Case presentation: A 56-year-old

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1 CLINICIAN UPDATE Selecting a Noninvasive Imaging Study After an Inconclusive Exercise Test Ron Blankstein, MD; Adam D. DeVore, MD Case presentation: A 56-year-old woman with obesity and dyslipidemia was referred for an exercise treadmill test to evaluate atypical chest pain. She exercised for 5 minutes 30 seconds (7 metabolic equivalents) on a standard Bruce protocol and stopped because of fatigue. Her heart rate increased from 82 to 148 bpm (90% of maximal predicted heart rate), and her blood pressure increased from 136/82 to 165/80 mm Hg. During the test, she developed 1-mm horizontal ST depressions in the inferolateral leads that resolved by 30 seconds into recovery. How should this patient be managed? Exercise treadmill testing (ETT) is an excellent initial test for the evaluation of patients with known or suspected cardiovascular disease who are able to exercise and have a normal baseline ECG. This safe and inexpensive test can be used to obtain information on functional capacity and the symptomatic, hemodynamic, and ECG responses to exercise. Although ETT provides valuable prognostic and diagnostic information, inconclusive test results are common (Table 1) and can lead to uncertainty about the likelihood of flow-limiting coronary artery disease. In such scenarios, further testing may be useful to improve diagnostic certainty and to refine risk assessment (the Figure). 1 In some instances, the choice of testing will depend on the availability and expertise of the institution. However, several different types of testing are often available from which the clinician can choose. Although in many cases the available literature cannot be used to definitively recommend one particular modality over another, understanding the fundamental differences in data provided by each examination and the strengths and limitations of the various available techniques can be useful in guiding the choice of further testing. This Clinician Update describes the different available noninvasive tests that can be performed after an inconclusive ETT and focuses on patient factors that are important to consider when deciding which test to obtain. Stress Echocardiography Stress echocardiography is a wellvalidated test that can diagnose the presence of obstructive coronary artery disease (CAD) by visualizing stressinduced wall motion abnormalities. 2 The accuracy of this test relies on the ability to obtain high-quality functional images of all myocardial segments under both stress (pharmacological or exercise) and rest conditions. Thus, patients with poor acoustic windows (eg, obesity, obstructive lung disease) may have reduced image quality, which can lower the diagnostic accuracy of the examination. The accuracy of this examination may also be reduced in patients with resting wall motion abnormalities (eg, prior infarction, severe left ventricular dysfunction, right ventricular pacing, prior cardiac surgery) or significant hypertension. In patients unable to achieve adequate workload with exercise, dobutamine stress echocardiography can be performed (Table 2). The lack of radiation exposure makes this a compelling option for young patients. Although stress echocardiography has a high specificity for the detection of angiographically significant disease, this test is not intended for detecting subclinical atherosclerosis. From the Noninvasive Cardiovascular Imaging Program, Departments of Medicine (Cardiovascular Division) and Radiology and the Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Mass. Correspondence to Ron Blankstein, MD, FACC, Noninvasive Cardiovascular Imaging Program, Department of Medicine (Cardiovascular Division) and Department Radiology, Brigham and Women s Hospital, 75 Francis St, Room Shapiro 5096, Boston, MA (Circulation. 2010;122: ) 2010 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 Blankstein and DeVore Choice of Noninvasive Imaging After ETT 1515 Table 1. Examples of Inconclusive ETTs Reason Example Impact on Diagnostic Accuracy Insufficient workload Inability to achieve an appropriate peak heart rate response during exercise Reduced sensitivity Baseline ECG changes Resting ST segment depressions 1 mm Reduced specificity LVH with repolarization abnormalities Rapid resolution of ECG changes Discordance between symptoms and test results Resolution of exercise-induced ST-segment depressions in early recovery (eg, 1 min) Typical angina during exercise in a high-risk patient but no diagnostic ECG changes Inadequate blood pressure response (eg, increase in SBP 25 mm Hg) in the absence of valvular disease or heart failure LVH indicates left ventricular hypertrophy; SBP, systolic blood pressure. Reduced specificity Increased risk Reduced negative predictive value Nuclear Stress Testing (Single Photon Emission Computed Tomography/Positron Emission Tomography) Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) and positron emission tomography (PET) is designed to detect flow-limiting CAD. The robust prognostic value of these techniques is based on the premise that clinical risk increases with the extent and severity of perfusion abnormalities. 3,4 This information is also valuable in determining the need for medical therapy versus revascularization because patients with moderate to severe myocardial ischemia are more likely to derive survival benefit from coronary revascularization. 5 Attenuation artifacts (which are more common in obese patients and women with extensive breast tissue) may decrease the specificity of the examination. Much less frequently, false negatives can occur in patients with global reduction in myocardial blood flow (ie, balanced ischemia ) caused by left main or multivessel disease. In general, nuclear techniques tend to underestimate the extent of CAD. 6 Unless a coronary calcium score can be acquired (requires SPECT/ computed tomography [CT] or PET/CT platforms) or a quantitative PET to assess myocardial blood flow reserve is performed, this test cannot identify the presence of nonobstructive atherosclerosis. Compared with SPECT, PET MPI has superior image resolution, better attenuation correction, and higher diagnostic accuracy. The rapid half-life of radiotracers used in PET results in a lower radiation dose and a faster protocol, although current protocols cannot be performed with exercise. Cardiac Magnetic Resonance Imaging (MRI) Cardiac MRI enables high-resolution imaging of cardiac structure, function, and morphology without any radiation exposure. When obstructive CAD is suspected, analysis of myocardial perfusion defects during pharmacologically induced vasodilation and under resting conditions can be used to identify areas of ischemia, and lateenhancement imaging can be used to identify areas of prior infarction. 7 In patients with contraindications to vasodilators (Table 2), a dobutamine MRI can be performed to assess for stress-induced wall motion abnormalities. In addition, other valuable information such as left and right ventricular function or the presence of infiltrative heart disease can be obtained. Despite the attractive features of this examination, cardiac stress MRI is a complex examination that is currently limited by lack of availability. This test cannot be performed in patients who are claustrophobic or who have implanted ferromagnetic objects (eg, defibrillator). However, patients with coronary stents and most types of orthopedic implants can safely undergo an MRI. Because of the rare (ie, only several hundred case reported worldwide) but potentially life-threatening complication of nephrogenic systemic fibrosis, a condition that results primarily in fibrosis of the skin but may also affect multiple organs, administration of gadolinium is contraindicated in patients with a creatinine clearance 30 ml/min. 8 Data from a multicenter trial directly comparing stress perfusion MRI with SPECT imaging and invasive coronary angiography showed a similar diagnostic accuracy of these 2 modalities. Although MRI does not have attenuation artifacts and is less susceptible to false negatives from balanced ischemia, a limitation unique to cardiac magnetic resonance perfusion is that images may show false-positive defects related to transient dark rim artifacts in the subendocardium. If not properly recognized, such artifacts may limit the specificity of MRI perfusion imaging for detecting small subendocardial perfusion defects. Coronary CT Angiography Coronary CT angiography (CTA) can be used to obtain high-resolution contrast-enhanced images of the coronary arteries. This test requires normal kidney function (eg, creatinine 1.5 mg/dl) and a low resting heart rate, often achieved by prescan treatment with -blockers. When performed after an equivocal ETT, the high negative predictive value of this examination can be used to exclude the

3 1516 Circulation October 12, 2010 Figure. Imaging modalities that are available for further evaluation after an equivocal ETT. Nuclear MPI (top left) provides information on myocardial perfusion during rest and stress conditions and can be used to estimate the extent and severity of myocardial ischemia and infarction. The PET images show normal myocardial perfusion at rest and a large stress-induced perfusion defect in the distribution of the left anterior descending artery (LAD). Coronary CTA (top right) can be used to visualize the coronary arteries in multiple planes and provides information on the presence, extent, and severity of atherosclerotic plaque. In the example shown, a large amount of plaque is present in the proximal left anterior descending artery. A short-axis (en face) view of the coronary lumen (red box) shows a large eccentric area of noncalcified plaque (shaded light orange to improve visualization) with positive vessel remodeling. The right coronary artery (RCA) and left circumflex (LCx) have no plaque or stenosis. During a stress cardiac MRI (bottom left), myocardial perfusion is assessed during stress and rest by obtaining serial imaging during the first pass of gadolinium. The example shows stress-induced perfusion defects that are partially reversible and involve the basal and mid anterior and anterolateral walls, as well as the inferior wall (red arrows). Late-enhancement imaging can be used to identify the area of scar, inflammation, or infiltration. With this technique, areas of prior infarction appear bright and are located in the subendocardium, whereas normal myocardium appears black. MRI can also be used to quantify right and left ventricular function. When acute pathology (eg, myocarditis) is suspected, T2-weighted imaging can be performed to visualize areas of myocardial edema. Stress echocardiography (bottom right) can identify either a fixed wall motion abnormality (ie, scar from prior infarct) or a stress-induced wall motion abnormality (ie, physiological manifestation of ischemia). The example provided shows end-diastolic and end-systolic images in the 4-chamber view at rest and at peak stress. There is normal wall motion during rest, but a stress-induced wall motion abnormality is present that involves the distal septum and apex. VLA indicates vertical long axis; HLA, horizontal long axis. presence of CAD. However, compared with the plethora of data demonstrating the prognostic value of nuclear MPI techniques, relatively few studies have evaluated the prognostic value of CTA. 9 The available data indicate that the extent and severity of coronary plaque may have a significant impact on prognosis. 10 Notably, the value of these anatomic markers may be incremental to the data provided by MPI 11 because CTA can identify nonobstructive CAD in instances when MPI results may otherwise be normal. In appropriately selected patients, the information provided by CTA has the potential to lead to risk reclassification and thus could have a significant impact on subsequent medical therapies. 12 Despite favorable initial data with this technique, CTA has a low specificity for detecting significant stenosis, especially when extensive calcified

4 Blankstein and DeVore Choice of Noninvasive Imaging After ETT 1517 Table 2. Important Contraindications and Warning of Selected Pharmacological Stress Agents Contraindications Caution/Warning Dobutamine Hypertrophic cardiomyopathy with dynamic LVOT gradient Atrial fibrillation may cause rapid ventricular response Unstable ventricular arrhythmias Hypovolemia may potentiate lowering of blood pressure Use with caution after myocardial infarction Adenosine High-grade AV block (second and third degree) or sinus node dysfunction unless functional pacemaker present May cause profound vasodilation with subsequent hypotension; use with caution in patients with autonomic dysfunction, hypovolemia, cerebrovascular insufficiency, or severe stenotic valvular disease Known or suspected bronchoconstrictive or bronchospastic lung disease Use with caution in patients with unstable angina Regadenoson Similar to adenosine, although current ongoing trials are investigating safety in patients with bronchoconstrictive or bronchospastic lung disease; when regadenoson is administered to such patients, resuscitative measures should be available Dipyridamole Similar to other vasodilators but may be safer for patients with AV block; use with caution in patients with hepatic impairment LVOT indicates left ventricular outflow tract; AV, atrioventricular. plaque is present. Likewise, and in keeping with other anatomic techniques, CTA has poor positive predictive value for the detection of ischemia. 13 Thus, CTA is less useful in high-risk populations with extensive coronary calcifications or when determining the potential role for revascularization. Finally, the increased use of CTA has led to concerns relating to patient radiation dose. Although numerous recent techniques have been introduced that can dramatically reduce the dose of this examination, wider adoption and implementation of these strategies are needed. Factors to Consider When Choosing Between Modalities Will This Test Change Patient Management? Further imaging should be obtained only if the results of such testing could cause a change in patient management. For instance, some low-risk patients, particularly if asymptomatic, may not need any further testing after an inconclusive ETT if an excellent prognosis can be established from clinical data and exercise capacity. Pretest Probability of Disease/Goal of Further Testing If clinical uncertainty exists and further imaging is contemplated, consider the pretest probability of obstructive CAD and the goals of testing (Table 3). In low- to intermediate-risk patients, CTA may be used to exclude the presence of obstructive CAD. If nonobstructive atherosclerosis is identified, appropriate preventive strategies can be recommended. On the other hand, high-risk patients or those with known CAD will benefit from perfusion-based imaging. In such patients, knowledge about the presence and amount of ischemia will be most useful for optimal patient management, whereas the identification of coronary plaque of uncertain hemodynamic significance will be less helpful. Reason for Inconclusive ETT If inconclusive ETT results are due to inadequate heart rate response, subsequent testing should use pharmacological testing or cardiac CT. However, if inconclusive results occur because of equivocal ECG changes, repeat exercise testing with SPECT or echocardiography can be performed. Although PET and stress MRI cannot be performed with exercise, these modalities can use pharmacological stress and may be useful in obese patients who are more likely to have attenuation artifacts (with SPECT) or poor acoustic windows (with echocardiography). Table 3. Goals of Testing After Inconclusive ETT Identification of a need for immediate treatment for symptomatic patients Secondary prevention of known CAD Primary prevention of future disease Patient Age/Radiation Young patients, especially female patients, are most vulnerable to the potential harmful effects of radiation exposure. In such patients, if further testing in needed, stress echocardiography or MRI should be advised. Cardiac CT for young patients (eg, 45 years of age) could be considered in centers where the available technology and expertise would allow a very low estimated effective dose (eg, 5 msv, a dose that is lower than invasive angiography and less than half of the typical dose associated with contemporary nuclear techniques). Is Other Information Needed? Imaging after an inconclusive ETT can often provide useful information beyond just establishing the risk of CAD. Although the choice of test type should be based primarily on the primary goals of the test, other clinical questions often influence the choice of examination type. For instance, cardiac CT enables visualization of the aortic root and proximal segments of the pulmonary arteries. At times, other reasons that could account for a patient s symptoms, such as hiatal hernia or lung disease, are identified. Echocardiography permits an evaluation of ventricular function and valvular pathology. In addition to quantifying ventricular function, MRI provides unique data about myocardial edema, scar, or infiltration and can identify the presence of pericarditis or myocarditis.

5 1518 Circulation October 12, 2010 Case Resolution Our patient had a coronary CTA that identified a small amount of plaque in the proximal and mid right coronary artery that did not cause any luminal narrowing and was not thought to cause her symptoms. Given her young age, the scan was performed with a low radiation dose (estimated effective dose, 3.2 msv). Nevertheless, in light of her risk factors and the finding of nonobstructive CAD, she was counseled on weight reduction through diet and exercise and started receiving lipid-lowering therapy. Conclusions Further testing after an inconclusive ETT can be used to improve the diagnostic accuracy for detecting obstructive CAD and enhancing risk assessment. Although these data can be obtained by numerous imaging modalities, an evaluation of the goals of testing and consideration of patient factors such as pretest likelihood of disease, contraindications to various testing options, and body habitus considerations can be helpful for ensuring that subsequent testing will be used in an efficient and useful manner. None. Disclosures References 1. Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, Mark DB, McCallister BD, Mooss AN, O Reilly MG, Winters WL Jr, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC Jr. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. 2002;106: Pellikka PA, Nagueh SF, Elhendy AA, Kuehl CA, Sawada SG. 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