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Dr. Konstantinos C. Koskinas
Non-invasive testing can detect myocardial ischemia and also offers visualisation of the coronary anatomy. Here discussed are the advantages, costs, diagnostic accuracy and appropriateness of each available modality in a given patient as recommended by the 2013 European Society of Cardiology guidelines on stable coronary artery disease.
When assessing a patient with clinically suspected stable coronary artery disease (SCAD), two questions are in order to establish a diagnosis:
Initial diagnostic assessment of individuals with suspected SCAD has clinical evaluation as cornerstone (Fig.1) (1).
Gender-related implications of the estimated PTP values are shown in Table 1.
Non-invasive modalities for diagnosis of SCAD are either functional tests - non-imaging stress tests or stress tests combined with imaging - that detect inducible myocardial ischemia, or modalities that visualise coronary anatomy.
Although ECG is a time-honored, simple, generally safe, and is the least costly of non-imaging tests, it has a sensitivity (true positive rate) of 45-50% and specificity (true negative rate) of 85-90%, suggesting a higher efficacy for exclusion rather than confirmation of diagnosis of SCAD. It performs well at intermediate PTPs - between 15–65% - in patients with normal (interpretable) resting ECGs without ST–T abnormalities.
The addition of imaging to exercise testing provides incremental benefit for accurate diagnosis of obstructive CAD with an acceptable increase in cost (4, 5); however, whether this diagnostic performance translates into clinical outcomes is not yet established (6). Advantages of stress imaging include 1) accurate assessment in the presence of resting ECG abnormalities, 2) option of using pharmacological testing in patients who cannot exercise adequately, and 3) the ability to quantify and localise areas of ischemia. The diagnostic endpoint of stress imaging for detection of inducible ischemia is either left ventricular (LV) wall motion [stress echocardiography; stress cardiac magnetic resonance (CMR)], or myocardial perfusion [myocardial perfusion scintigraphy using single photon emission computed tomography (SPECT) or positron emission tomography (PET); perfusion CMR]. Stress imaging may be performed either with exercise or pharmacologically.
The sensitivity and specificity of stress echocardiography are 80-85% and 80-88%, respectively. The diagnostic endpoint is wall thickening and new or worsening wall motion abnormalities with stress. Additional criteria for an abnormal stress echocardiogram are dilatation and decline of global LV systolic function with stress. Intravenous contrast agents can improve endocardial border delineation and thus, diagnostic accuracy (7). In patients unable to exercise adequately, the pharmacological agent of choice is the inotropic agent dobutamine. Dobutamine however, is contraindicated in the presence of severe hypertension, hemodynamically significant LV outflow obstruction, or sustained ventricular arrhythmias. Vasodilators such as dipyridamole are alternative (second-line) pharmacological agents. Advantages of stress echocardiography include 1) wide availability, 2) relatively low cost, and 3) lack of ionising radiation. Stress echocardiography provides valuable information regarding the distribution and extent of myocardial ischemia. Additionally, stress echocardiography is unique to provide clinically valuable insights regarding hemodynamics during stress (e.g., exercise parameters of diastolic function and valvular heart disease), and it has better spatial resolution compared with SPECT that allows for detection of subendocardial ischemia. Presence of resting regional wall abnormalities and inter-observer variability may limit its diagnostic accuracy. Suboptimal image quality may be obtained as a result of patient body habitus (obesity), lung disease, or respiratory motion.
Technetium 99m is used more commonly than thallium 201 for SPECT. The sensitivity and specificity of exercise stress SPECT are 73-92% and 63-87%, respectively. The respective figures for vasodilator stress SPECT are 90% and 75-87%. In comparison, SPECT has better sensitivity whereas stress echocardiography has a higher specificity for diagnosis of SCAD. Reduced regional trace uptake during stress compared with preserved perfusion at rest is the hallmark of reversible myocardial ischemia; transient ischemic dilatation at stress and extensive stress-induced wall motion abnormalities are additional markers of significant CAD.
The agents of choice are vasodilators: adenosine, dipyridamole, or regadenoson. Dobutamine is preferred when vasodilators are contraindicated, such as in the presence of bronchospastic airway disease or severe obstructive pulmonary disease, significant hypotension, sick sinus syndrome, a high degree atrio-ventricular block, current use of aminophylline, and caffeine ingestion within 12 hours before testing. Advantages of SPECT over stress echocardiography include satisfactory quality imaging despite presence of lung disease, and reliable assessment of ischemia in the presence of resting wall motion abnormalities. If left bundle branch block or ventricular paced rhythm is present, exercise stress MPI may result in septal artifacts (false-positive septal defects) due to dyssynchronous septal motion, thus reducing diagnostic specificity (8). In these cases, vasodilators instead of exercise stress imaging (even if the patient can exercise) result in fewer false-positive results by reducing tachycardia and attenuating dyssynchrony-related artifacts. Limitations of SPECT include patient exposure to non-trivial radiation, relatively long acquisition protocols and high cost, poor spatial resolution that limits detection of subendocardial ischemia, and artifacts related to respiratory motion, breast tissue, or sub-diaphragmatic attenuation. Because relative perfusion is assessed, SPECT has reduced sensitivity for detecting diffuse ischemia due to left main disease or 3-vessel disease.
Although less well studied than SPECT, PET has better diagnostic accuracy for detection of CAD, including in women (9). Advantages of PET over SPECT include lower radiation exposure, higher resolution, and fewer attenuation artifacts that allow for better image quality even in obese patients. In addition, PET can uniquely quantify blood flow, thus allowing detection of microvascular angina. The main limitations of PET are limited availability and increased cost.
The imaging endpoint of CMR for diagnosis of SCAD depends on the stress agent: CMR may detect either ischemia-induced wall motion abnormalities (dobutamine stress CMR) or myocardial perfusion (vasodilator stress CMR). Dobutamine stress CMR has an estimated sensitivity and specificity of 79-88% and 81-91%, respectively, for detection of obstructive CAD and can be useful in patients with suboptimal image quality on stress echocardiography (e.g., poor acoustic window due to obesity or lung disease) (10). Perfusion CMR has a sensitivity and specificity of 67-94% and 61-85%, respectively, and its accuracy is comparable to nuclear perfusion imaging (11, 12). Quantitative CMR perfusion measurements correlate well with fractional flow reserve measurements of hemodynamically significant coronary stenoses (13). Advantages of CMR for perfusion imaging include lack of radiation, high spatial resolution, ability to perform absolute quantification of perfusion, limited operator dependence, signal characteristics that are largely independent of the patient’s body habitus, and additional information on cardiac structure and function provided in a comprehensive CMR study. Limitations pertain mainly to high cost, limited availability and expertise, and limited functional analysis in the presence of arrhythmias.
Improvements in temporal and spatial resolution of coronary computed tomography angiography (CTA) have enabled evaluation of coronary arteries with high image quality (14). Coronary CTA has a sensitivity of 95-99% and specificity of 64-83% for detection of obstructive CAD. The diagnostic performance is higher in patients within the lower range of intermediate PTP (15-50%) for SCAD, and it is therefore most useful for ruling out rather than confirming diagnosis of SCAD. Diagnostic accuracy appears to be similarly high among women (15). Strict patient selection is crucial for satisfactory image quality and diagnostic accuracy. Coronary CTA should only be considered in individuals without severe obesity, with adequate breath holding capabilities, an Agatston calcium score <400, in sinus rhythm and with a heart rate <65 beats per minute (possibly achieved by administration of beta blockers). A major advantage of coronary CTA in appropriately selected patients is the very high negative predictive value that can reassure physicians to safely defer performance of ICA. Disadvantages of the method include relatively limited (yet growing) availability, high radiation, and reduced image quality in the presence of arrhythmias or elevated heart rate.
As outlined above, available non-invasive modalities for diagnosis of SCAD differ distinctly in terms of diagnostic accuracies, predictive values, and costs. In patients with clinically suspected SCAD, three key question need to be answered to determine patient suitability for non-invasive testing, type of stress (exercise vs. pharmacologic), and functional vs. anatomic testing endpoint:
Non-invasive testing is not recommended in patients who are deemed eligible for direct referral for ICA or unsuitable for specific cardiac testing (Figure 1). Furthermore, non-invasive modalities are not recommended for the purpose of establishing diagnosis in individuals with low (<15%) or high (>85%) PTP of SCAD.
When functional stress imaging is chosen, selection of the exact modality for a given patient is based on specific characteristics that may adversely affect the performance or interpretability of a test. Basic principles regarding suitability of certain patient groups for certain testing modes are summarised below. It is important to remember, however, that for many patients there may not be a single appropriate test, but rather more than 1 or even all tests may be reasonably well suited. In the latter case, physician judgment and available local expertise should determine the correct test for an individual patient (17).
The value of non-invasive anatomic evaluation of CAD as an alternative to functional testing is also emphasised if certain strict prerequisites are met.
In individuals with clinically suspected SCAD, possible strategies for initial diagnosis may range from no specific testing to non-invasive cardiac testing to direct referral for ICA. Non-invasive testing to establish diagnosis of SCAD is appropriate for patient with an intermediate pre-test probability of disease. Appropriate selection of the exact non-invasive modality that is most suitable for a given patient is based on clinical characteristics in combination with local resources and specific features of different testing modalities.
Table 1. Clinical pre-test probabilities of SCAD in patients with stable chest pain symptoms. Adapted from (1).
Men with Typical Angina
Women with Typical Angina
Men with Atypical Angina
Women with Atypical Angina
Men with Non-Anginal pain
WomenMen with Non-Anginal pain
Fig. 1: Diagnostic triage of patients with suspected coronary artery disease.
1 – 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Montalescot G, et al. Eur Heart J. 2013;34(38):2949-3003.
2 – Meta-analysis of exercise testing to detect coronary artery disease in women. Kwok Y, Kim C, Grady D, et al. Am J Cardiol. 1999;83:660–666.
3 – Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, et al. Circulation. 2001;104:1694-1740.
4 – A randomized trial of exercise treadmill ECG versus stress SPECT myocardial perfusionimaging as an initial diagnostic strategy in stable patients with chest pain and suspected CAD: cost analysis. Sabharwal NK, Stoykova B, Taneja AK, et al. J Nucl Cardiol. 2007;14:174-186.
5 –Value of stress myocardial perfusion single photon emission computed tomography in patients with normal resting electrocardiograms: an evaluation of incremental prognostic value and cost-effectiveness. Hachamovitch R, Berman DS, Kiat H, et al. Circulation. 2002;105:823-829.
6 – Comparative effectiveness of exercise electrocardiography with or without myocardial perfusion single photon emission computed tomography in women with suspected coronary artery disease: results from the What Is the Optimal Method for Ischemia Evaluation in Women (WOMEN) trial. Shaw LJ, Mieres JH, Hendel RH, et al. Circulation. 2011;124:1239-1249.
7 – Safety and efficacy of commercially available ultrasound contrast agents for rest and stress echocardiography. A multicenter experience. Dolan MS, Gala SS, Dodla S, Abdelmoneim SS, Xie F, Cloutier D, et al. J Am Coll Cardiol. 2009;53(1):32-38.
8 – Diagnostic and prognostic value of gated myocardial perfusion single-photon emission computed tomography in low-risk patients with left bundle-branch block. Evangelista L, Nai Fovino L, Saladini F, Saladini G, Razzolini R, Mormino GP, et al. Nucl Med Commun. 2012 ;33(5):491-497.
9 – Diagnostic accuracy of rubidium-82 myocardial perfusion imaging with hybrid positron emission tomography/computed tomography in the detection of coronary artery disease. Sampson UK, Dorbala S, Limaye A, et al. J Am Coll Cardiol. 2007;49:1052-1058.
10 – Utility of fast cine magnetic resonance imaging and display for the detection of myocardial ischemia in patients not well suited for second harmonic stress echocardiography. Hundley WG, Hamilton CA, Thomas MS, et al. Circulation. 1999;100:1697-1702.
11 – Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial. Greenwood JP, Maredia N, Younger JF, Brown JM, Nixon J, Everett CC, et al. Lancet 2012; 379:453-460.
12 – MR-IMPACTII: Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary artery disease Trial: perfusion-cardiac magnetic resonance vs. single-photon emission computed tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial. Schwitter J,Wacker CM, Wilke N, Al-Saadi N, Sauer E, Huettle K, et al. Eur Heart J 2012; 34(10):775-781.
13 – High-resolution magnetic resonance myocardial perfusion imaging at 3.0-Tesla to detect hemodynamically significant coronary stenosis as determined by fractional flow reserve. Lockie T, Ishida M, Perera D, Chiribiri A, De Silva K, Kozerke S, et al. J Am Coll Cardiol 2011;57:70-75.
14 – The present state of coronary computed tomography angiography a process in evolution. Min JK, Shaw LJ, Berman DS. J Am Coll Cardiol. 2010;55:957-965.
15 – Gender influence on the diagnostic accuracy of 64-slice multislice computed tomography coronary angiography for detection of obstructive coronary artery disease. Pundziute G, Schuijf JD, Jukema JW, et al. Heart. 2008;94:48-52.
16 – Noninvasive assessment of myocardial perfusion. Salerno M, Beller GA. Circ Cardiovasc Imaging. 2009;2:412-424.
17 – ACCF/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease. Wolk MJ, et al. J Am Coll Cardiol. 2014;63(4):380-406.
Address for correspondence:Konstantinos C. Koskinas, MD, MSc, FESC 3rd Department of Cardiology, Hippokrateion Hospital, Aristotle University Medical School 49 Konstantinoupoleos Street,546 42 Thessaloniki, GreeceTel: +30 2310 892076 Email: firstname.lastname@example.org Authors disclosures: None declared.Other ressources:View here the guideline track on stable coronary artery disease