induced stress, therefore, it is restricted to pharmacologic stress induction.11

Based on the AHA/ACC guidelines, PET/SPECT MPI are indicated in patients who present with intermediate PTP and acute chest pain with or without known CAD diagnosis.4 The guidelines suggest that PET is preferred over SPECT in patient with intermediate- to high-risk PTP who present with stable chest pain and no known CAD diagnosis to improve diagnostic accuracy.4

Anatomical noninvasive imaging

Coronary computed tomography angiography. CCTA is an anatomical imaging test used to visualize the coronary artery lumen and wall. When used with I.V. contrast, the test has a high sensitivity (96%) and specificity (82%) to detect coronary artery stenosis.10,25 Due to minimal radiation and contrast exposure, CCTA is considered the first-choice imaging test to rule out CAD, particularly in patients with low- to intermediate clinical likelihood of CAD, no previous diagnosis of CAD, and characteristics associated with a good image quality and with a high likelihood of normal study findings.3,4,20,28,29

There are several disadvantages and contraindications to the use of CCTA. Due to the usage of a contrast agent, renal disease (estimated glomerular filtration rate less than 60 mL/min) is a relative contraindication to CCTA, as it may result in contrast-induced nephropathy.30 The test cannot be confidently used in individuals with obesity, extensive coronary calcification, a heart rate greater than 80 beats/minute that cannot be lowered pharmacologically, irregular heart rhythms (that is, atrial fibrillation), coronary artery stents, and previous coronary artery bypass grafts.3,7,30 Obesity poses several challenges for accurate CCTA imaging due to the potential size constraints of the machine and the increased noise in the resulting images.30 Extensive coronary calcification also poses issues for accurate imaging, leading to high X-ray attenuation (reduction in intensity).31 Issues regarding the heart rate and irregular heart rhythms go hand in hand, as the best image quality is achieved with a low heart rate (ideally less than or equal to 60 beats/minute) and regular rhythm.32,33 To achieve the ideal heart rate, the NP should consider beta-blockers such as metoprolol or, if there is significant hepatic dysfunction, atenolol, orally or I.V., as first-line pharmacologic intervention.30 The 2016 Society of Cardiovascular Computed Tomography (SCCT) guidelines for CCTA describe two potential approaches to achieve the ideal heart rate: 1) a staggered dosage of metoprolol, ranging from 50 to 100 mg P.O., based on the presenting resting heart rate administered 1 hour prior to the scan, or 2) metoprolol 50 mg P.O. 12 hours prior to the test followed by an additional 50-100 mg P.O. 1 hour prior to the scan; in both cases additional I.V. beta-blockers can be administered if the ideal heart rate has not been achieved.30,34-36 For patients with a CCTA positive for a functionally significant coronary lesion, FFR_CT can be used to aid in the clinical decision-making regarding which patients may benefit from invasive evaluation.15

In a recently published multicenter, pragmatic, randomized trial, the Diagnostic Imaging Strategies for Patients with Stable Chest Pain and Intermediate Risk of Coronary Artery Disease (DISCHARGE) trial, CCTA was compared with ICA to determine whether it is an accurate alternative.37 The trial included 3,667 patients who had intermediate PTP (10% to 60%) of obstructive CAD and were referred to undergo ICA. The patients were randomly assigned to undergo either CCTA (n = 1,833) or ICA (n = 1,834). Of the 3,667 patients, 3,561 (CCTA, n = 1,808; ICA, n = 1,753) were included in the analysis. The study found that over a 3.5-year follow-up period, major adverse cardiovascular events (that is, cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 38 patients (2.1%) in the CCTA group and in 52 patients (3.0%) in the ICA group (hazard ratio, 0.70; 95% confidence interval, 0.46 to 1.07; P = .10). During the same follow-up period, more patients in the CCTA group underwent additional functional tests than those in the ICA group (n = 336 [18.6%] and n = 227 [12.9%], respectively). However, 30 major procedure-related complications were associated with ICA compared with only 7 with CCTA. Furthermore, patients in the CCTA group underwent a lower frequency of coronary revascularization procedures than those in the ICA group, 256 patients (14.2%) to 315 patients (18.0%), respectively. The study concluded that CCTA resulted in no significant differences compared with ICA when it came to the incidence of major adverse cardiovascular events; however, it was associated with a lower risk of major procedure-related complications and revascularization procedures.37

The guidelines note that CCTA is contraindicated in patients who present with irregular heart rhythms, significant renal dysfunction, and contrast media allergies.20

Overview of different noninvasive anatomical and functional imaging modalities to assess coronary artery disease

Computed tomography-based fractional flow reserve. FFR_CT has become a promising alternative to SPECT and PET, providing practitioners with the functional significance of CAD derived from a CCTA.38 Pijls et al. defined FFR as the maximum blood flow to the myocardium in the presence of a coronary artery stenosis divided by the theoretical normal maximum flow. This calculation gives the practitioner an idea of the maximum myocardial flow that can be achieved despite the presence of coronary stenosis, with an FFR of 1.0 being considered normal.39 Conventional invasively measured FFR only measures the pressure inside a single vessel through a wire and may be measured during ICA.40 FFR_CT can calculate the pressure and flow throughout the entire coronary tree through an interactive three-dimensional coronary model and can be determined through CCTA images.40 When interpreting invasive FFR readings, it is recommended that pressure is assessed at least 2-3 cm distal to the stenosis to avoid pressure recovery phenomenon, in which there is an increase in pressure downstream from the stenosis.41,42 Likewise, it is recommended to use the FFR_CT value found 1-2 cm distally of the stenosis.40 The Fractional Flow Reserve-Derived from Computed Tomography Coronary Angiography in the Assessment and Management of Stable Chest Pain (FORECAST) trial, a randomized controlled trial conducted in the United Kingdom over a 9-month period, concluded that there was not a significant difference in cost between the use of FFR_CT and standard ICA; however, the use of FFR_CT led to a 22% reduction in the use of ICA.43 The reduced need for invasive testing could result in greater comfort and decreased risk for procedure-related complications and therefore greater quality of life for patients. A primary disadvantage of using FFR_CT is the need for high-enough quality CCTA images to use the technique.44,45 As a result of this disadvantage, patients may need to undergo additional or alternative testing to better evaluate lesions if the image quality is not high enough.

The AHA/ACC guidelines consider FFR_CT imaging a sequential or add-on test.4 Based on these guidelines, it is recommended that the NP orders FFR_CT imaging for patients who have an intermediate PTP and coronary artery stenosis of 40% to 90% in a proximal or middle coronary segment on CCTA.

Invasive testing

The Task Force on myocardial revascularization of the ESC and European Association for Cardio-Thoracic Surgery (EACTS) state that, for diagnostic purposes, invasive testing (that is, ICA) is only necessary in patients with suspected CAD if noninvasive testing is inconclusive or if noninvasive testing suggests high event risk.46 The 2019 ESC guidelines recommend that for patients who have been determined to have a high clinical likelihood of CAD, symptoms unresponsive to medication or typical angina at low levels of exercise, and initial clinical evaluation suggesting high event risk, early invasive testing without previous noninvasive testing be carried out.3

Conclusion

This article presented an updated overview of the noninvasive imaging modalities used to diagnose suspected CAD. The imaging techniques outlined in this paper should be selected based on the patients' presenting symptoms, risk factors, and PTP scores. The local expertise and the availability of each modality should be considered when selecting a noninvasive technique to evaluate symptomatic patients. In addition to following the guidelines, NPs must use their clinical reasoning skills to decide on the best noninvasive procedure for each individual patient.

REFERENCES