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Multimodality Imaging in Cardiovascular Medicine

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Christopher M. Kramer, MD

Professor of Medicine and Radiology Director, Cardiovascular Imaging Center University of Virginia Health System Charlottesville, Virgina

New York

Acquisitions Editor: Richard Winters Cover Design: Joe Tenerelli Compositor: S4Carlisle Publishing Services Printer: Sheridan Press Visit our website at www.demosmedpub.com © 2011 Demos Medical Publishing, LLC. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Library of Congress Cataloging-in-Publication Data â•… Multimodality imaging in cardiovascular medicine / [edited by] Christopher M. Kramer. â•…â•…â•… p.; cm. â•… Includes bibliographical references and index. â•… ISBN 978-1-933864-74-7 â•‡ 1.â•‡ Cardiovascular system—Diseases—Diagnosis—Atlases.â•… 2.â•‡ Diagnostic imaging—Atlases. I. Kramer, Christopher M. â•… [DNLM: 1. Cardiovascular Diseases—diagnosis—Atlases.â•… 2.â•‡ Diagnostic Imaging—methods—Atlases. WG 17 M961 2011] â•… RC670.M85 2011 â•… 616.1075—dc22 2010024864 Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particular our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, express or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Special discounts on bulk quantities of Demos Medical Publishing books are available to corporations, professional associations, pharmaceutical companies, health care organizations, and other qualifying groups. For details, please contact: Special Sales Department Demos Medical Publishing 11 W. 42nd Street, 15th Floor New York, NY 10036 Phone:â•‡ 800–532–8663 or 212–683–0072 Fax:â•… 212–941–7842 E-mail:â•… [email protected]

Made in the United States of America 10â•‡ 11â•‡ 12â•‡ 13â•‡ 14â•…â•… 5â•‡ 4â•‡ 3â•‡ 2â•‡ 1

Contents

Prefaceâ•… vii Acknowledgmentsâ•… ix Contributorsâ•… xi

1â•… Chest Pain: Typical Anginaâ•…â•… 1

Marcelo F. Di Carli

2â•…Atypical Chest Pain and Other Presentations of an

â•‡ 9â•…Multimodality Imaging in Hypertrophic Cardiomyopathyâ•…â•… 127 â•‡ Deborah H. Kwon and Milind Y. Desai

Intermediate Likelihood of Obstructive Coronary Artery Diseaseâ•…â•… 22 Aiden Abidov, Daniel S. Berman, and Rory Hachamovitch

10â•…Chronic Myocardial Ischemia

3â•… Acute ST Elevation Myocardial Infarctionâ•…â•… 45

11â•…Multimodality Imaging in Valvular Heart

Diseaseâ•…â•… 158 â•‡ Sonal Chandra, Amit R. Patel, and Lissa Sugeng

Zelmira Curillova and Scott D. Solomon

4â•…Noninvasive Imaging in Patients With Suspected

Unstable Angina or Non-ST Elevation Myocardial Infarctionâ•…â•… 58 Benjamin W. Kron and Kevin Wei

and Viabilityâ•…â•… 138 â•‡Caroline A. Daly, Otavio R. Coelho-Filho, and Raymond Y. Kwong

12â•… Aortic Dissectionâ•…â•… 192 â•‡Christopher J. François, Benjamin R. Landgraf, and Thorsten A. Bley

5â•… Post-MI Risk Stratificationâ•…â•… 71

13â•… Claudicationâ•…â•… 209

Mark R. Vesely, James A. Arrighi, Gagandeep S. Gurm, Harisha Kommana, and Vasken Dilsizian

â•‡Ali Z. Merchant, Georgeta Mihai, Anurag Sahu, and Sanjay Rajagopalan

6â•…Evaluation After Coronary Revascularizationâ•…â•… 92

14â•… Preoperative Risk Stratificationâ•…â•… 229

Joanne D. Schuijf, Ernst E. van der Wall, and Jeroen J. Bax

â•‡ Radosav Vidakovic´ and Don Poldermans

7â•…Diagnostic Tests for Clinically Suspected Acute

â•‡ Mark A. Fogel

Pulmonary Embolismâ•…â•… 103 Menno V. Huisman, Inge C. M. Mos, Albert de Roos, Lucia J. M. Kroft, and F. A. Klok

8â•…Contemporary Cardiac Imaging in Dyspnea Due to Heart Failureâ•…â•… 111 Martin St. John Sutton, Ted Plappert, and Yan Wang

15â•… Congenital Heart Diseaseâ•…â•… 238 16â•…Constrictive Pericarditis Versus Restrictive Cardiomyopathyâ•…â•… 252 â•‡ Andrew S. Flett and James C. Moon

17â•… Differential Diagnosis of Cardiomyopathiesâ•…â•… 263 â•‡Chirine Parsai, Rory O’Hanlon, and Sanjay K. Prasad

v

Contents

vi

18â•…Multimodality Imaging in Atrial

20â•… Cardiac Massesâ•…â•… 316

Arrhythmiasâ•…â•… 284 â•‡Ewa Dembowski, Joseph A. Lodato, and Amit R. Patel

â•‡ Victor A. Ferrari and Ari B. Goldberg

19â•…Noninvasive Atherosclerosis Imaging for Risk Stratificationâ•…â•… 299 â•‡ Allen J. Taylor and Patrick J. Devine

Indexâ•… 333

Preface

T

he cardiovascular imaging community has entered the era of multimodality imaging. Gone are the days when imagers identified themselves as echocardiographers or nuclear specialists, and so on. Practitioners in the field must become facile in multiple imaging modalities as each modality has its strengths and weaknesses. The different modalities now play a complementary role in the diagnostic armamentarium. New applications of echocardiography, nuclear imaging, cardiovascular magnetic resonance, and cardiac computed tomography are rapidly developing and it is imperative that trainees and practitioners alike remain up to date in the latest developments. It is becoming increasingly difficult to remain abreast of these advances in each individual modality and thus it is no longer practical to focus on one at a time. In addition, training guidelines are changing and multimodality training has become the norm. In the future, a comprehensive imaging examination is likely to help guide and certify trainees. However, before

that comes to pass, now is the time for reference texts as well as journals to move into this new era. It is in this light that we introduce this multimodality imaging atlas. We have enlisted the leading imagers in their field to contribute state-of-the-art chapters replete with outstanding multimodality imaging examples of cardiovascular pathophysiology as well as corresponding text to put the images into context at the interface with patient care. It was our aim to create a comprehensive clinically oriented atlas/text that would allow the practitioner to use as a problem-based reference to better understand which imaging modality or modalities may be of most benefit in which clinical situation. We encourage you to use the atlas in this way. We hope you benefit from reading it and using it in your practice of cardiovascular imaging as much as we did from putting it together. Christopher M. Kramer, MD

vii


Acknowledgments

I would like to thank all of the authors for their outstanding contributions and Richard Winters for all of his help throughout the process of creating this book. Thanks also

to my family (Cathy, Alex, and Zach) for all their love and support.

ix


Contributors

Aiden Abidov, MD, PhD Chair Department of Cardiology Sarver Heart Center Tucson, Arizona James A. Arrighi, MD Associate Professor of Medicine and Diagnostic Imaging Department of Medicine Alpert Medical School Brown University Director of Nuclear Cardiology Rhode Island Hospital Providence, Rhode Island

Zelmira Curillova, MD Instructor in Medicine Department of Medicine Boston Veterans Administration Medical Center Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Caroline A. Daly, MB, MSc, PhD, MRCPI Department of Cardiology CREST Unit St. James’s Hospital Dublin, Ireland

Jeroen J. Bax, MD, PhD Department of Cardiology Leiden University Medical Center Leiden, The Netherlands

Ewa Dembowski, MD Cardiology Fellow Department of Medicine University of Chicago Chicago, Illinois

Daniel S. Berman, MD Director Department of Nuclear Cardiology/Cardiac Imaging Cedars-Sinai Medical Center Professor of Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, California

Milind Y. Desai, MD Director, Cardiac CT and MR Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio

Thorsten A. Bley, MD Assistant Professor Department of Diagnostic and Interventional Radiology University Medical Center Hamburg-Eppendorf Hamburg, Germany Sonal Chandra, MD Assistant Professor Department of Cardiology University of Chicago Medical Center Chicago, Illinois Otavio R. Coelho-Filho, MD Cardiovascular Magnetic Resonance Fellow Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts

Patrick J. Devine, MD Department of Medicine Walter Reed Army Medical Center Assistant Professor of Medicine Georgetown University Washington, District of Columbia Assistant Professor of Medicine Uniformed Services University of the Health Sciences Bethesda, Maryland Marcelo F. Di Carli, MD Director of Noninvasive Cardiovascular Imaging Program Chief of Nuclear Medicine Department of Radiology and Medicine Brigham and Women’s Hospital Boston, Massachusetts

xi

xii

Vasken Dilsizian, MD Professor of Medicine and Radiology Director, Division of Nuclear Medicine Department of Diagnostic Radiology and â•… Nuclear Medicine University of Maryland School of Medicine Baltimore, Maryland Victor A. Ferrari, MD Professor of Medicine and Radiology Associate Director Noninvasive Imaging Laboratory Department of Medicine (Cardiovascular) University of Pennsylvania Philadelphia, Pennsylvania Andrew S. Flett, BSc, MRCP Heart Hospital Imaging Centre The Heart Hospital London, United Kingdom Mark A. Fogel, MD Professor of Cardiology and Radiology Director of Cardiac Magnetic Resonance The Childrens Hospital of Phildelphia Philadelphia, Pennsylvania Christopher J. François, MD Assistant Professor Department of Radiology University of Wisconsin, Madison Clinical Science Center Madison, Wisconsin Ari B. Goldberg, MD, PhD Fellow, Cardiovascular Imaging Department of Radiology University of Pennsylvania School of Medical Center Philadelphia, Pennsylvania Gagandeep S. Gurm, MD Resident Department of Diagnostic Radiology University of Maryland School of Medicine Baltimore, Maryland Rory Hachamovitch, MD, MSc Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Contributors

Menno V. Huisman, MD, PhD Department of General Internal Medicine, â•… Endocrinology Leiden University Medical Center Leiden, The Netherlands F. A. Klok MD, PhD Department of General Internal Medicine, Endocrinology Leiden University Medical Center Leiden, The Netherlands Harisha Kommana, MD Radiology Resident Department of Radiology University of Texas Medical Branch Galveston, Texas Christopher M. Kramer, MD Professor of Medicine and Radiology Director, Cardiovascular Imaging Center University of Virginia Health System Charlottesville, Virginia Lucia J. M. Kroft, MD, PhD Department of Radiology Leiden University Medical Center Leiden, The Netherlands Benjamin W. Kron, BA Research Assistant Department of Cardiovascular Division Oregon Health & Science University Portland, Oregon Deborah H. Kwon, MD Fellow Department of Cardiovascular Medicine Heart and Vascular Institute Cleveland Clinic Cleveland, Ohio Raymond Y. Kwong, MD, MPH Director of Cardiac Magnetic Resonance Imaging Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts

xiii

Contributors

Benjamin R. Landgraf, BS Medical Student Department of Radiology University of Wisconsin, Madison Clinical Science Center Madison, Wisconsin Joseph A. Lodato, MD Department of Cardiology Mid-Atlantic Permanente Medical Group Largo, Maryland Ali Z. Merchant, MD Cardiology Fellow Department of Internal Medicine The Ohio State University Columbus, Ohio Georgeta Mihai, PhD Research Scientist Department of Cardiovascular Medicine Ohio State University Columbus, Ohio James C. Moon, MD, MRCP Heart Hospital Imaging Centre The Heart Hospital London, United Kingdom Inge C. M. Mos, MD Department of General Internal Medicine, Endocrinology Leiden University Medical Center Leiden, The Netherlands

Ted Plappert, CVT Echocardiography Laboratory Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Don Poldermans, MD, PhD Professor of Medicine Department of Surgery Erasmus Medical Centre Rotterdam, The Netherlands Sanjay K. Prasad, MD Consultant Cardiologist Department of Cardiovascular Magnetic Resonance Royal Brompton Hospital London, England Sanjay Rajagopalan, MD Wolfe Professor of Medicine and Radiology Director, Vascular Medicine Program Department of Cardiovascular Medicine Ohio State University Medical Center Columbus, Ohio Albert de Roos, MD Professor of Radiology Department of Radiology Leiden University Medical Center Leiden, The Netherlands Anurag Sahu, MD Clinical Assistant Professor of Medicine Division of Cardiology Columbus, Ohio

Rory O’Hanlon, MD, MRCPI Consultant Cardiologist Department of Cardiology St. Vincents University Hospital Dublin, Ireland

Joanne D. Schuijf, PhD Department of Cardiology Leiden University Medical Center Leiden, The Netherlands

Chirine Parsai, MD, PhD Department of Cardiology Polyclinique les Fleurs Ollioules, France

Scott D. Solomon, MD Professor of Medicine Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts

Amit R. Patel, MD Assistant Professor Department of Cardiology University of Chicago Medical Center Chicago, Illinois

Lissa Sugeng, MD Assistant Professor Department of Cardiology University of Chicago Medical Center Chicago, Illinois

xiv

Contributors

Martin St. John Sutton, MBBS John W. Bryfogle Professor of Cardiac Imaging University of Pennsylvania Medical Center Philadelphia, Pennsylvania

Radosav Vidakovic´, MD, PhD Department of Cardiology Clinical Hospital Center, Zemun Belgrade, Serbia

Allen J. Taylor, MD, FACC, FAHA Department of Medicine (Cardiology) Washington Hospital Center Professor of Medicine Georgetown University Washington, DC

Yan Wang, RDCS Echocardiography Laboratory Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

Ernst E. van der Wall, MD, PhD Professor Department of Cardiology Leiden University Medical Center Leiden, The Netherlands Mark R. Vesely, MD Assistant Professor of Medicine Division of Cardiology University of Maryland School of Medicine Baltimore, Maryland

Kevin Wei, MD Associate Professor of Medicine Cardiovascular Division Oregon Health & Science University Portland, Oregon



1

Chest Pain: Typical Angina

MA RCELO F. DI C ARLI During the last 2 decades, we have witnessed a significant improvement in the prevention and management of atherosclerotic heart disease and its devastating consequences. Despite these efforts, however, coronary artery disease (CAD) remains highly prevalent, and it represents a health care burden in industrialized and developing countries. This has resulted in a continued expansion and refinement of our noninvasive armamentarium and an intense debate regarding the strengths and weaknesses of competing imaging technologies and their appropriate clinical use. The introduction and dissemination of new technology provides the potential for expanding our diagnostic tools while also enhancing risk prediction, which is discussed throughout the book. This chapter reviews the relative contribution of noninvasive imaging modalities to diagnosis, risk prediction, and guiding management in patients with known or suspected CAD presenting with typical angina, with a focus on patients with stable chest pain syndrome.

and/or rest LV function, coronary anatomy) and what is the accuracy of the information provided. For example, Single photon emission computed tomography (SPECT), Positron emission tomography (PET), and CMR provide stress and rest perfusion information, but the latter 2 methodologies may be superior clinical tools if the imaging data improve diagnostic accuracy, better represent the actual extent of disease, and are potentially subject to less artifact. The advantage of PET over SPECT will be further enhanced, as discussed later, if it provides additional clinically relevant information not provided by SPECT, such as coronary flow reserve data. On the other hand, computed tomography angiography (CTA) represents the first means to assess anatomic CAD noninvasively, thus, a potential replacement for invasive angiography. Additionally, CTA is also a means to assess atherosclerosis, both with respect to its presence and potentially defining plaque morphology.

jâ•…N ONINVASIVE IMAGING APPROACHES

Role of Exercise Electrocardiography jâ•… CONCEPTUAL FRAMEWORK The basis for the diagnostic application of imaging tests in patients without known CAD presenting with typical angina should be viewed in light of the concept of sequential Bayesian analysis of disease probability. This analysis requires knowledge of the prevalence of the disease in the population being tested (pretest probability) as well as the sensitivity and specificity of the imaging test. In the setting of typical angina, the prevalence or pretest probability of CAD then differs on the basis of age, gender, and coronary risk factors. The presence of typical angina identifies a patient cohort with intermediate or high probability of CAD [1]. The information provided by noninvasive imaging generally falls into 1 of 3 categories, myocardial perfusion, left ventricular (LV) function, or coronary artery anatomy. The clinical utility, value, and role of a noninvasive modality are based on 2 test characteristics—what type of information is provided (eg, stress perfusion, stress

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA) guidelines recommend that most patients with a normal or nearly normal resting ECG who can adequately exercise undergo standard Exercise Treadmill Test (ETT) as the initial testing strategy. The guidelines further suggest that patients who are categorized as low risk by ETT be treated initially with medical therapy and those as high risk be referred for coronary angiography. The management of intermediate-risk patients is less certain. These patients will often require additional testing, either stress imaging or coronary angiography, to more accurately characterize risk [2]. This paradigm is based on certain assumptions. Patients who are classified as low risk or high risk should be accurately classified. Annual mortality rates in low-risk patients should be 1% and in high-risk patients 3%. The number of patients classified as intermediate risk should not be too large, as these patients generally will require a second test to refine risk stratification. Stress imaging (SPECT) has been shown to accurately 1

2

classify patients who are initially classified as intermediate risk by ETT [1,3]. Following this staged strategy of apply ing the low-cost ETT to the entire population and reserving more expensive SPECT imaging to refine risk stratification to patients initially classified as intermediate risk by ETT is more cost effective than applying stress or anatomic imaging as the initial test in the entire population. Cardiac CT

Coronary Artery Calcium Scoring Voluminous plaques are more prone to calcification, and stenotic lesions frequently contain large amounts of cal cium [4]. There is growing, consistent evidence that coro nary artery calcium (CAC) scores are generally predictive of a higher likelihood of ischemia (reflecting obstructive CAD), and the available data support the concept of a threshold phenomenon governing this relationship [5–10]. Indeed, the frequency of myocardial ischemia increases significantly with increasing CAC scores, especially among patients with CAC 400 [5–10] (Figure 1.1). Given the fact that CAC scores are not specific markers of obstruc tive CAD [11], however, one should be cautious in con sidering integrating this information into management decisions regarding coronary angiography, especially in patients with low-risk stress tests. Conversely, CAC scores 400, especially in symptomatic patients with intermedi ate-high likelihood of CAD as in those with typical angina, may be less effective in excluding CAD especially in young subjects and women [12]. In a recent study of symptomatic patients with intermediate likelihood of CAD, the absence


of CAC only afforded a negative predictive value (NPV) of 84% to exclude ischemia [10]. As discussed in the next section, CAC scores have a more important prognostic value, especially when combined with stress nuclear imaging.

Coronary CT Angiography In patients without prior revascularization, the available evidence suggests that on a per-patient basis, the average weighted sensitivity for detecting at least 1 coronary artery with 50% stenosis is 94% (range, 75%–100%), whereas the average specificity is 77% (range, 49%–100%) [13]. The corresponding average positive predictive value (PPV) and negative predictive value (NPV) are 84% (range, 50%–100%) and 87% (range, 35%–100%), respec tively, and the overall diagnostic accuracy is 89% (range, 68%–100%). Three multicenter trials (2 of them single ven dor [14,15]) evaluating the diagnostic accuracy of CTA-64 have been completed and recently published [14–16]. The results of these 3 studies confirm the robustness of CTA-64 for complete visualization of the coronary tree (Figure 1.2) and are summarized in Table 1.1. Except for the ACCURACY study, these reported accuracies of CTA to date should be interpreted in light of the relatively narrow range of CAD likelihood in patients examined (ie, high or intermediate high), as evidenced by the high prevalence of obstructive CAD in these series (56%–68%) [13,15,16]. Further, results are generally lim ited to relatively large vessel sizes (1.5 mm), excluding the results of smaller or uninterpretable vessels (generally distal vessels and side branches), the inclusion of which

F igure 1 . 1 â•… Frequency of inducible ischemia, as assessed by stress nuclear perfusion imaging, by coronary artery calcium scores, as assessed by computed tomography. These series included asymptomatic patients undergoing screening [5–7], patients undergoing clinical testing due to symptoms [9,10], or a combination [8].

C H A P T ER 1

•


3

F igure 1 . 2 â•… Multiplanar reformatted coronary angiographic views obtained with 64-slice multidetector computed tomography scanner. The

images show complete visualization of the coronary tree with calcified and noncalcified plaques. LAD, left anterior descending artery; LCX, proximal left circumflex artery; LM, left main artery; OM, obtuse marginal branch; RPL, right posterolateral branch; RCA, right coronary artery.

jâ•… Table 1.1â•… Diagnostic accuracy of coronary CTA in multicenter clinical trials ACCURACY [14]

CorE 64 [15]

European [16]

Weighted Average

Patients

230

291

360

881

Calcium score

No exclusions based on calcium score

,600

,600

—

CAD prevalence

25%

56%

68%

53%

Sensitivity

95%

85%

99%

93%

Specificity

83%

90%

64%

77%

PPV

64%

91%

86%

82%

NPV

99%

83%

97%

93%

CAD, coronary artery disease; CAT, computed tomography angiography; PPV, positive predictive value; NPV, negative predictive value.

lowers diagnostic accuracy. An ongoing problem with CT is that high-density objects such as calcified coronary plaques and stent struts limit its ability to accurately delin eate the degree of coronary luminal narrowing [14,17,18] (Figure 1.3). Of note, the CorE 64 [15] and the European [16] trials selected patients with calcium scores 600.

Like with invasive coronary angiography, there is emerging data supporting the notion that assessments of the extent of CAD by CTA can also provide useful prog nostic information [19–23]. A low 1-year cardiac event rate was reported for patients without obstructive CAD on Coronary computed tomography angiography (CCTA)

4


data suggest that the presence of noncalcified plaques (Figure 1.5) may also add prognostic information beyond the severity of underlying angiographic stenosis [24].

Evaluation of Coronary Artery Stents As mentioned earlier, the visualization of the coronary lumen within stents by CTA is more challenging than the evaluation of the native coronary arteries due to the bloom ing artifacts caused by table metal (Figure 1.6). To date, a limited number of studies assessing the value of CTA to detect in-stent restenosis have been published [25–30]. However, they all show a consistently low sensitivity to identify in-stent restenosis. The limited spatial resolution of CT [31,32], type of stent [31,32], and, especially, stent diameter (3 mm being associated with the highest num ber of partial lumen visualization and nondiagnostic scans) contribute to limited clinical results. F igure 1 . 3 â•… Multiplanar reformatted view of the right coronary artery (RCA) obtained with volumetric 320-slice multidetector computed tomography scanner. The image shows complete visualization of the RCA with a severely calcified plaque in its proximal segment leading to overestimation of underlying coronary stenosis. Follow-up invasive coronary angiography demonstrated nonobstructive plaque in this segment. Image courtesy of Dr. Frank Rybicki, Brigham and Women’s Hospital, Boston, MA.

(0.6% of 1371 patients) [23]. For patients with obstruc tive CAD, the results from 5 published reports revealed a 1-year cardiac event rate of 14.5% [23]. In the Â�largest study published to date [20], event rates were higher for patients with CCTA-defined proximal left anterior descending CAD and multivessel CAD, and survival worsened with higher CAD Prognostic Index scores (Figure 1.4). Preliminary

Evaluation of Bypass Grafts Assessing patency and progression of CAD in bypass grafts is less challenging than in the native coronary arteries, as they are generally larger and less subject to motion. Occasionally, evaluation of internal mammary grafts can be difficult due to blooming artifact from metal clips. On a per-graft basis, the average sensitivity for detecting at least 1 graft with 50% stenosis or total occlusion is 99% (range, 96%–100%), whereas the average specificity is 93% (range, 68%–100%). The corresponding average positive and NPVs are 83% (range, 37%–98%) and 99% (range, 98%–100%), respec tively, and the overall diagnostic accuracy is 97% (range, 95%–99%) [33–40]. Importantly, there is no appreciable difference in the reported diagnostic accuracies for the detec tion of stenosis or total occlusions between arterial and vein

F igure 1 . 4 â•…One-year all-cause death rates by extent and severity of Coronary computed tomography angiography (CCTA) results in 1127

patients. LAD: left anterior descending coronary artery. Reproduced with permission from Ref. 23.

C H A P T ER 1

•


5

F igure 1 . 5 â•… Selected multiplanar reformatted computed tomography

angiography view of the left coronary artery. There is nonobstructive Â� calcified plaque of the left main (LM) and proximal left circumflex (LCX) coronary arteries. In addition, there is a noncalcified plaque in the proximal segment of the left anterior descending artery with significant luminal narrowing (arrow).

grafts. In general, false-positive findings are related to diffi culties in evaluating distal anastomosis [39]. Despite the high degree of accuracy to detect occlusions and stenosis within grafts, CTA has limited value in the evaluation of the patient with recurrent chest pain after Coronary artery bypass graft (CABG) because this also requires an assessment of the native coronary arteries, which are more challenging because they are usually small and heavily calcified (Figure 1.6). Stress Echocardiography The hallmark of myocardial ischemia during stress echo cardiography is the induction of new regional wall motion abnormalities and reduced systolic wall thickening. This approach can be used in conjunction with exercise or dobutamine stress. The average weighted sensitivity and specificity of exercise echocardiography (15 studies, n 5 1849 patients) are 84% and 82%, respectively, which is similar to 80% and 84%, respectively, for dobutamine echocardiography (28 studies, n 5 2246 patients) [41]. The advantages of stress echocardiography include its relatively good diagnostic accuracy, widespread availability, no use of ionizing radiation, and low cost. Limitations of stress echocardiography include the challenges associated with image acquisition at peak exercise because of exer tional hyperpnoea and cardiac excursion, the fact that rapid recovery of wall motion abnormalities can be seen with mild ischemia (especially with 1-vessel disease, which limits sensi tivity), detection of residual ischemia within an infarcted ter ritory is difficult because of resting wall motion abnormality, the technique is highly operator dependent for acquisition of

F igure 1 . 6 â•…Examples of computed tomography angiography evaluation after revascularization. Panels A and B show an example of a patient with a stent in the proximal left anterior descending LAD coronary artery (arrow). Although patency of the stent is readily assessable, evaluation of Â�in-stent restenosis is more difficult due to metallic artifact leading to partial visualization of the coronary lumen. Panels C, D, E, F, and G show an example of a computed tomography angiogram in a patient after coronary artery bypass graft. Assessment of coronary artery disease progression within grafts is relatively straightforward, whereas progression of disease in the native vessels is more difficult because they are usually very small and heavily calcified. LAD, left anterior descending artery; LIMA, left internal mammary graft; OM, obtuse marginal branch; SVG, safenous vein graft; RCA, right coronary artery. Reproduced with permission from Ref. 13.

echocardiographic data and analysis of images, and the fact that good-quality complete images viewing all myocardial segments occurs in only 85% of patients. Newer techniques including second harmonic imaging and the use of intrave nous contrast agents improve image quality, but their effect on diagnostic accuracy has not been well documented. The use of IV contrast agents may also allow assessment of myo cardial perfusion [42]. However, limited data are available to establish this role for echocardiography. Like with nuclear perfusion imaging, stress echocardiog raphy is often used for risk stratification in patients with suspected or known CAD. A negative stress echocardiogram is associated with an excellent prognosis, allowing identifi cation of patients at low risk. A recent review suggests an annual hard event rate (death or myocardial infarction) of 1.2% for a normal stress echocardiogram as compared with 7.0% for an abnormal study [41,43,44]. Conversely, risk of

6

F igure 1 . 7 â•…Rates of total mortality after exercise stress echocardiography in patients with low, intermediate, and high Duke treadmill scores. Patients are further stratified by the stress echocardiography results (normal, 1-, 2-, or 3-vessels with abnormality). Data obtained from Ref. 44.

severe adverse events increases with the magnitude of abnor malities on stress echocardiography [43,44] (Figure 1.7). Stress Nuclear Imaging SPECT is the most common form of stress imaging tests. PET has advantages compared to SPECT (discussed later), but it is not widely available and thus considered an emerg ing technology in clinical practice.

Technical Considerations for PET and SPECT Several technical advantages account for the improved image quality and diagnostic ability of PET compared to SPECT including (1) routine measured (depth independent) attenuation correction, which decreases false positives and, thus, increases specificity; (2) high spatial and contrast res olution (heart-to-background ratio) that allows improved detection of small perfusion defects, thereby decreasing false negatives and increasing sensitivity; (3) high temporal resolution that allows fast dynamic imaging of tracer kinet ics, which makes absolute quantification of myocardial per fusion (in mL/min/g of tissue) possible. In addition, the use of short-lived radiopharmaceuticals allows fast, sequential assessment of regional myocardial perfusion (eg, rest and stress), thereby improving laboratory efficiency and patient throughput. Although these technical advantages have been recognized for a long time, access to PET for routine detection of CAD remains somewhat limited. Recent U.S. Food and Drug Administration approval of PET agents for imaging myocardial perfusion (ie, 82Rubidium [generator product] and 13N-ammonia [cyclotron product]) and the subsequent changes in reimbursement are responsible for much of the recent growth in clinical cardiac PET. Despite these advantages, SPECT scanners and imaging radiotrac ers (eg, 99mTc agents and 201Thallium) are still more widely available and less expensive than PET scanners and posi tron emitting radiotracers (eg, 82Rubidium, 13N-ammonia).


Nuclear perfusion imaging is a robust approach for diagnosing obstructive CAD, quantifying the magnitude of myocardium at risk, assessing the extent of tissue viabil ity, and guiding therapeutic management (ie, selection of patients for revascularization). The published literature with SPECT suggests that its average sensitivity for detecting 50% angiographic stenosis is 87% (range, 71%–97%), whereas the average specificity is 73% (range, 36%–100%) [45]. With the use of attenuation correction methods, the specificity improves especially among patients undergoing exercise stress testing [45]. With PET perfusion imaging, the reported average sensitivity for detecting 50% angio graphic stenosis is 91% (range, 83%–100%), whereas the average specificity is 89% (range, 73%–100%) [46]. One of the most valuable clinical applications of nuclear perfusion imaging is for risk prediction. It is well established that patients with a normal SPECT study exhibit a median rate of major adverse cardiac events of 0.6% per annum [47] (Figure 1.8). Importantly, the risk of death and myocardial infarction increases linearly with increasing magnitude of perfusion abnormalities [48,49] (Figure 1.9). As with stress echocardiography, stress imag ing results further risk stratify patients into low-risk versus higher-risk subgroups even after stratifying for preimaging results [50], a demonstration of clinical incremental prog nostic value (Figure 1.10). These findings are important in symptomatic cohorts and reflect the value of evaluating the physiology of the disease state in addition to the anatomic extent and severity of stenoses. Thus, although obstructive coronary disease may be present, normal perfusion find ings reveal that the disease is not flow limiting and that it is not prognostically significant. Despite its widespread use and clinical acceptance, a recognized limitation of this approach is that it often uncovers only coronary territories supplied by the most severe stenosis and, consequently, it is relatively insen sitive to accurately delineate the extent of obstructive angiographic CAD especially in the setting of multivessel disease [51,52]. Recent evidence suggests that 2 quan titative approaches may be able to help mitigate this limitation, at least in part. One of them relates to PET’s unique ability to assess LV function at rest and during peak stress (as opposed to poststress with SPECT) [52]. The data suggest that in normal subjects, left ventricular ejection fraction (LVEF) increases during peak vasodila tor stress [52]. In patients with obstructive CAD, how ever, the delta change in LVEF (from baseline to peak stress) is inversely related to the extent of obstructive angiographic CAD. Indeed, patients with multivessel or left main disease show a frank drop in LVEF during peak stress even in the absence of apparent perfusion defects (Figure 1.11). In contrast, those without significant CAD or with 1-vessel disease show a normal increase in LVEF (Figure 1.11). Consequently, the diagnostic sensitivity of gated PET for correctly ascertaining the presence of

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F igure 1 . 8 â•…Example of a normal myocardial perfusion single photon emission computed tomography study obtained using a 1-day 99mTc sestamibi protocol.

F igure 1 . 9 â•…Example of a severely abnormal myocardial perfusion single photon emission computed tomography study obtained using a 1-day

Tc sestamibi protocol. The images demonstrate a large and severe perfusion defect throughout the anterior, septal, and apical walls, showing complete reversibility consistent with extensive stress-induced ischemia throughout the left anterior descending coronary artery (LAD) territory. Follow-up invasive coronary angiography confirmed the presence of severe proximal LAD disease.

99m


8

F igure 1 . 1 0 â•…Rates of cardiac death and myocardial

infarction over a 19-month follow-up in patients without prior coronary artery disease undergoing stress single photon emission computed tomography ( SPECT). Patients are separated into low, intermediate, and high Duke treadmill scores. Patients are further stratified by the stress SPECT results (normal, mild, and moderately to severe abnormal scans). Significant difference in event rates across scan categories (P , .01) is present in the intermediate and high Duke treadmill score subgroups as a function of scan result. Reproduced with permission from Ref. 50.

F igure 1 . 1 1 â•… Gated rest-stress

Rubidium myocardial perfusion positron emission tomography (PET) images illustrating the added value of left ventricular function over the perfusion information. Panel A (left) demonstrates a normal rise in left ventricular ejection fraction (LVEF) from rest to peak stress (bottom) in a patient with angiographic single-vessel coronary artery disease (CAD), showing a single perfusion defect in the inferior wall on the PET images (arrows). Panel B (right) demonstrates an abnormal drop in left ventricular ejection fraction (LVEF) from rest to peak stress in a patient with angiographic multivessel vessel CAD, also showing a single perfusion defect in the inferolateral wall on the PET images (arrows). Reproduced with permission from Ref. 13. 82

multivessel disease increases from 50% to 79% [52]. A recent study suggests that measurements of so-called LVEF reserve also have prognostic implications [53] (Figure 1.12). The second approach is based on the ability of PET to enable absolute measurements of myocardial blood flow (in mL/min/g) and coronary vasodilator reserve [54–57]. In patients with so-called balanced ischemia or diffuse CAD, measurements of coronary vasodila tor reserve would uncover areas of myocardium at risk that would generally be missed by performing

only relative assessments of myocardial perfusion [58] (Figure 1.13). These estimates of coronary vasodilator reserve appear to contribute to risk prediction, which would be Â�especially in patients with normal perfusion [59] (Figure 1.14). It is important to point out, however, that neither of these approaches has been tested in pro spective clinical trials. Another limitation of the myocardial perfusion Â�imaging approach is that it fails to describe the presence and extent of subclinical atherosclerosis [60,61]. This is not unexpected since the myocardial perfusion imaging

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F igure 1 . 1 2 â•…Annualized rates of cardiac events (cardiac death

and nonfatal myocardial infarction) and all-cause death were lower in patients with left ventricular ejection fraction (LVEF) reserve 0% compared to those with LVEF reserve ,0%. *P , .001 for cardiac events and all-cause death. Reproduced with permission from Ref. 53.

F igure 1 . 1 3 â•… The top panel shows a stress-rest 82Rubidium positron emission tomography scan demonstrating a large and severe perfusion defect throughout the inferior and inferolateral left ventricular walls, which was fixed. The lower panel demonstrates the results of the quantitative analysis using the approach developed at Brigham and Women’s Hospital, Boston, MA. The data demonstrate severely impaired Â�dipyridamole-stimulated myocardial blood flow (MBF) resulting in a markedly reduced coronary flow reserve (CFR). Coronary angiography demonstrated total occlusion of the right and left circumflex coronary arteries and a severe stenosis in the mid-left anterior descending artery. LAD, left anterior descending coronary artery; LCX, proximal left circumflex coronary artery; RCA, right coronary artery MACE, major adverse cardiac events. Reproduced from Ref. 46, with permission from the Society of Nuclear Medicine.

F igure 1 . 1 4 â•… Unadjusted Kaplan-Meier survival curves showing value of coronary flow reserve (CFR), as assessed by 13N-ammonia positron emission tomography in predicting outcome up to 3 years. Reproduced with permission from Ref. 59.

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method is designed and targeted on the Â�identification of flow-limiting stenoses. This is potentially important Â�especially in patient subgroups with intermediate-high clinical risk in whom there may be extensive Â�subclinical CAD and may explain, at least in part, the limitations of perfusion imaging alone to identify low-risk patients among those with high clinical risk (eg, diabetes, Â�end-stage renal disease) [47].

Dual-Modality CT and Nuclear Perfusion Imaging The potential to acquire and quantify rest and stress myo cardial perfusion and noncontrast CT scan for CAC scor ing from a single dual-modality study may offer a unique opportunity to expand the prognostic value of stress nuclear imaging. The rationale for this integrated approach is predicated on the fact that the perfusion imaging approach is designed to uncover only obstructive atherosclero sis and, thus, insensitive for detecting subclinical disease (Figure 1.15) [62]. The CAC score, reflecting the anatomic extent of atherosclerosis [63], may offer an opportunity to


improve the conventional models for risk assessment using nuclear imaging alone (especially in patients with normal perfusion), a finding that may serve as a more rational basis for personalizing the intensity and goals of medical therapy in a more cost-effective manner. For example, recent data suggest that quantification of CAC scores at the time of stress nuclear imaging using a dual-modality approach can enhance risk predictions in patients with suspected CAD [10]. In a consecutive series of 621 patients without prior CAD undergoing stress PET imaging and CAC scoring in the same clinical setting, risk-adjusted analysis demon strated that for any degree of perfusion abnormality, there was a stepwise increase in adverse events (death and myo cardial infarction) with increasing CAC scores. This find ing was observed in patients with and without evidence of ischemia on PET MPI. The annualized event rate in patients with normal PET MPI and no CAC was substantially lower than that among those with normal PET MPI and a CAC 1000 (Figure 1.16). Likewise, the annualized event rate in patients with ischemia on PET MPI and no CAC was lower than that among those with ischemia and a CAC 1000.

F igure 1 . 1 5 â•…Illustration of the complementary role of nuclear perfusion imaging and computed tomography calcium scoring using integrated hybrid imaging. The top panel shows the stress-rest myocardial perfusion positron emission tomography (PET) scan of a patient with atypical chest pain. This patient had a calcium score of zero. The lower panel shows the stress-rest myocardial perfusion PET scan of a similar patient with atypical chest pain and dyspnea. By contrast, this patient had extensive atherosclerosis with a calcium score of 1130. The 2 examples show that flow-limiting disease was excluded in both patients; the 2 differed in the extent of underlying atherosclerosis, which may indicate different clinical risk. SA, short axis; VLA, vertical long axis; HLA, horizontal long axis. Reproduced from Ref. 62.

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CAD, which as discussed earlier is one of the pitfalls of stress perfusion scintigraphy (Figure 1.17). Although CT coronary angiography as an adjunct to perfusion imaging could expand the opportunities to identify patients with noncalcified plaques at greater risk of adverse cardio vascular events, it is unclear how much added prognos tic information there is in the contrast CT scan over the simple CAC scan [67]. Stress Cardiac Magnetic Resonance Imaging

F igure 1 . 1 6 â•…Adjusted survival curves for freedom from death or myocardial infarction (MI) adjusted for age, sex, symptoms, and conventional coronary artery disease risk factors in patients without ischemia (A) and with ischemia (B). CAC, coronary artery Â�calcium. Reproduced from Ref. 10.

As discussed here, CTA provides excellent diagnostic sensitivity for stenoses in the proximal and mid segments (1.5 mm in diameter) of the main coronary arteries. This limitation is unlikely to change because a significant improvement in spatial resolution for CT will have to be coupled with a substantial increase in radiation dose in order to maintain noise and image quality constant. However, this limitation of CT can be offset by the MPI information that is generally not affected by the location of coronary stenoses. First clinical results appear encour aging, and they support the notion that dual-modality imaging may offer superior diagnostic information with regard to identification of the culprit vessel [64–66]. For example, Rispler et al reported a significant improvement in specificity (63%–95%) and PPV (31%–77%) without a change in sensitivity or NPV for detection of obstruc tive CAD as defined by quantitative coronary angiogra phy in a cohort of 56 patients with known or suspected CAD undergoing hybrid SPECT/CTA imaging [66]. On the other hand, CTA improves the detection of multivessel

The 2 approaches used with CMR to evaluate known or suspected CAD include the assessment of regional myo cardial perfusion or wall motion, the latter being anal ogous to dobutamine echocardiography. The logistics for stress MRI studies require the use of pharmacologic stress agents including vasodilators and dobutamine. Myocardial perfusion is evaluated by injecting a bolus of contrast agent followed by continuous data acquisition as the contrast passes through the cardiac chambers and into the myocardium. Relative perfusion deficits are rec ognized as regions of low signal intensity (black) within the myocardium (Figure 1.18). In addition, delayed imaging allows detection of bright areas of myocardial scar (white), which further enhances the utility of this approach for diagnosis of CAD (so-called delayed gado linium enhancement) (Figure 1.18). The major advantage of dobutamine-CMR over dobu tamine echocardiography is better image quality and sharper definition of endocardial borders against blood pool. Consequently, dobutamine-CMR appears to have higher diagnostic accuracy than dobutamine echocardiog raphy for detection of CAD [68], especially in patients with poor acoustic window [69]. A limitation of high-dose dobutamine stress CMR is that it bears the potential risk of severe side effects, such as hypotension, and severe ven tricular arrhythmias in the inhospitable environment of the MR scanner. The advantage of stress perfusion CMR over SPECT is its clearly higher spatial resolution allowing detection of Â�subendocardial defects that may be missed by SPECT [70]. The major limitation of perfusion CMR is the common Â�presence of so-called dark-rim artifacts, which may cause false-positive readings. The addition of the delayed enhancement information in a stepwise interpreta tion algorithm has been proposed as a way to avoid falsepositive readings [71]. Although this approach may clearly help in patients with prior CAD, its impact in patients with suspected CAD may be more limited. Additionally, quan tification of the severity of stress-induced peri-infarct isch emia is more challenging than that with nuclear techniques (Figure 1.19). In a recent review of the published literature [72], stress-induced wall motion abnormalities imaging dem onstrated a sensitivity of 83% and specificity of 86% on a patient level. Stress myocardial perfusion imaging

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F igure 1 . 1 7 â•… Three-dimensional volumerendered myocardial perfusion positron emission tomography images obtained with 82 Rubidium with overlaying coronary computed tomography angiographic images (top panel), and corresponding invasive coronary angiographic views (lower panel) of a 65-yearold diabetic patient presenting with atypical chest pain. The perfusion images demonstrate moderate perfusion defects in the anterior and inferolateral walls, corresponding to stenosis in the left anterior descending and proximal left circumflex (LCX) coronary arteries (arrows). This image fusion display allows detection of culprit coronary stenosis and can be helpful in guiding targeted interventions. RCA, right coronary artery.

F igure 1 . 1 8 â•…Example of stress, rest, and

delayed CMR images in a diabetic middle-aged man with exertional dyspnea who has LVH and normal LVF with a small area of inferior hypokinesis. Images represent short-axis views of the left ventricle in basal (left) and apical (right) planes. The stress images demonstrate extensive, concentric areas of subendocardial hypoperfusion (arrows). The rest images demonstrate only a small subendocardial perfusion deficit in the inferior and inferoseptal walls, matching the area of gadolinium enhancement on the delayed images. This study is consistent with extensive 3-vessel territory ischemia with a relatively small area of subendocardial scar in the right coronary territory. The patient was found to have severe 3-Â�vessel coronary artery disease on invasive coronary angiography. Images are courtesy of Dr. Raymond Kwong, Brigham and Women’s Hospital, Boston, MA. CMR, cardiac magnetic resonance; LVH, left ventricular hypertrophy; LVF, left ventricular function.


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F igure 1 . 1 9 â•…Example of stress, rest, and delayed cardiac magnetic resonance (CMR) images in a man with known coronary artery disease prior myocardial infarction (MI), and stenting of the left anterior descending coronary artery (LAD). Images represent mid short-axis views of the left ventricle. The stress images demonstrate extensive anterior, anterolateral, and septal subendocardial hypoperfusion (arrows). The rest images demonstrate residual areas of subendocardial perfusion deficit in the anterolateral and septal walls, matching the area of gadolinium enhancement on the delayed images. This study is consistent with a large area of prior MI throughout the LAD territory with evidence of some residual stress-induced peri-infarct ischemia. However, quantification of the magnitude of residual ischemia is more challenging owing to the presence of prior MI in the same territory. Image courtesy of Dr. Raymond Kwong, Brigham and Women’s Hospital, Boston, MA.

demonstrated a sensitivity of 91% and specificity of 81% on a patient level. As with the CT literature, the summary sensitivities and specificities for perfusion imaging and stress-induced wall motion abnormalities imaging in this meta-analysis were obtained in patients with a high prev alence of CAD (prior MI) selected to undergo coronary angiography Â�(disease prevalence was 71% for the stress perfusion studies and 57% for the wall motion studies). Limited data in patients without prior CAD (especially without prior MI) suggest that diagnostic accuracy of the myocardial Â�perfusion approach may be more modest [71]. The combination of wall motion and myocardial perfusion analysis in response to dobutamine stress improves sensi tivity for the diagnosis of CAD but does not enhance over all diagnostic accuracy because of a concomitant decrease in specificity [73]. There is growing, consistent evidence that ischemia measurements derived from stress CMR studies also have prognostic significance [74]. In line with the nuclear and echocardiography literature, a normal CMR study is asso ciated with a good prognosis [69,74–79]. Conversely, the presence of new wall motion abnormalities [69,75,79], regional perfusion defects [77], the combination of wall motion abnormalities and perfusion defects [76,78], and the presence of late gadolinium enhancement [77,78,80] were all predictors of adverse events.

jâ•…S ELECTING A TESTING STRATEGY IN PATIENTS WITH OUT KNOWN CAD As discussed above, there are many options for the evalua tion of a patient with suspected CAD presenting with typical angina symptoms. The critical questions to be answered by a testing strategy include the following: (1) Does the presence of typical angina reflect obstructive CAD? (2) What is the short- and long-term risk? (3) Does the patient need to be considered for revascularization? The ACC/AHA guidelines recommend that most patients with a normal or nearly normal resting ECG who can adequately exercise undergo a standard ETT as the initial testing strategy. The guidelines further suggest that patients who are categorized as low risk by ETT be treated initially with medical therapy and those who are high risk be referred for coronary angiography. The management of intermediate-risk patients is less certain. These patients will often require additional testing, either stress imaging or coronary angiography, to more accurately character ize risk [2]. One potential caveat with this approach is that the number of patients classified as intermediate risk should not be too large, as these patients generally will require a second test to refine risk stratification. This con cept may be especially important for patients with typical angina, who by definition are an intermediate-high risk


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Low-Intermediate (50%)

ETT

Low risk

High (>90%)

Stress imaging

Int-high risk Low-int risk

Medical therapy

High risk

Cath/revascularization

F igure 1 . 2 0 â•… Possible testing strategy for patients with suspected coronary artery disease (CAD) presenting with typical angina. Strategy is based on established guidelines as well as consideration of added clinical and economic outcomes of each procedure for each patient subset. ETT, Exercise Treadmill Test.

cohort. Stress imaging with either SPECT or echocardiog raphy has been shown to accurately classify patients who are initially classified as intermediate risk by ETT [1,3] (Figures 1.7, 1.10, and 1.20). Following this staged strat egy of applying the low-cost ETT to the entire popula tion and reserving more expensive imaging to refine risk stratification for patients initially classified as interme diate risk by ETT is more cost effective than applying stress or anatomic imaging as the initial test in the entire population. An imaging strategy is the recommended first step for patients who are unable to exercise and/or those with abnormal resting ECGs [45,81]. Importantly, the most recent documents regarding appropriate use of radionuclide and echocardiography imaging also con sidered that imaging may be an appropriate first step in patients with intermediate-high likelihood of CAD, as for example, those presenting with typical angina [82,83] (Figure 1.21). In considering the potential clinical appli cation of imaging modalities, the evidence supporting the role of assessment of ischemia versus anatomy must be considered. From the discussion here, a normal CTA is helpful as it effectively excludes the presence of obstruc tive CAD and the need for further testing, defines a low clinical risk, and makes management decisions straight forward. Because of its limited accuracy to define stenosis

severity [84,85] and predict flow-limiting disease [86], however, abnormal CTA results are more problematic to interpret and to use as the basis for defining the poten tial need of invasive coronary angiography and revascu larization. Consequently, CTA may be an effective first imaging strategy if the number of abnormal scans is not excessively large (eg, younger patients, low-intermediate CAD likelihood) (Figure 1.21), as those patients will require a second test for defining subsequent manage ment. Patients with typical angina are by definition more likely to have obstructive CAD, which may render the CTA-first approach less effective. The justification of stress imaging in testing Â�strategies has hinged on the identification of patients who may benefit from a revascularization strategy by means of noninvasive estimates of jeopardized myocardium rather than angiography-derived anatomy. The advantages of this approach include avoidance of excess catheteriza tions with their associated cost and risk and the potential oculostenotic reflex [87] and identification of patients with extensive ischemia [88] as a means to identify revascularization candidates (Figure 1.22). The value of ischemia information for optimizing clinical deci sion making has been demonstrated by multiple stud ies. Revascularization in patients with 3-vessel CAD was associated with enhanced survival only in those patients

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F igure 1 . 2 1 â•…Alternative optimized testing strategy for patients with suspected coronary artery disease (CAD) presenting with typical angina.

Strategy is based on established guidelines as well as consideration of added clinical and economic outcomes of each procedure for each patient subset. CTA, computed tomography angiography.

F igure 1 . 2 2 â•… Natural log of the hazard function (based on Cox proportional hazards model) versus percent of the myocardium ischemic on stress single photon emission computed tomography. Separate lines depicting the relationship between risk and ischemia are shown for patients treated with medical therapy (Medical Rx) and revascularization (Revasc). Significant difference across ischemia for risk and between treatment groups (interaction from

multivariable model P , .01). Reproduced from Ref. 87.

with ischemic ETT results, whereas medical therapy was a superior initial therapy in patients without this finding [89]. Similar findings were reported in the COURAGE nuclear Â�substudy [90] and in risk-adjusted analysis of large registries [87]. The benefit of an ischemia-guided

approach to management is further supported by inva sive estimates of flow-limiting stenosis (eg, fractional flow reserve, FFR) [91]. In the setting of an FFR 0.75, revascularization can be safely deferred without increased patient risk, despite the Â�presence of what visually appears

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to be a significant stenosis [91]. Indeed, cardiac event rates are extremely low in these patients; even lower than predicted if treated with PCI [92], and this differential risk appears to be sustainable long term [93]. This is further supported by a recent report from a ran domized clinical trial evaluating the efficacy of revascular ization decisions using an angiographically guided versus a functionally guided (as assessed by FFR) percutaneous coro nary intervention (PCI) in patients with multivessel CAD [94]. In this study, routine use of an FFR-guided approach signifi cantly reduced the rate of the composite endpoint of death, nonfatal myocardial infarction, and repeat revascularization by 28% at 1 year compared to the angiographically guided strategy. In addition, both groups have high and comparable rates of angina-free patients at 1 year [94]. Furthermore, in patients with visually defined left main coronary disease, an FFR 0.75 was associated with excellent 3-year Â�survival and freedom from major adverse cardiovascular events [92]. Conversely, event rates are increased when lesions with FFR 0.75 are not revascularized [95]. The acceptable diagnostic accuracy of stress imaging approaches, along with their robust risk stratification, and the ability of ischemia information to identify patients who would benefit from revascularization suggest a potential role as a first imaging strategy in patients with intermediatehigh likelihood of CAD or as a follow-up to abnormal CTA findings (Figure 1.21). Although the available data suggest similar diagnostic accuracy for SPECT, PET, echo cardiography, and CMR, the choice of strategy depends on availability and local expertise. Special Groups Women.â•… The use of exercise testing in women presents dif ficulties that are not experienced in men. These difficulties reflect the differences between men and women regarding the prevalence of CAD and the sensitivity and specific ity of exercise testing. Although obstructive CAD is one of the principal causes of death in women, the prevalence (and thus the pretest probability) of this disease is lower in women than it is in men of comparable age, especially in premenopausal women. Compared with men, the lower pretest probability of disease in women means that more test results are false positive. For example, almost half the women with angina symptoms in the CASS study, many of whom had positive exercise test results, had normal coro nary arteriograms. Exercise testing is less sensitive in women than it is in men, and some studies have found it also to be less spe cific [1,96,97]. Indeed, ECG changes during exercise have been reported to be of diminished accuracy in women as a result of more frequent resting ST-T-wave changes, lower ECG voltage, and hormonal factors such as endog enous estrogen in premenopausal women and hormone replacement therapy in postmenopausal women [97]. The


inability of many women to exercise to maximum aerobic capacity, the greater prevalence of mitral valve prolapse and syndrome X in women, and differences in microvas cular function (leading perhaps to coronary spasm) are other reasons that may help explain the differences with men. The difficulties of using exercise testing for diagnos ing obstructive CAD in women have led to speculation that stress imaging may be preferred over standard stress testing [97]. Although the optimal strategy for diagnos ing obstructive CAD in women remains to be defined, the current recommendations suggest that there are currently insufficient data to justify replacing standard exercise testing with stress imaging when evaluating symptomatic women for CAD [1,96,97]. Elderly.â•… ACC/AHA guidelines recommend that the stan dard ETT be used as the initial stress testing modality in patients without prior revascularization who can ade quately exercise and who have a normal or near normal resting ECG [81,96,98]. The guidelines acknowledge that published data on stress testing in the elderly are limited but do not recommend altering this recommendation simply on the basis of age. Factors influencing the utility of stan dard ETT include the fact that functional capacity often is compromised from muscle weakness and deconditioning, making the decision about an exercise test versus a phar macologic stress test more important. Elderly patients are more likely to hold the handrails tightly, thus reducing the validity of treadmill time for estimating metabolic equiv alents (METs). Arrhythmias occur more frequently with increasing age, especially at higher workloads. According to the guidelines, many elderly patients will be candidates for stress imaging, either due to resting ECG abnormali ties or inability to exercise. Even in those elderly patients who are candidates for standard ETT, however, the limited published data suggest that a large percentage (one-half to two-thirds) will be classified as intermediate risk [99], which will often necessitate performing another test. Furthermore, the subset classified as low risk may not be correctly classified (annual mortality rate is not 1%). Due to the fact that coronary calcification increases with age and that coronary CTA has limited diagnostic accu racy in the setting of dense calcifications limited value, stress imaging may be considered as the initial stress test modality in the elderly. Diabetes and Renal Dysfunction.â•… Certain subsets of patients appear to benefit significantly from stress imaging. Diabetics with an abnormal perfusion scan or an abnor mal stress echo have a higher subsequent event rate than nondiabetic patients with the same extent or severity of abnormality [100–102]. Similarly, patients with chronic renal disease can be well risk stratified by either stress per fusion imaging or stress echocardiography in the absence

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of symptoms of CAD [103–105]. Accelerated CAD is a fre quent complication of renal disease, and use of noninvasive imaging for prognostication avoids the risk of administer ing contrast, necessary with CT angiography or coronary angiography.

jâ•…S ELECTING A STRATEGY IN PATIENTS WITH KNOWN CAD Use and selection of testing strategies in patients with typical angina and established CAD (ie, prior angiogra phy, prior MI, prior revascularization) differ from those without prior CAD [81,96,98]. Although standard ETT may help distinguish cardiac from noncardiac chest pain, exercise ECG has a number of limitations following MI and revascularization (especially CABG). These patients frequently have rest ECG abnormalities. In addition, there is a clinical need to document both the magnitude and site of ischemia. Consequently, imaging tests are preferred for evaluating patients in this group. There are also important differences in the effec tiveness of imaging tests in these patients. As discussed above, coronary CTA is limited in patients with prior

revascularization. Patients who have previously undergone CABG are a particularly heterogeneous group with respect to the Â�anatomic basis of ischemia and its implications for subsequent morbidity and mortality. In addition to graft attrition, progression of native CAD is not uncommon in symptomatic patients. Although bypass grafts are good tar gets for CTA, the native circulation is not [13]. Likewise, blooming artifacts from metallic stents also limit the appli cation of CTA in patients with prior PCI [13]. Although newer stent material may change the potential role of CTA in the future, it is probably not the first line of testing in these patients. If an anatomic strategy is indicated, direct referral to invasive angiography is recommended [106]. Stress imaging approaches are especially useful and preferred in symptomatic patients with established CAD (Figure 1.23). As in patients without prior CAD, normal imaging studies in symptomatic patients with established CAD also identify a low-risk cohort. In those with abnor mal stress imaging studies, the degree of abnormality relates to post-test risk [1,98]. In addition, stress imaging approaches can localize and quantify the magnitude of isch emia (especially with perfusion imaging), thereby assisting in planning targeted revascularization procedures. Like in patients without prior CAD, the choice of stress imaging strategy depends on availability and local expertise.

Typical Angina

ETT (?)

Low risk

Stress imaging

Int-high risk

Low-int risk

Medical therapy

High risk

Cath/revascularization

F igure 1 . 2 3 â•… Possible testing strategy for patients with known coronary artery disease (CAD) presenting with typical angina. Strategy is based

on established guidelines as well as consideration of added clinical and economic outcomes of each procedure for each patient subset. ETT, Exercise Treadmill Test.


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jâ•… CONCLUSIONS Innovation in noninvasive cardiovascular imaging is rap idly advancing our ability to image in great detail the structure and function in the heart and vasculature. This innovation in imaging promises to provide new insights into pathophysiology of disease, earlier detection of dis ease, and quantitative methods to evaluate response to therapeutic interventions. Multiple imaging modalities targeting various aspects of cardiac and vascular anatomy and/or function are avail able, and each provide potentially useful information in the evaluation of patients with typical angina. To date, there is limited data on head-to-head comparisons between imag ing modalities, and there is considerable controversy on the relative value of imaging technologies. Consequently, selec tion of the best test for an individual patient remains an art that should focus on risk stratification and prediction of which patients may benefit from revascularization. The goals of future investigation will be to refine these technolo gies, address the issue of cost-effectiveness, and validate a range of clinical applications in large-scale clinical trials.

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â•‡ 14.

â•‡ 15.

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2

Atypical Chest Pain and Other Presentations of an Intermediate Likelihood of Obstructive Coronary Artery Disease

jâ•‡General Considerations in Pretest Evaluation

of Patients with Atypical Chest Pain

AIDEN ABIDOV Da NIEL S. B ERMa N RO RY H aC haMOVITC h According to the 2008 Heart Disease and Stroke Statistics Update [1], an estimated 80 700 000 American adults (1 in 3) have 1 or more types of cardiovascular diseases (CVD). Approximately 16 000 000 of these patients have established coronary artery disease (CAD), and many more have undiagnosed coronary lesions that may represent as either atypical symptoms or, in many cases, manifest as either myocardial infarction with irreversible damage to myocardium, or cardiac death. Nearly 2400 Americans die of cardiac conditions each day, an average of 1 death every 37 seconds. Cardiovascular mortality claims approximately as many lives each year as cancer, chronic lung disorders, accidents, and diabetes mellitus combined [2]. According to the Statistics Update, in 2005 there were 6 734 000 outpatient department visits with a primary diagnosis of cardiovascular disorder; approximately 1 of every 6 hospital stays, or almost 6 million, resulted from CVD [1]. The total inpatient hospital cost for cardiac disorders was $71.2 billion, approximately one-fourth of the total cost of hospital care in the United States. This huge social burden requires us to seek further improved diagnostic modalities and algorithms, allowing to identify patients with early and thus more easily correctable forms of disease as well as to distinguish those with atypical presentations and intermediate likelihood of CAD. Chest pain (CP) is one of the most frequent complaints encountered in clinical practice, both acutely in the 22

Emergency Department (ED) and as a chronic symptom during the outpatient clinical encounters. Since consequences related to a possibility of missed and untreated acute coronary syndromes (ACS) or chronic obstructive CAD might be associated with a potentially fatal outcome, clinicians tend to overdiagnose and overinvestigate the symptomatology. In the modern algorithms, initial steps in the evaluation of patients with CP include important procedures focused on exclusion of CAD as a cause of pain [3]; this includes a CAD-oriented history, physical examination, and resting ECG, with 2 or more sets of cardiac enzymes if the presentation is either acute or subacute. A simple set of 3 questions has been recommended to differentiate a typical anginal CP from either atypical angina or nonanginal CP [4,5] (Table 2.1). These 3 large jâ•…Table 2.1â•…Clinical classification of chest pain Typical Angina (Definite)

Atypical Angina (Probable)

Noncardiac Chest Pain

1.â•‡Substernal chest discomfort with a characteristic quality and duration that is: 2.â•‡provoked by exertion or emotional stress

Meets 2 of the given Meets 1 or none of characteristics the typical anginal characteristics

3.â•‡relieved by rest or NTG. NTG, nitroglycerin. Reproduced with permission from Ref. 3; modified from Ref. 4.

C H A P TER 2

•

Atypical Chest Pain and Other Presentations

categories of CP along with the patients’ age and gender are widely employed as the predictors of pretest likelihood of obstructive CAD, estimated using either an original Diamond–Forrester [4,6], CASS [7], or modified ACC/ AHA classification [3], the latter of which is a simplification of the Diamond publications. In more sophisticated analysis of likelihood of CAD, the number and type of risk factors should also be taken into account [8]. Atypical angina in the 40 to 70 years age group is associated with an intermediate pretest likelihood of CAD (22%–72%, depending on age and gender). The intermediate likelihood of CAD has been defined in various ranges, extending from 10% to 90% [3], 15% to 85% [9], 20% to 80%, and 30% to 70%; cardiac imaging in these patients provides the most significant diagnostic yield and helps in clinical decision-making process (Figure 2.1). In patients with a low likelihood of CAD, even when symptomatic, the likelihood of disease is so low that further testing is not considered warranted. In patients with a high likelihood of CAD, the diagnosis of CAD is usually considered established. Additional testing, if needed, is performed for riskstratification purposes and for guiding patient management, rather than for diagnostic purposes.

23

There are several clinical categories of patients who are falling into the category of intermediate likelihood of CAD. In general, these include not only most patients with atypical angina, but also younger patients, particularly women, with typical angina, and older patients, particularly men, with nonanginal chest pain. This chapter discusses the use of stress imaging for ischemia and cardiac CT examinations in patients with atypical angina and other presentations in which there is an intermediate pretest likelihood of obstructive CAD. Within our discussion of imaging for ischemia, we have chosen to limit it to nuclear cardiology methods. For application in patients with an intermediate likelihood of CAD, however, other stress imaging modalities including echocardiography and cardiac magnetic resonance have clearly been shown to have widespread application. When a stress imaging modality is being selected, factors such as availability of equipment, technical expertise, and clinical expertise found at an individual testing site are considered more important than differences in the capabilities of the modalities in selecting a test for a given patient. Clinical application of the advanced imaging modalities can significantly increase an effectiveness of the clinical

F i g u r e 2 . 1â•…Clinical case of the patient with low-intermediate pretest likelihood of coronary artery disease (CAD): a 50-year-old female without history of prior CAD, presenting to ED with atypical chest pain and exertional shortness of breath. Her prior medical history is remarkable for hypertension and smoking. Her resting ECG demonstrated sinus rhythm, isolated premature ventricular beats and diffuse nonspecific T-wave abnormalities. She was referred for the dual isotope rest-stress myocardial perfusion imaging. Rest perfusion was normal (bottom rows). The patient performed treadmill exercise for a total of 4:23 minutes and achieved 130 beats per minute (76% of the maximal predicted heart rate). The exercise was discontinued due to a worsened shortness of breath and chest pain. There were borderline ischemic ECG changes noted. Poststress perfusion images (top rows) demonstrate large area of the reversible perfusion defect involving distal and midanterior and antero-lateral segments seen to be reversible on rest images (bottom rows). The patient was referred for invasive coronary angiography which demonstrated presence of 90% stenosis of the large first diagonal branch, moderate disease of the left circumflex artery and 50% to 75% proximal and mid right coronary artery. The patient underwent successful percutaneous coronary intervention and stent implantation to first diagonal branch, with subsequent symptomatic improvement. SAX, short axis; VLA, vertical long axis; HLA, horizontal long axis.

24

decision-making process in patients with atypical presenting symptoms and others with an intermediate pretest likelihood of CAD, by several mechanisms: (1) identifying patients at increased risk who should undergo invasive evaluation of their coronary arteries and possible revascularization, (2) revealing those who are at low risk of cardiac events and/or have a low posttest likelihood of obstructive CAD, and thus, potentially eliminating need for further testing, and reassuring worried patients and families in their favorable prognosis, (3) switching attention of the clinicians from cardiac diagnostic path to identifying a need in evaluating other systems in order to find a clear noncardiac reason for CP, at times utilizing pathological findings discovered on the cardiac scan images (tumors, pericardial, and pleural disorders, pulmonary embolism, aortic pathology, hiatal hernia, etc.), (4) identifying potential targets for revascularization in patients who are candidates for invasive coronary angiography (ICA), and (5) providing follow-up in patients who develop atypical symptoms post-revascularization. The chapter first reviews the applications of nuclear cardiology studies in these patients, followed by the review of applications of cardiac computed tomography (CT), and finishes with a discussion of an integrated approach to these assessments, with the choice in test depending on the initial pretest likelihood of CAD.


prone and supine imaging are also considered to be associated with improvement in reader confidence. With respect to vasodilator positron emission tomoÂ� graphy (PET) MPI, a meta-analysis of 19 recent studies has recently been published reporting 92% sensitivity and 85% specificity [16] for detecting CAD. Bateman et al have compared the diagnostic accuracy of PET versus SPECT in 2 large cohorts undergoing blinded interpretation [17]. Both sensitivity and specificity are higher with PET, and overall accuracy is higher in men and women as well as in obese and nonobese patients (Figure 2.2). The accuracy of PET has been reported to also be higher for identifying patients with multivessel and left main disease (48% vs. 71%, P 5 .03) (Figure 2.3). The most likely reasons for higher sensitivity and specificity of PET versus SPECT are the routine use of robust attenuation correction and the greater linearity of myocardial uptake versus flow of the PET perfusion agents than of the currently available Tc-99m agents. Also, vasodilator PET using Rb-82, imaging is performed during as opposed to after pharmacologic stress, providing the opportunity to evaluate peak-stress ventricular function. Another attribute of PET MPI that has not yet been fully explored is the ability of this modality to assess absolute myocardial perfusion and rest/stress flow reserve. Referral or Verification Bias

A major limitation in assessing the diagnostic accuracy of SPECT or PET MPI for CAD is current clinical reality jâ•…D I AGNOS T IC A CC URACY OF SPECT that the test result influences the decision to perform ICA, AN D PET M PI: GENERAL ASP ECTS an invasive gold standard, thereby biasing the population The accuracy of diagnostic testing for CAD is defined available for analysis of sensitivity and specificity. Using a clinically on the basis of sensitivity and specificity for multivariable analysis, Hachamovitch et al have recently identification of angiographically significant stenoses, most demonstrated that the extent of ischemia by SPECT MPI commonly employing either a 50% or a 70% diameter-Â� provided 83% of the information appearing to determine narrowing cutoff. ACC/AHA/ASNC guidelines on car- referral for catheterization [18]. Thus, in estimating the diac radionuclide imaging report a pooled sensitivity and true sensitivity and specificity of noninvasive testing, this specificity of 87% and 73% for exercise single photon referral or workup bias must be taken into account [19]. emission computed tomography (SPECT) myocardial As routine patient workup results in preferential Â�catheterization perfusion imaging (MPI) (based on 33 published studies) of patients with abnormal (ischemic) test results, this referand 89% and 75% for vasodilator SPECT MPI (based ral bias leads to an overestimation of test Â�sensitivity and a on 17 published studies) for detection of CAD [10]. An reduction in test specificity with the latter showing the most improved predictive accuracy by nuclear testing over Â�dramatic change. pretest information and ECG stress testing has been consistently documented [11]. In women, the specificity of Normalcy Rate SPECT MPI is increased with gated 99mTc-based agents compared to ungated 201Tl SPECT MPI, attributed to The normalcy rate has been advocated as a means of assessless susceptibility to breast attenuation of gated SPECT ing test specificity without requiring the angiographic stanMPI with 99mTc-based agents [12]. The ability to immedi- dard [20]. Normalcy rate has been defined as the percentage ately reacquire SPECT images with 99mTc-based agents of patients with normal test results in a population with a low when either attenuation or motion artifact is suspected likelihood of disease, usually employing a ,5% criterion. The further increases specificity with these agents [13,14]. recent ACC/AHA/ASNC guidelines report a normalcy rate Improvements in specificity have also been reported with for SPECT MPI of 91%. Even in obese patients, normalcy the use of attenuation correction algorithms [15]. The rates .90% have been reported when attenuation correction use of ECG gating attenuation correction, and combined or combined supine/prone imaging is employed [13].

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2 . 2 â•…Clinical case of the 69-year-old female patient, presenting with atypical chest pain and no prior coronary artery disease. Initially, the patient underwent stress-rest Tc-99 sestamibi single photon emission computed tomography myocardial perfusion imaging which was equivocal with possible soft tissue attenuation (upper plate). Subsequent stress-rest Rb-82 positron emission tomography (lower plate) was perfectly normal. Figure

F i g u r e 2 . 3 â•…Diagnostic performance of cardiac positron emission tomography (PET) compared to single photon emission computed tomography (SPECT) myocardial perfusion imaging by gender, body mass index (BMI) and in multivessel disease (MVD). Reproduced with permission from the Ref. 17.

Diagnostic Impact of MPI In the lower range of intermediate CAD likelihood (eg, 0.15–0.50), many advocate the use of exercise tolerance testing (ETT) alone, without imaging [3]. Although patients with pre-ETT likelihood of CAD in the 0.50 to 0.85 range could also be considered candidates for ETT alone, [10,21]

many experts consider SPECT or PET MPI to be the appropriate first test since a negative ETT would not result in a low CAD likelihood. Patients with an indeterminate CAD likelihood after ETT (eg, intermediate-risk Duke treadmill score [10,22], are candidates for MPI. Patients with ECG uninterpretable for ETT [eg, left ventricular hypertrophy

26

(LVH), digoxin, Wolff-Parkinson-White (WPW), .1 mm resting ST depression, LBBB, permanent pacemaker, etc.] are candidates for MPI rather than ETT. As noted below, the development of CT coronary angiography may alter this approach, possibly becoming the first diagnostic test toward the lower part of the pretest likelihood spectrum.


considered likely that the relationships between PET MPI subsequent patient outcomes will be at least as strong as those observed with SPECT MPI. In the discussion that follows, the principles applied to SPECT MPI are considered equally applicable to PET MPI.

Incremental Prognostic Value jâ•…RISK ASS ESSMENT Principles of Risk Stratification A widely used paradigm in patient management is that of a risk-based approach to patients with suspected CAD in whom symptoms are nonlimiting. In patients referred directly to catheterization for any reason, pericatheterization SPECT or PET MPI may serve to identify the culprit lesion. However, in less symptomatic patients, precatheterization risk assessment is more important. With a riskbased approach, the focus is not on predicting the presence of CAD but on identifying patients at risk for specific, potentially preventable adverse events. Subsequent management focuses on reducing the risk of these outcomes, whether cardiac death, nonfatal MI or CAD progression. Invasive diagnostic and therapeutic procedures are limited to those patients who are most likely to benefit from them. The basic concept underlying the use of nuclear testing for risk stratification is that patients known to be at high or low risk for events would not need risk stratification with nuclear imaging since they are already stratified. However in those patients with uncertain clinical presentation and in intermediate likelihood if CAD and/or uncertain prognostic risk, MPI is able to provide a robust data, allowing individual assessment and management of each patient with challenging symptoms.

Risk Thresholds For the purposes of risk assessment, it has been proposed that low risk be defined as a ,1% annual cardiac mortality rate and intermediate risk could be defined by the range of 1% to 3% per year [21]). Since the mortality risk for patients undergoing revascularization is at least 1%, symptomatic patients with a less than 1% annual mortality rate would not appear to be candidates for revascularization to improve survival. It has been suggested that a .3% annual mortality rate is a threshold to identify patients with symptoms whose mortality rate can be improved by coronary artery bypass surgery (CABS) [23]. Based on combined published literature, SPECT or PET MPI is most appropriate in patients with .l% annual mortality and intermediate or high likelihood of CAD. There is far less written about the prognostic implications of PET MPI than for SPECT MPI. However, given the overall higher accuracy of PET MPI for detecting obstructive CAD, it is

The clinical value of MPI for prognostic assessment of CAD results from the incremental or added prognostic information yielded by this modality over all data available prior to the test (clinical, historical, and stress data), as first demonstrated by Ladenheim et al [24].

Event Risk After a Normal Scan A synthesis of available data reveals that a normal scan is generally associated with a ,1% annual risk of cardiac death or MI. A meta-analysis of the prognostic value of a normal stress perfusion scan (N 5 29 788) reveals that the annual risk of MI or cardiac death after a normal perfusion scan is 0.5% (95% CI 0.3%–0.7%). [25] This low event rate is critical in applying nuclear test information to risk stratification, since in the absence of symptoms, patients with normal perfusion scans can be managed conservatively. This approach includes follow-up for signs of clinical worsening and treatment of cardiac risk factors and related symptoms. Despite the low risk associated with normal SPECT studies, a limited number of studies have reported somewhat higher levels of risk. Recently, a study examining predictors of risk and its temporal characteristics in a series of 7376 patients with normal stress SPECT MPI identified the use of pharmacologic stress and the presence of known CAD (Figure 2.4A), diabetes mellitus (in particular, female diabetics), and advanced age as markers of increased risk and shortened time to a hard event (eg, risk in the first year of follow-up was less than in the second year) [26]. Hence, a dynamic temporal component of risk was present and the existence of a warranty period for specific patient groups was defined (Figure 2.4B). This increased risk after normal SPECT in a small subset of patients is due to the presence of comorbidities that increase baseline risk of all patients (diabetes mellitus, age, inability to exercise, prior CAD, dyspnea) as the presenting symptom [5] and, in some patients, the possibility that extensive CAD was missed due to balanced reduction of flow. The latter would lead to a severe underestimation of the extent of ischemia by SPECT MPI. Although many of these patients can be detected by ancillary markers—such as LV transient ischemic dilation [27], a rest to post stress fall in LVEF, or increased lung tracer uptake—in some patients with high-risk anatomic lesions, SPECT MPI will appear completely normal. In a recent study reported from our center, 13% of patients with left main coronary artery disease of sufficient severity to warrant referral for revascularization had minimal findings (equivocal) on SPECT MPI (Figure 2.5) [28].

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F i g u r e 2 . 4 â•… Annual rates of hard events in patients after normal single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The following subgroups are shown: women versus men, patients with and/without history (Hx) of coronary artery disease (CAD) and patients undergoing adenosine versus exercise stress. A significant risk is noted in the patients with Hx CAD, *P , .001. (A) Rates of hard events in first and second years of follow-up after normal SPECT MPI. Four examples are given: a 50-year-old male undergoing exercise stress with no history of CAD, an 80-year-old male undergoing adenosine stress with no history of CAD, a 50-year-old male with a history of CAD, and an 80-year-old male with a history of CAD. In patients with no history of CAD, the event rates in the first and second years after SPECT MPI are not different; however, the event rate for normal SPECT MPI goes up significantly with increased patient risk. In patients with previous CAD, the event rates in the second year after SPECT MPI were greater than in the first year, and there is additional increase in the event rate with clinical risk (B). Reproduced with permission from Ref. 26.

Event Risk with Abnormal Scans The relationship of varying extent and severity of perfusion abnormalities with cardiac outcomes has been reported in a variety of patient subsets [3,21,29,30] consistently; increasing scan abnormality is associated with an increasing risk of cardiac events. Although both reversible and fixed stress perfusion defects are predictors of prognosis, those at highest risk of cardiac events are patients with extensive stress abnormalities. Prognosis is also dependent on both the severity and extent of perfusion defects, correlates of the stenosis magnitude, and the amount of myocardium subtended by the stenosed vessels [31]. As these parameters worsen, risk of major cardiac outcomes increase (Figure 2.6). Annual cardiac event rates have been reported to range from 0.3% to 4.2% for patients with normal, mild, moderate, and severely abnormal perfusion scans, with significant variability associated with each level of defect extent and severity. Similar findings have been described with 201Tl and with 99mTc tetrofosmin [25,32].

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F i g u r e 2 . 5 â•…Detection rates of LM CAD in all patients with high risk of abnormality by perfusion and nonperfusion data on gated myocardial perfusion single photon emission computed tomography. *, P , .05 versus greater than 10% myocardium at stress. †, P , .001. Abnl WM, abnormal wall motion; EF, ejection fraction; LM CAD, left main coronary artery disease; Myo, % myocardium hypoperfused at stress; TID, transient ischemic dilation. Reproduced with permission from the Ref. 28.

F i g u r e 2 . 6 â•…The prognostic value of the stress perfusion defect (% myocardium abnormal at stress) (horizontal axis) is plotted versus the cardiac death rate (vertical axis) for 17 and 20 segment scoring systems. The cardiac mortality rate rises steadily with either approach, and there are no significant differences between the 17 and 20 segment systems when analyzed in this normalized manner. Based on data from Ref. 30. Reproduced with permission from Ref. 83.

Mildly Abnormal SPECT MPI Previously, we had described patients with mildly abnormal scans to be at intermediate risk for MI but at low risk for subsequent mortality [33]. Although the overall observation holds true for groups of patients, risk assessment in an individual patient is improved by taking into account findings other than those of the scan. The presence of high-risk clinical or historical markers identifies a subset of patients at greater risk for any level of scan abnormality, that is, prescan data yield incremental prognostic information


Risk-adjusted Cardiac Mortality (%)

28

20

Exercise

jâ•… Table 2.2â•… Summary MPI variable: Perfusion Scale

16

Adenosine

Categorya

SSS

12

Age 60-80

None

0–1

,2

Equivocal

2–3

2–4

Mild

4–6

5–9

Moderate

7–13

10–19

Severeb

14

20

Age 80 DM W

8

DM M 4

nonDM W nonDM M

0

5-10%

>20% 10-20% % myocardium Ischemic

F i g u r e 2 . 7 â•…Rates of risk-adjusted cardiac mortality as a function of

% myocardium ischemic (5%–10%, 10%–20% and .20%) in medically treated patients [exercise vs. adenosine stress, patients aged ,60 years, 60 to 80 years and .80 years, diabetic (DM) men (M) versus women (W) and nondiabetic men and women]. Although predicted cardiac mortality increases with increasing % myocardium ischemic, the rates at any level of ischemia varies widely at any level of ischemia as a function of clinical information. Based on data from Ref. 18. Reproduced with permission from Ref. 82.

% Defect

Nonperfusion High-Risk Markers, transient ischemia dilation (TID) increased lung uptake, increased right ventricular (RV) uptake, ejection fraction (EF) ,45%, 5% fall in EF, stress-induced wall motion abnormality, severe defect (score 3 or 4) [28,83,87]. Increase category by 1 level if any nonperfusion high-risk markers. EF  35%, high risk irrespective of perfusion category.

a

b

over SPECT MPI results (Figure 2.7) [18,33–35]. Hence, although patients with mildly abnormal SPECT MPI results generally are at low risk of cardiac death, the risk is higher in a variety of subgroups with significant comorbidities and presentations (eg, advanced age, diabetes mellitus, atrial fibrillation, pharmacologic stress, reduced left ventricular function, dyspnea) [5,36]. In addition to these conditions, increased risk in patients with mildly abnormal scans is likely if there are ancillary high risk makers. Table 2.2 shows categories for the magnitude of myocardial perfusion abnormality on SPECT MPI including consideration of these high risk markers.

Moderate to Severely Abnormal SPECT MPI This category of scan abnormality is associated with the highest levels of risk. Anticipated patient risk is greatest in patients with high risk cardiovascular comorbidities, increased left ventricular size/reduced LV function, extensive scar, and so on. As discussed below, patients in this SPECT MPI category with extensive ischemia are most likely to benefit from revascularization as opposed to conservative management. Using MPI for Medical Decision Making: Assessing Risk Versus Potential Survival Benefit Beyond risk-stratification, optimal selection of patient treatment is based on reasonable estimates of potential patient benefit with one treatment option versus an alternative. To this end, a major step forward is the recently evolved paradigm indicating that rather than identify patient risk, the role of MPI in a testing strategy is the identification of patients who may accrue a survival benefit from revascularization as opposed to those who lack a survival benefit from this procedure and, conversely,

F i g u r e 2 . 8 â•…Relationship between % myocardium ischemic and log of the hazard ratio in 10 647 patients without known CAD treated either with medical therapy (Rx) (dashed line) or early revascularization (,60 days post single photon emission computed tomography myocardial perfusion imaging; solid line) based on multivariable modeling. In the setting of little or no ischemia, medical therapy is associated with superior survival; with increasing amounts of ischemia a progressive survival benefit with revascularization (Reverse) over medical therapy is present. 95% confidence intervals are shown by the closely dotted lines. Reproduced with permission from Ref. 18.

which patients will have a superior survival with medical therapy alone. In a study examining 10 627 patients without prior MI or revascularization who underwent stress SPECT MPI, a survival benefit was present for patients undergoing medical therapy versus revascularization in the setting of no or mild ischemia, whereas patients undergoing revascularization had an increasing survival benefit over patients undergoing medical therapy when moderate to severe ischemia was present (.10% of the total myocardium ischemic) (Figure 2.8) [18]. This survival benefit was particularly striking in higher-risk patients


1 0

30% 20%

–2

10%

change in risk with revasc

0% 0

20%

40%

60%

80%

100%

Gated SPECT EF Figure 2.9â•… Relationship between gated single photon emission computed

tomography ejection fraction (EF) and log of the hazard ratio in 5366 patients based on multivariable modeling. Solid lines represent predicted survival for 0%, 10%, 20% and 30% myocardium ischemic in patients treated medically. Dashed lines represent predicted survival for patients treated with revascularization for all values of % myocardium ischemic. Overall, risk increased with decreasing EF. For any value of EF, however, risk also increased as % myocardium ischemic increased, indicating an incremental value for % myocardium ischemic over EF. Compared to risk in patients treated medically, risk in patients undergoing early revascularization was independent of the % myocardium ischemic present (as evidenced by a single (dashed) line representing survival after revascularization for all degrees of ischemia). Risk in the early revascularization patients was similar to the risk of medically treated patients with 10% myocardium ischemic, throughout the range of EF. Reproduced with permission from Ref. 38.

frequently presenting with atypical symptoms (elderly, requiring adenosine stress, and women, especially diabetics). These results have been extended to incorporate gated SPECT MPI EF information [38]. Comparing the roles in risk assessment of perfusion and function data, although EF, percent myocardium ischemic and the percent myocardium fixed are all predictors of cardiac death, the former is by far the best predictor of cardiac mortality. On the other hand, only inducible ischemia identified patients who would benefit from revascularization in comparison to medical therapy (Figure 2.9). With increasing amounts of ischemia, increasing survival benefit for revascularization over medical therapy was found, irrespective of EF. On the other hand, as shown by previous randomized control trials, the absolute benefit to be gained from a therapeutic strategy, for any level of ischemia present, is proportional to underlying patient risk. Thus, in assessing treatment options in an individual patient, cardiac risk factors, comorbidities, and EF all have to be considered along with ischemia in order to determine the potential advantages of a specific therapeutic strategy. Use of SPECT MPI in Guiding Decisions for Catheterization and Revascularization Several investigators have shown that SPECT MPI results appear to heavily influence post-SPECT MPI clinical decision making. Among patients with normal scans, only a small proportion undergo early post-SPECT MPI cardiac

1.0 0.8

Atyp

0.6

Asx

0.4

2

Medical Rx: % ischemic

A

–1

log Relative Hazard

3

C

TAP

0.2

Revasc

0.0

4

B

29

Probability of Referral to Early Revasc

•

C H A P TER 2

0

12.5%

25%

37.5%

50%

% Total Myocardium Ischemic F i g u r e 2 . 1 0 â•…Relationship between % myocardium ischemic and

probability of referral to early revascularization (,60 days post single photon emission computed tomography myocardial perfusion imaging. Results based on multivariable modeling in 10 647 patients. In this study, % myocardium ischemic was most strongly associated with referral to revascularization (83% of all information used for decision making). Further, patients’ presenting symptoms also influenced this process as evidenced by greater likelihood of referral at any level of ischemia with typical (TAP) versus atypical (Atyp) versus asymptomatic (Asx) patients. Reproduced with permission from Ref. 18.

catheterization, usually as a result of clinical symptomatology [39]. As first shown by Hachamovitch and colleagues, the extent and severity of reversible defects shown by the SPECT MPI result is the dominant factor driving subsequent resource utilization, regardless of the presenting symptoms [18] (Figure 2.10). Regarding the cost-Â�effectiveness of this approach, Shaw et al [40] in a multicenter study of 11 249 patients, showed that a strategy of SPECT MPI with selective subsequent catheterization produced a substantial reduction (31%–50%) in costs for all levels of pretest clinical risks compared to a direct catheterization approach (Figure 2.11), with essentially identical outcomes as assessed by cardiac death and myocardial infarction rates. Importantly, in the SPECT MPI strategy, rates of revascularization, cardiac catheterization after normal SPECT MPI, and the frequency of normal coronary angiographic findings were significantly reduced [33,41]. A recent landmark study, the Clinical Outcomes UtilizÂ� ing Revascularization and Aggressive Drug Evaluation (COURAGE) trial [42] was designed to assess a superiority of PCI coupled with optimal medical therapy in reducing the risk of death and nonfatal myocardial infarction in patients with stable CAD, as compared with optimal medical therapy alone. The population in the study was highly selected: out of 35 539 screened patients, only 2287 were enrolled in the study. The patients were randomized to undergo PCI with optimal medical therapy (PCI group, n 5 1149 patients) and 1138 to receive optimal medical therapy alone (OMT group, n 5 1138 patients). Patients were followed for an average of 4.5 years. OMT patients were allowed to cross over to revascularization

30

F i g u r e 2 . 1 1 â•…Comparative cost between screening strategies employing direct catheterization (Cath) and myocardial perfusion imaging (MPI) with selective Cath. Low, Int, and High represent low-risk, intermediaterisk, and high-risk subsets of the patients with stable angina. Shown are the initial diagnostic costs (solid bars) and follow-up costs including costs of revascularization (gray bars). A 30% to 41% reduction in costs was noted in each category. Hard event rates were similar with the 2 strategies, but the revascularization rate was twice as high in the direct cath group. Reproduced with permission from Ref. 41.

if they had progressive or refractory symptoms. The main results of the trial, published in the New England Journal of Medicine in 2007, have shown that as an initial management strategy in patients with stable CAD, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to OMT. The authors concluded that “as an initial management approach, OMT without routine PCI can


be implemented safely in the majority of patients with stable CAD. However, approximately one-third of these patients may subsequently require revascularization for symptom control or for subsequent development of an ACD.” Since the COURAGE Trial showed no survival advantage with the addition of PCI, the question must be raised as to whether stress imaging has a role in guiding selection of patients for revascularization. If patients do not benefit from revascularization, and catheterization is not needed, stress imaging would also not be needed to identify the potential catheterization candidate. However, as a part of the COURAGE study, an important substudy [43] addressed how SPECT MPI testing may shape clinical outcomes. In this substudy of 314 patients in whom both prerandomization and 6 to 18 month postrandomization SPECT MPI was performed, patients assigned to PCI and OMT demonstrated significantly greater ischemia reduction when compared to patients receiving OMT alone [PCI 1 OMT: 33% (n 5 159); OMT alone: 19% (n 5 155); P 5 .0004]. Importantly, among the relatively smaller subset of patients with moderate-to-severe pretreatment ischemia, a significantly greater proportion showed significant ischemia reduction (5% reduction in ischemic myocardium) with a strategy of PCI 1 OMT as opposed to OMT (78% vs. 52%; P 5 0.007). Hence, despite the lack of improved survival with PCI 1 OMT versus OMT alone in the main COURAGE study [41], the former may be a superior approach to reduce ischemic burden, particularly in patients with extensive ischemia. Thus, the substudy provides supportive evidence that imaging of myocardial ischemia could affect patient outcomes through guiding decisions for revascularization. Of note, the posttherapy residual ischemia was strongly predictive of outcomes in both the PCI and the OMT alone groups (Figure 2.12). Hopefully, this hypothesis

F i g u r e 2 . 1 2 â•… Results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation Nuclear Substudy [43]: Kaplan–Meier survival

for patients by residual ischemia including 0%, 1% to 4.9%, 5% to 9.9%, and 10% ischemic myocardium, respectively, after 6 to 18 months of percutaneous coronary intervention 1 OMT or OMT. Overall event-free survival was 100%, 84.4%, 77.7%, and 60.7%, respectively, for 0%, 1% to 4.9%, 5% to 9.9%, and 10% ischemic myocardium (P , .001). A. In a risk-adjusted Cox model (controlling for randomized treatment), this difference was not significant (P 5 .09). B, Unadjusted (dark gray bars) and risk-adjusted (light gray bars) hazard ratios for the extent and severity of residual ischemia at 6 to 18 months of follow-up. Reproduced with permission from Ref. 43.

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generating research will lead to a randomized clinical trial testing whether patients with moderate-to-severe ischemia benefit from a revascularization approach.

jâ•…M PI I N EVAL U ATI ON OF AC UT E CHEST PA I N Because of the relationship to closure of a coronary artery, SPECT MPI is an effective means of detecting patients with acute ischemic syndromes. Although the diagnosis of acute MI is frequently straightforward, in many patients it is not. For patients with normal or nondiagnostic initial ECGs on presentation to the ED, an important clinical problem is to distinguish those with ACS requiring hospital admission from those who may be safely discharged. Because most patients presenting with acute chest pain subsequently rule out for acute ischemic syndromes, chest pain units have been instituted for the acute evaluation of chest pain patients presenting to the ED.99mTc-sestamibi or tetrofosmin SPECT MPI, with injection during chest pain, provides an excellent opportunity to reduce clinical indecision in the acute evaluation of chest pain (Figure 2.13). A number of studies have demonstrated a role for SPECT

31

MPI in the initial evaluation of these patients. A normal rest 99mTc-sestamibi or tetrafosmin SPECT MPI study has a 99% negative predictive value. A prospective, randomized, controlled multicenter trial examined whether incorporating acute rest SPECT MPI into an ED evaluation strategy of patients presenting with suspected acute ischemia improved initial ED triage [44]. A significant reduction in hospitalization was noted in patients with normal SPECT MPI studies. Guidelines for MPI in the ED Several considerations are important for effective application of SPECT or PET MPI in the ED. In patients with prior MI, the studies are generally not useful, unless the results of previous MPI are immediately available for comparison. Also, combined assessment of perfusion and function should be routinely performed in order to minimize the false-negative rate. Combined supine and prone imaging or attenuation correction is very useful in reducing the false-positive rate. An abnormal rest MPI study triggers admission and therapy for an acute ischemic syndrome. Patients with normal rest studies, after negative enzymes are obtained, frequently undergo stress MPI to evaluate underlying CAD. If no stress or rest abnormality of perfusion or function is observed, patients are typically

F i g u r e 2 . 1 3 â•… Resting sestamibi (MIBI)

injected during chest pain in emergency department (top) and 3 days post-PCI of the left circumflex coronary artery (LCX) (bottom) in a patient with no electrocardiogram or enzyme abnormalities. Clear evidence of extensive myocardial salvage in LCX territory is shown. Reproduced with permission from Ref. 83.

2 . 1 4 â•…Normal rest 201Tl single photon emission computed tomography (bottom) followed by adenosine 99m Tc-sestamibi (ADEN MIBI) (top) in a patient with intermittent chest pain, which had resolved prior to rest 201Tl injection. Reversible defects are seen in the left anterior descending and left circumflex territories. Angiography revealed 50% left main, 100% left anterior descending, 90% left circumflex, and 50% right coronary artery stenoses. Reproduced with permission from Ref. 82. Figure

32

discharged from the ED. Those with evidence of ischemia (Figure 2.14) or infarct are admitted.

jâ•…USE OF SPECT MP I IN SPECI FIC PAT IE NT POP U LAT I ONS WITH F REQUE NTLY ATYPI CAL CL I NICAL P RESENTAT ION S UGGEST IVE OF CAD A principal strength of nuclear cardiology is that large databases have been accumulated resulting in evidence documenting the effectiveness of SPECT MPI for risk stratification of appropriately selected patients with intermediate likelihood of CAD and/or unclear pretest clinical symptomatology. This evidence has resulted in several Class I indications for the use of stress SPECT MPI [10]. Due to the far fewer publications with PET, the guidelines, in general, have been confined to recommendations regarding SPECT; however, as noted above, they can be considered to also apply to PET MPI. Several specific lines of evidence are described below. 1. Evidence supporting nuclear imaging for patients with an intermediate risk or indeterminate treadmill test: Several reports support nuclear testing in patients with uninterpretable or intermediate exercise ECG response [10]. An initial report from Cedars-Sinai demonstrated that SPECT MPI was most effective in risk stratification and governing management of patients with Â�intermediate Duke treadmill score (DTS) [45]. Patients with a low DTS (hard-event rate ,1%) or high DTS (hard-event rate 7.7%) did not show further risk stratification with SPECT MPI. However, patients with an intermediate DTS, comprising the majority of patients studied, had an intermediate risk of hard events; patients with a normal SPECT MPI scan had very low event rates and were infrequently catheterized, those with moderately abnormal scans had intermediate rates of events and catheterization, and those with moderately to severely abnormal scans had higher rates of events and catheterization. Similar results were seen in subsequent multicenter studies reporting event rates and catheterization rates [10]. 2. Gender-based differences in the prognostic value of SPECT MPI: Female patients are often present with either atypical symptoms and usually stratified into lower risk categories despite presence of the significant CAD. Recent guidelines for cardiac imaging in women, taking into consideration these difficulties in the management of women with suspected CAD have been published by the AHA [46]. In women, due to breast tissue artifact, falsepositive SPECT MPI examinations are most notable in the anterior and anterolateral segments of the heart and are more common with Tl-201 than with the Tc-99m agents [47,48]. Improved accuracy has been reported with use of the Tc-99m agents as well with combined acquisition of gated EF and wall motion imaging, prone


imaging, and with the use of validated attenuation correction algorithms [48–51], with the resultant sensitivity and specificity being similar in women and men. â•…Regarding prognosis, pooled data including more than 7500 women noted annual rates of cardiac death or nonfatal MI of 0.4% for women with low risk or normal SPECT MPI [52]. High risk findings elevated a woman’s risk by nearly 10-fold with annual rates of major cardiac events of 6.3% for all women and 10.9% for diabetic subsets of women [52]. Separate criteria for abnormality have been recommended for ventricular function in women and men, resulting in similar prognostic content of combined perfusion and function information from gated SPECT in men and women [53]. â•…â•… Endothelial dysfunction and microvascular disease have been proposed as mechanisms for false-positive stress testing results in women, suggesting that some of these studies may represent true perfusion abnormalities without large vessel CAD. Recent evidence suggests that these SPECT MPI perfusion findings may be associated with increased near-term risk of major cardiac events [54], suggesting that prognostically important coronary disease states not involving obstructive CAD occur more frequently in women than in men, and that SPECT MPI could provide a tool for detection of this process. Due to the routine use of attenuation correction with PET, its application in women may be associated with reduced false positives due to breast attenuation. Combined prone and supine imaging with SPECT or attenuation correction with SPECT have also been shown to reduce the false-positive rate of SPECT MPI in women [14]. 3. Evidence supporting nuclear imaging for elderly patients: Another clinical subset population of patients with atypical symptomatology is that of elderly patients. With recent increased longevity of the population and the increasing prevalence of CAD as a function of age, large numbers of elderly patients are requiring diagnostic and/or prognostic assessment for CAD. The DTS, useful in many patient subsets, has been reported to be less effective in risk stratification of elderly patients [55]. The Mayo Clinic group reported that exercise SPECT MPI provides effective risk stratification in elderly men and elderly women. A cohort of 247 patients 75 years of age, patients undergoing Tl-201 SPECT MPI, was Â�followed for a median of 6.4 years for cardiac death. The summed stress score from SPECT MPI was significantly associated with cardiac death, but the DTS was not. The summed stress score from SPECT MPI classified 49% of patients as low risk and 35% of patients as high risk, with annual cardiac mortality rates of 0.8% and 5.8% respectively. Long proponents of the ETT alone as the initial test, the Mayo group concluded that if their results can be confirmed in future studies, exercise SPECT rather than ETT may emerge as the initial

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exercise testing modality in both women and men aged 75 years, even those who are able to exercise [55]. â•…Pharmacologic stress testing is increasingly being applied in the elderly who frequently are unable to exercise adequately and the elderly comprise a high proportion of patients undergoing pharmacologic stress imaging. For elderly patients as well as for those with functional limitations, similar risk assessment is possible with exercise and pharmacologic stress SPECT [29]. Consistent with data on other functionally impaired patients, the prognostic value of SPECT MPI is associated with higher cardiac event rates for normal to severely abnormal test results. These results were extended to dobutamine stress [56]. Recent evidence has shown a survival benefit with revascularization in elderly patients with extensive ischemia [56A]. 4. Evidence supporting MPI for African-American and other Ethnic Minority Patients: The rate of cardiac death or MI in African Americans with a normal SPECT MPI is approximately 2% per year, [10] likely a result of higher risk burden [54]. In a recent series, 2-year CV death or MI were compared in 1993 African American and 464 Hispanic patients as compared with 5258 Caucasian, non-Hispanics undergoing stress Tc-99m tetrofosmin SPECT MPI [32]. Moderateseverely abnormal SPECT MPI occurred more often in ethnic minority patients. The prognostic results noted a 1.4- to 1.6-fold and 2.3- to 5.6-fold higher risk of hard events in African American and Hispanic patients, respectively, with mild and moderate-severely abnormal SPECT MPI findings, (P , .0001 vs. Caucasians), apparently due to higher degree of comorbidity.

33

jâ•…ROLE OF CO RONA RY CT ANGI O GRAPHY I N EVAL UAT ION OF PATIE NTS W ITH ATYP ICAL CH EST PA IN CT Coronary Calcium Scanning Chronologically, noncontrast ECG-gated cardiac CT evolved before coronary CT angiography (CCTA) as the initial clinically relevant application of cardiac CT; it has enabled the accurate measurement of coronary artery calcification, opening up the opportunity for improved assessment of patients with subclinical coronary atherosclerosis. Coronary artery calcium (CAC) is thought to develop in the body’s attempt to contain and stabilize inflamed coronary plaque [57]. Coronary artery calcification is considered pathognomonic of coronary atherosclerosis. In general, evidence of CAC reflects a more advanced stage of plaque development. A quantitative relationship has been demonstrated between CAC and histopathologic evidence of coronary plaque area. Moreover, calcified plaque assessment correlates with pathologic assessment of the total amount of calcified plus noncalcified plaque [58]. As such, CAC serves as an indirect but proportional marker for global atherosclerotic burden. A large number of studies in tens of thousands of asymptomatic patients have consistently documented strong prognostic value of CAC scores. Estimators of risk with consideration of the CAC distribution by age, gender, and other clinical variables have been developed in order to further fine-tune the prediction of cardiac risk [59–61]. In this regard, a recent study reported distribution of the follow-up cardiac events by coronary calcium score (CCS) in 4 ethnic groups in the population of 6722 patients from

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F i g u r e 2 . 1 5 â•… Unadjusted Kaplan–Meier cumulative-event curves for coronary events among participants with coronary artery calcium scores of 0, 1 to 100, 101 to 300, and .300. Panel A shows the rates for major coronary events (myocardial infarction and death from coronary heart disease), and panel B shows the rates for any coronary event. The differences among all curves are statistically significant (P , .001). Reproduced with permission from Ref. 62.

3 4Multimodality Imaging in Cardiovascular Medicine

33 35

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>400 P = 0.87 F i g u r e 2 . 1 7 â•…Distribution of coronary artery calcium (CAC) scores for the 1119 patients manifesting a normal myocardial perfusion single100–400 photon emission computed tomography (MPS) (left) and the 76 patients P = 0.86 with an ischemic MPS (right). Reproduced with permission from Ref. 64. 1–100 P = 0.57

2 . 1 6 â•…Rates of incident coronary artery disease (CAD)/1000 person years at risk by joint categories of absolute Â�coronary artery calcium (CAC) group and age-sex-race/ethnicity–specific percentiles displays the rates of incident CAD/1000 person years at risk by joint categories of absolute CAC group and age-, sex-, and race/ ethnicity-Â�specific percentiles. Within a particular level of age-Â�specific, sexspecific, and race/ethnicity-specific percentile, there remains a clear trend of increasing risk across levels of the absolute CAC groups. In contrast, once absolute CAC category is fixed, there is no Â�increasing trend across levels of age-specific, sex-specific, and race/ethnicity-Â�specific categories. Reproduced with permission from Ref. 63. Figure

The Multi-Ethnic Study of Atherosclerosis (MESA) registry [62]. CAC was a significant predictor of both major cardiac events (cardiac death or MI) and any coronary events in overall population (Figure 2.15) as well as separately in all 4 ethnic groups in this study during a median follow-up of 3.9 years. Moreover, the new analysis of the data from the same registry [63] demonstrates that risk stratification based on standard absolute cutoff points of CAC (,100, 100–400 and .400 Agatston units) performed much better than agesex-race/ethnicity–specific percentiles in terms of model fit and discrimination (Figure 2.16). Recently, further analysis of the MESA data demonstrated that the CAC score significantly improved cardiac risk prediction over standard risk variables [61A]. That CAC and SPECT MPI measurements provide complementary information in assessing patients with suspected CAD has been shown in a large study from our lab compared to the frequency of ischemia on MPI with the magnitude of CAC abnormality in a total of 1195 patients without known coronary disease, who underwent both stress MPI and CAC tomography within 7.2 6 44.8 days [64]. Among the patients with a CAC ,100 in our study, MPI ischemia was rare, occurring in ,2% of such patients (Figure 2.17). As the CAC score increased in magnitude

above 100, the frequency of myocardial ischemia on MPI increased progressively. This study has brought up several important clinical considerations. First, it helped to define indications for stress MPI referral after CAC imaging. According to the results, a referral of patients for MPI is generally not needed when the CAC score is ,100 due to the very low likelihood of observing inducible myocardial ischemia in such patients. Conversely, when the CAC score is greater than 400, stress MPI (or other stress imaging modality, such as stress echocardiography or stress MRI) would appear to be generally beneficial, because the frequency of inducible ischemia is substantial within this CAC range, even in asymptomatic patients. Another aspect of our study was of particular importance in documenting the insensitivity of MPI for detecting coronary atherosclerosis (in contrast to detecting patients with hemodynamically significant CAD). Of 1119 patients with normal MPI, a large proportion had high enough CCS that there would be consensus that aggressive medical management is warranted: 56% had CCS .100 and 31% had CCS .400 (Figure 2.17). The wide range of CAC scores in the study population patients with normal MPI studies exposes an important limitation relevant to all forms of so-called “physiologic” stress imaging testing: they do not effectively screen for subclinical atherosclerosis. These findings suggest that if testing begins with MPS in a given patient, without known CAD further assessment of atherosclerotic burden by CAC testing in those with normal scans may be useful in assessment of the need for aggressive attempts to prevent coronary events (Figure 2.18). To date, however, there is little data to indicate that aggressive treatment of patients with subclinical atherosclerosis defined by CAC reduces subsequent cardiac events. In a randomized clinical trial, a part of the St Francis Heart Study showed a trend to less progression of the CCS in patients treated with statins versus a control group, but failed to reach

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35

A

B

F i g u r e 2 . 1 8 â•…Clinical case of the 67-year-old male patient, presenting with chronic atypical chest pain; past medical history is remarkable for hyperlipidemia. Initial stress-rest myocardial perfusion imaging demonstrated normal perfusion (A). Subsequent coronary computed tomography angiography (B), however, shows areas of extensive coronary calcifications of all 3 major epicardial coronary arteries (total calcium score 5 1212 Agatston units), and moderately obstructive disease (50%–69% range) of the mid LAD, and first diagonal and second diagonal branches. LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery; LM, left main.

statistical significance [65]. There is an increasing trend toward recommendation of CAC testing for asymptomatic at intermediate clinical risk, and for aggressive treatment of those with prognostically important amounts of CAC. As noted above, when the CAC score is .400, stress imaging for silent myocardial ischemia is now considered appropriate [66]. A recent study [67] has provided data supporting the approach that when such testing for ischemia is negative, the short-term cardiac event rates are low. In analysis of 1089 patients who had nonischemic exercise MPI after CAC testing, during a mean followup of 32 6 16 months, less than 1% underwent early

revascularization, and the annualized cardiac event rate was ,1% in all CAC subgroups, including those with CAC scores .1000. In summary, CAC measurements appear useful in patients with an intermediate clinical risk, when the need for aggressive preventive measures is not already clear. Currently there is increasing recommendations by prevention specialists that a CAC score of .100 defines a patient population deserving prevention therapy according to secondary prevention guidelines. There is consensus in the guidelines and appropriate use criteria that a score .400 defines a threshold above which merits prevention therapy


36

according to secondary prevention guidelines further testing for ischemia is considered appropriate. Importantly, however, in patients with atypical angina and other symptoms resulting in an intermediate likelihood of obstructive CAD, CAC scanning is not considered a sufficiently accurate test to rule out obstructive CAD as the cause of the symptoms. Patients may present with an obstructive noncalcified coronary plaque as being responsible for their first symptoms of CAD. In these patients, either ischemia testing, as discussed above, or CCTA would be more appropriate tests.

jâ•…C ORONA RY C T ANGI O GRAPHY: DI AGNOS TIC A ND PRO GNOS TIC IMPA CT I N DI FFERENT CLI NICAL POP ULAT IONS Although considered possible since the initial description by Hounsfield of computed tomography [68], the era of CCTA did not begin to grow significantly until 1998 when the first 4-slice multislice CT (MSCT) Â�scanners with rotation times of less than0.5 seconds became clinically available [69]. For practical purposes, the introduction of the 16-slice MSCT

scanners in 2001 marked the start of the rapid growth phase of CCTA [70]. This Â�development allowed routine visualization of even small coronary Â�segments, sparking a flame of interest from cardiologists and radiologists. Then in 2004, the introduction of 64-slice MSCT scanners resulted in a bonfire. By 2005, 4 major manufacturers were offering 64-slice scanners, providing CCTA with true 3D data in isotropic voxels of ∼0.5 mm and complete studies in 5 to10 heartbeats. In March 2005, a new society of cardiovascular CT (SCCT) was founded, and by July 2008, SCCT had over 4000 members, representing the most rapidly growing cardiac society on record. This modality has now begun to be applied in routine clinical practice; however, the extent to which it will be used in preference to stress imaging methods in patients with atypical angina or other symptoms indicating an intermediate likelihood of CAD has not yet been determined. Numerous studies of the diagnostic accuracy of the CCTA have been performed comparing CCTA to ICA. These studies have limitations such as referral bias discussed above for MPI, as well as limitations related to the use of ICA as a gold standard per se. The issues of referral bias are less prominent with CCTA than with MPI since nearly all of the correlative studies have been performed on patients already determined as needing ICA, in contrast to the MPI correlative studies in C

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F i g u r e 2 . 1 9 â•… Left panel: pooled estimates (18 studies; n 5 1286; 95% credible interval) for different levels of analysis. Left main artery: owing to numerical difficulties with the hierarchical summary receiver operating characteristic symmetric model, sensitivity (A) and specificity (B) were pooled using the weighted average method, and confidence intervals rather than credible intervals were reported. Right panel: Median (C) positive and (D) negative predictive values (PPV and NPV) across studies (range). CABG, coronary artery bypass graft; LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery. Reproduced with permission from Ref. 72.


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phy angiography (CCTA) per segmental analysis categorized by diameter stenoses on quantitative coronory angiography (QCA). In the graph, the diagnostic performance of CTCA is shown according to various diameter stenoses as measured by QCA in a per-segment analysis. The absolute number of segments per stenosis category is shown in the table. The highest frequencies of overestimated (FP) and underestimated (FN) coronary stenoses by CCTA were clustered around the cutoff value of 50% diameter reduction (significant coronary stenosis). FN, false negative; FP, false positive; TN, true negative; TP, true positive. Reproduced with permission from Ref. 73.

which the decision to perform ICA was frequently governed by the MPI test result itself. This new modality has been subjected to more assessments of sensitivity and specificity in patient groups being sent for invasive coronary angiography than any of the other noninvasive cardiac imaging modalities. On the basis of a large body of evidence, CCTA is considered the most accurate noninvasive test for the detection of CAD as defined by invasive coronary angiography. Meta-analyses of the sensitivity and specificity of CCTA have recently been published [71,72]. In one of these, pooled data from 18 CCTA studies were presented [72]; in this analysis, diagnostic performance of CCTA was found to be excellent (Figure 2.19). Recently, 3 large multicenter trials regarding the accuracy of CCTA for detecting CAD by ICA have been published. The most recent of these was a prospective, multicenter, multivendor study conducted with real-world analysis (no patients or segments were excluded because of impaired image quality attributable to either coronary motion or calcifications), involved 360 symptomatic patients with acute and stable anginal syndromes who were between 50 and 70 years of age and were referred for diagnostic conventional ICA, which was compared with CCTA [73]. In this population of patients with intermediate-to-high and high pretest likelihood of CAD, CCTA was reliable for ruling out significant CAD. Specificity of the CCTA in this study was lower than in most other reports, probably due to the inclusion of all segments and patients despite observed artifacts. An important observation from this study is presented in Figure 2.20; the

AUC (95% C.I.) = 0.95 (0.92, 0.97)

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F i g u r e 2 . 2 1 â•… Results of the ACCURACY trial. Receiver-operating

characteristic curve for identification of patients by coronary computed tomographic angiography (CCTA) with .70% coronary artery stenosis by quantitative coronary angiography. The points on the plot represent the 6 categories of interpretation for CCTA used in this study: 0 5 100% stenosis; 1 5 70% to 99% stenosis; 2 5 50% to 69% stenosis; 3 5 30% to 49% stenosis; 4 5 , 30% stenosis; and 5 5 no stenosis. The ROC shows the degree of the CAD . 70% stenosis prediction by invasive angiography. AUC 5 area under the receiver-operating characteristic curve; CI 5 confidence interval. Bottom: diagnostic performance of the CCTA (per-patient analysis). Reproduced with permission from Ref. 74.

majority of the false-positive and false-negative studies were clustered around the cutoff of the 50% luminal stenosis. Another important recently published prospective multicenter trial (ACCURACY; Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) [74] investigated 230 symptomatic patients with intermediate-to high and high likelihood of CAD who were referred for the ICA; in this study, 64-slice CCTA showed high diagnostic accuracy for detection of obstructive coronary stenosis at both thresholds of 50% and 70% stenosis (Figure 2.21). The authors also concluded that the 99% negative predictive value at the patient and vessel level observed in this study, establishes CCTA as an effective noninvasive alternative to ICA to rule out obstructive CAD. In this study, the prevalence of greater than 50% stenosis was 25%. Similar high diagnostic accuracy of the CCTA compared to ICA was demonstrated in CACTUS (Coronary Angiography by Computed Tomography with the use of a submillimeter resolution) trial [75], which included 243 patients with an intermediate pretest probability for CAD. In a subsequent multicenter trial, The CORE 64 (The Coronary Artery Evaluation using 64-Row Multidetector Computed Tomography Angiography) study, the overall accuracy was similar, but with somewhat lower negative predictive value [76]. However, this difference is most likely attributed to the manner in which lesions were assessed in the presence of coronary artery calcification that may obscure the coronary lumen as well as to differences in prevalence of obstructive CAD in the various studies. In CORE 64 the prevalence of greater than 50% stenosis was 56%.

38

F i g u r e 2 . 2 2 â•… Clinical case of a 42-year-old male patient presenting with shortness of breath and atypical chest pain. Risk factors: smoking family Hx of early coronary artery disease (CAD) his resting electrocardiogram was normal. Coronary computed tomography angiography (shown) was normal, ruling out CAD as a reason for the patient’s symptoms. LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery.

F i g u r e 2 . 2 3 â•… High degree stenosis of the proximal right coronary

artery on coronary computed tomography angiography (A) of the 50-year-old female patient presenting with shortness of breath and chest pain; severity and location of the lesion were confirmed on the invasive coronary angiogram (B).

In patients with an intermediate likelihood of CAD, the clinical implications of a normal CCTA study are Â�generally clear; the high negative predictive value implies that the symptoms leading to testing are very unlikely to be due to obstructive CAD (Figure 2.22). The Â�clinical Â�implications of the abnormal CCTA study are often, Â�however, less clear. Although the coronary angiographic correlations have been excellent (Figure 2.23), the Â�correlations between CCTA and functional measures of ischemia have been much lower. In the studies to date in which both SPECT MPI and CCTA have been Â�performed, less than 50% of the patients with CCTA studies showing .50% stenosis demonstrated ischemia by SPECT MPI (Figure 2.24) [77]. Since a stenosis of 70% severity is now more widely required as an angiographic criterion for the need for revascularization, it would be of interest to see the relationship between CCTA and ischemia using this angiographic cut-point. However, given the lack of excellent correlation even between invasive angiographic stenosis and fractional flow reserve, the current gold standard for hemodynamic significance [78,79],


it is likely that a large proportion of such lesions, even with the 70% stenosis criterion, will not demonstrate ischemia. CCTA is a new modality in the armamentarium of the advanced cardiac imaging. Thus, prognostic data available still cover either relatively small populations or provides a limited (either short-term or midterm) follow-up length. Nevertheless, initial publications in this field demonstrate powerful predictive value of CCTA, with excellent prognosis in those patients who have no evidence of atherosclerosis on their index scan [9,80]. Recently, more detailed analysis of a larger population (n 5 1127) has shown that in patients with chest pain, CCTA identifies increased risk for all-cause death [81]. In this population, a negative CCTA was associated with extremely low all-cause mortality. Notably, the CCTA predictors of death included proximal LAD stenosis and number of vessels with .50% and .70% stenosis. Of importance, there was an appropriate increase in the death rate associated with each step of increased jeopardy when the CCTA was assessed by the Duke Prognostic CAD Index (Figure 2.25). A significant additive prognostic value of the combined CCTA and MPI results is also of importance; in a recent communication in this field, presence of both abnormal CTA and MPI carried a substantially worse prognosis than any on these tests alone (Figure 2.26) [82]. In this European study, 541 patients who had both MPI and CCTA, were followed up for a median of 672 days; hard event rate in patients with none or mild CAD as defined by CCTA (,50% stenosis), was 1.8% per year versus 4.8% per year in patients with significant CAD (50% stenosis). A normal MPI (SSS , 4) and abnormal MPI (SSS  4) were associated with an event rate of 1.1% and 3.8% per year, respectively. CCTA and MPI findings were associated with synergistic prognostic impact, and their combined utilization resulted in significantly improved prediction of cardiac events (P , .005) [82].

F i g u r e 2 . 2 4 â•… Available to-date studies demonstrating positive and negative predictive values of the coronary computed tomography angiography (CCTA) stenosis .50% in predicting myocardial perfusion imaging ischemia. Reproduced with permission from Ref. 77.

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1.00

39

None or Mild (10% ischemia or 5-10% ischemia + ancillary risk market

CCTA

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No compelling anatomy Safe discharge (1° prevention)

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Medical therapy & aggressive risk factor modification (2° prevention)

ICA + poss revasc

F i g u r e 2 . 2 8 â•… MPI approach to diagnosis and management of CAD in symptomatic patients (pts) with an intermediate pretest likelihood of CAD. Ancillary markers of high risk are those listed in Table 2.1. *With normal MPI in patients not already identified as requiring maximal medical therapy using secondary prevention guidelines, consider atherosclerosis imaging. CAD, coronary artery disease; ICA, invasive coronary angiography; CCS, coronary calcium scan. Reproduced with permission from Ref. 84.

than a binary normal and abnormal approach based on a % stenosis cut-point. In this regard, a recent manuscript [85] has shown that a graded classification of results of CCTA can reduce the need for additional testing to rule out angiographically significant CAD. With this system, if lesions by CCTA are seen to show less than 50% diameter narrowing, an angiographic lesion of greater than 70% is highly unlikely. If a lesion is considered to show 70% narrowing, ICA is unlikely to show ,50% stenosis. The lesions that remain in the clearly borderline group regarding the likelihood of ICA stenosis are those in the 50% to 69% narrowing group. An alternate approach in this intermediate likelihood group would be to perform ischemia testing with MPI as the initial test with consideration of CCTA when the results of MPI are uncertain (Figure 2.28). With this approach, patients with extensive ischemia would be referred to ICA. Patients with 5% to 10% ischemia would be further assessed for the presence of ancillary high risk markers (low EF, transient ischemic dilation, and so on; Table 2.2) or high risk conditions (advanced age, diabetes mellitus, atrial fibrillation, pharmacologic stress, and dyspnea). Those with one or more of these high risk markers or conditions could be candidates for ICA. In those with 5% to 10% ischemia and none of the high risk markers or conditions, consideration is given to the performance of CCTA. CCTA is also considered in patients with equivocal MPI or in whom the MPI results and the results of stress testing are markedly discordant (eg, severe ST depression with a normal MPI study). The reason for suggesting the use of CCTA in these patients is that a small percentage of patients with left main CAD might be missed by MPI in the absence of absolute flow measurements [28] (Figure 2.5).

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Atypical Chest Pain and Other Presentations41

F i g u r e 2 . 2 9 â•… MPI approach to diagnosis in management of CAD in

symptomatic patients with the intermediate pre test likelihood of CAD in circumstances where CCTA is not available or contraindicated. *ICA should also be considered in patients with less extensive atherosclerosis. When one or more ancillary high risk markers are present (see Table 2.2).

Another group in which CTA might be commonly employed is in patients with equivocal nuclear results or with a marked discordance in the clinical or ECG results and the nuclear results. Usefulness of CTA in patients with equivocal or nondiagnostic MPI was most recently demonstrated by Abidov et al [86]. The approach to the patient changes somewhat if facilities and /or expertise for CCTA are not available or CCTA is contraindicated (e.g., allergy to contrast, renal failure) or can not be accurately performed (e.g., atrial fibrulation) (Figure 2.29). In these circumstances, symptomatic patients with an intermediate likelihood of CAD or known CAD are candidates for SPECT or PET MPI. The widely available assessment of CCS can then be of further help in these patients in situations where MPI results are normal, equivocal, or discordant with clinical stress test results. Hybrid systems are now available allowing the combined assessments of anatomy and function [88,89]. Both PET and SPECT are intrinsically techniques without high Â�spatial resolution. Recently, PET/CT has become the Â�standard for almost all commercially available PET machines, linking the high resolution of CT with the functional richness of PET. SPECT/CT systems are now available from multiple Â�manufacturers. In the future, it is possible that SPECT systems with Â�dramatic increases in sensitivity as well as increases in spatial Â�resolution could become available, with the potential of rapid, dynamic SPECT and routine absolute quantifications of coronary flow. In some form, it is predicted that hybrid systems will play an increasingly important role for combined anatomic/functional imaging in the future. Of practical clinical relevance, these systems make it possible to combine testing of myocardial ischemia with assessment of coronary atherosclerosis

through the performance of a coronary calcium scan with CT of the hybrid device at the time that attenuation correction scanning is performed with either PET/CT or SPECT/ CT. At Cedars-Sinai Medical Center, we routinely provide a CCS with reports of PET MPI, and, anecdotally have found great value in this combination, as suggested by our previous work [64]. Which of the approaches described in this chapter is optimal has yet to be determined. A large randomized clinical trial. The PROMISE Trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) is currently being conducted by the National Lung, Heart, and Blood Institute. The study proposes to enroll 10,000 patients with symptoms suspicious for significant coronary artery disease requiring non emergent non invasive testing to be randomized to an anatomic strategy involving 64 slice coronary CT angiography versus a functional strategy employing stress testing with either exercise ECG, stress echo, or stress myocardial perfusion imaging. The patients will be followed for 30 months for complications of death, myocardial infarction, or unstable angina. The study will also be evaluated for comparative radiation exposure cost and quality of life. The study is designed with a coronary CT angiography superiority hypothesis, but also will be considered positive if a non inferiority endpoint is reached. Additional study will be needed to compare CCTA to the combination of MPI with evaluation of subclinical coronary atherosclerosis as can be provided routinely by the use of the hybrid PET/CT or SPECT/CT systems.

jâ•… FU T URE CO NSI DERATIONS Perhaps the greatest future potential of the discipline of nuclear cardiology lies in molecular imaging, due to the ability of the radiotracer technique to assess minute tracer concentrations of critical importance for this field. SPECT and PET methods are thousands of times more sensitive than ultrasound, MRI, or CT methods. Already, provocative information of the power of this approach has been demonstrated in assessing the activity of atherosclerotic disease. In the carotid arteries, for example, F-18 FDG PET has been studied for imaging plaque inflammation and Tc-99m annexin SPECT has been evaluated for imaging apoptosis within plaque—both accepted markers of plaque instability. Quite possibly, nuclear techniques may actually hold the key to one of the most elusive goals of imaging in CAD—that of detecting the vulnerable coronary plaque in need of aggressive intervention [90]. Another example of molecular imaging in patients with chest pain might be the use of beta-methyl-iodophenyl-pentadecanoic acid (BMIPP) [91]. This agent has been shown to reveal persistent metabolic abnormalities for greater than 24 hours after transient myocardial ischemia. A possible clinical

42Multimodality Imaging in Cardiovascular Medicine

application of BMIPP would be the assessment of patients presenting several hours to days after a possible severe ischemic episode, potentially providing direct evidence of the recent severe ischemia at a time when perfusion had returned to normal. Given the recent emergence of CCTA as an effective noninvasive procedure for CAD detection, it is likely that the growth rate of MPT will be reduced over the next several years from the double-digit annual growth that has been experienced for nearly 20 years. At the same time, the need for MPI in patients with equivocal CCTA studies, and the increased number of patients with known CAD in whom CCTA is not currently effective, is likely to keep the numbers of nuclear MPI studies in a similar range in what is being performed at this time. In the patients with known CAD, MPI approaches are likely to remain cost effective for identification of which of these patients are most likely to benefit from medical therapy versus coronary revascularization or myocardial reshaping procedures.

jâ•… ACKNOWLEDG MENT The authors thank Xingping Kang, MD for her expert assistance in preparation of the manuscript and illustrative materials for this chapter.

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3

Acute ST Elevation Myocardial Infarction

ZELMIRA CURILLOVA S c OTT D. SOLOMON It is estimated that about 500 000 acute ST elevation myocardial infarctions (STEMI) occur per year in the United States [1]. Although a substantial number of patients die suddenly in the first few hours of an acute myocardial infarction (MI), subsequent morbidity and mortality remain high in those who survive. This review will discuss the utility and limitations of various imaging methods to assess cardiac structure and function following acute MI.

jâ•… PATHOPHYSIOLOGY Acute cessation of regional perfusion, most commonly following a thrombotic occlusion of an epicardial coronary artery, initiates a cascade of metabolic, functional, and structural changes in the myocardial tissue subtended by the occluded artery. An acute lack of oxygen leads to cessation of aerobic metabolism, accumulation of catabolites, tissue acidosis, cell membrane dysfunction with resulting intracellular edema, and subsequent myocyte death. The irreversible tissue injury begins approximately at 20 minutes of coronary occlusion. The wave of myocardial necrosis spreads from the subendocardium toward the subepicardium, reflecting higher oxygen consumption in the subendocardial layer. Tissue necrosis is also accompanied by interstitial edema and cellular infiltration with leukocytes and red blood cells, then later on with macrophages and fibroblasts, ultimately followed by the formation of dense collagenous scar [2]. Reversible ischemia, from transient coronary occlusion or demand-induced ischemia can lead to conditions of depressed myocardial function without necrosis such as short-term hibernation or acute myocardial stunning. It is clinically important to differentiate these conditions of viable dysfunctional myocardium from irreversible myocardial injury since myocardial contractile function will likely improve, provided there is no recurrent ischemia [2].

jâ•…C LI NICAL AND DIFFERENTIAL DIAGNOSIS OF STEMI The clinical diagnosis of STEMI requires symptoms compatible with acute coronary syndrome and presence of new (or presumably new, if no prior electrocardiogram [ECG] is available) ST elevations in at least 2 contiguous leads accompanied by a typical rise and fall of biochemical markers of myocardial necrosis [3]. The majority of STEMI result from an acute thrombotic coronary occlusion in the setting of atherosclerotic coronary disease. However, other coronary events such as coronary embolism, coronary dissection, vasospasm, arteritis, or trauma to coronary arteries can lead to similar clinical presentation. Larson et al observed that in a large cohort of patients referred for cardiac catheterization for suspected acute STEMI, no culprit coronary lesion was found in 14% and about 10% of patients had no angiographic evidence of coronary atherosclerosis [4]. Many factors limit the ability of ECG to reliably diagnose acute MI. There are medical conditions other than acute thrombotic coronary occlusion that can present with ST segment elevation on the ECG. Examples include acute pericarditis or myopericarditis, stress-induced cardiomyopathy (Takotsubo syndrome), Prinzmetal’s angina, hypothermia, intracranial hemorrhage, hyperkalemia, pulmonary embolism, Brugada syndrome, left ventricular (LV) hypertrophy, or an early repolarization ECG pattern [2,5]. On the other hand, there are clinical situations where MI or myocardial ischemia is suspected, but the patient has nondiagnostic ECG (e.g. left bundle branch block [LBBB], paced rhythm) or nonclassic ECG changes (eg, isolated posterior or right ventricular MI). The biochemical markers of myocardial injury can be missing in patients presenting early from the onset of symptoms. On the other hand, elevation of these biomarkers is not necessarily indicative of ischemic etiology of myocardial damage and can also be observed in conditions such as acute myocarditis, stress-induced cardiomyopathy, acute pulmonary embolism, or sepsis.

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jâ•… ROLE OF IMAGING The time from onset of symptoms to the diagnosis and treatment of acute STEMI is crucial to maximize myocardial salvage. In cases where the clinical diagnosis of STEMI is clear, the focus should be on early reperfusion therapy. Therefore, performing additional imaging studies would not add any incremental diagnostic value and would further delay treatment. However, there is a role for additional imaging in clinical situations where the initial diagnosis of acute STEMI is unclear or where medical condition with contraindication to fibrinolytic or anticoagulation therapy is suspected (e.g. aortic dissection, pericarditis). There is an established role of cardiac imaging following acute presentation with STEMI that includes detection of mechanical complications of MI, post-MI risk stratification, assessment of infarct size, and overall prognosis (Table 3.1).

jâ•… ECH OCARDIOGRAPHY Major advantage of echocardiography over other imaging modalities in acute clinical situations is its wide availability and portability. As is the case with other imaging modalities, the role of echocardiography in patients presenting with acute STEMI is limited to situations where diagnosis of STEMI is uncertain or if other noncoronary etiology of acute chest pain or ST elevations is suspected.

Echocardiography is usually the first-line imaging modality for the detection of post-MI complications. Also explored in this section is the role of echocardiography in the assessment of infarct size, post-MI risk stratification, and prognosis. Diagnosis and Management

Initial Diagnosis and Differential Diagnosis A resting transthoracic echocardiogram is indicated for evaluation of patients with acute chest pain and suspected myocardial ischemia with nondiagnostic ECG or laboratory markers [6]. Common diagnostic dilemma includes patients presenting with chest pain and new or presumably new LBBB or ventricular-paced rhythm on the ECG. According to American College of Cardiology/American Heart Association practice guidelines for management of patients with acute STEMI, fibrinolytic therapy should be administered to STEMI patients with symptom onset within the previous 12 hours and new or presumably new LBBB, in the absence of contraindications [1]. Although patients with new LBBB presenting with MI belong to the high-risk group and achieve greater benefit from fibrinolytic therapy, there are often concerns about the validity of ECG criteria for MI diagnosis in this setting and about potential risks of therapy. Larson et al evaluated the frequency of false-positive catheterization laboratory activation in patients with suspected STEMI referred to a tertiary

jâ•… Table 3.1â•… Recommendations from the American College of Cardiology/American Heart Association guidelines for the management of patients with STEMI Class I Recommendation

Class IIa Recommendation

Class III Recommendation

1.â•‡Patients with STEMI should have a portable chest X-ray, but this should not delay implementation of reperfusion therapy (unless a potential contraindication, such as aortic dissection, is suspected).

ortable echocardiography is reasonable P to clarify the diagnosis of STEMI and allow risk stratification of patients presenting with chest pain, especially if the diagnosis of STEMI is confounded by left bundle branch or pacing or there is suspicion of posterior STEMI with anterior ST depressions.

S ingle photon emission computed tomography radionuclide imaging should not be performed to diagnose STEMI in patients for whom the diagnosis of STEMI is evident on the electrocardiogram.

2.â•‡Imaging studies such as a highquality portable chest X-ray, transthoracic and/or transesophageal echocardiography, and a contrastenhanced chest computed tomography or magnetic resonance imaging scan should be used to differentiate STEMI from aortic dissection in patients for whom the distinction is initially unclear. STEMI, ST elevation myocardial infarctions. From Ref. 1.

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cardiovascular center. In a subgroup of patients who presented with new or presumed new LBBB, no culprit coronary lesion was found in 44% and no angiographic evidence of coronary disease was found in 27% of these patients [4]. In this clinical scenario, additional valuable information can be derived from a bedside echocardiogram. The location and extent of new wall motion abnormalities detected helps triage these patients to the most appropriate management strategy. Myocardial injury in the left circumflex coronary artery territory can be ECG silent on a standard 12-lead ECG or the true posterior MI may manifest only by tall R waves and ST segment depression in the right precordial leads [7]. Confirmatory data from a bedside echocardiogram detecting new wall motion abnormalities in the left circumflex territory are very helpful in clinical decision making. ST elevations on the ECG in patients with chest pain can also be due to an acute pericarditis or myopericarditis. Given the elevated risk of pericardial hemorrhage and tamponade after fibrinolytic therapy in patients with pericarditis, it is important to differentiate it from acute STEMI [8]. Presence of pericardial effusion has been described in approximately 60% of acute pericarditis cases [9]. Therefore, if a pericardial effusion is detected on the echocardiogram, it favors diagnosis of pericarditis. However, an absence of pericardial effusion does not exclude acute pericarditis. Conversely, the detection of a new wall motion abnormality on the echocardiogram favors diagnosis of acute MI. Nevertheless, wall motion abnormalities and elevation of biomarkers of myocardial necrosis can also be present in myopericarditis. More diffuse pattern and noncoronary distribution of wall motion abnormalities in acute myopericarditis can help to differentiate it from an acute MI. In clinical practice, the differentiation of acute STEMI and acute pericarditis/myopericarditis can be challenging and in some cases it may be necessary to perform coronary angiogram to rule out an acute MI [10].

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The transthoracic echocardiogram can detect the presence of a dissection flap in the ascending thoracic aorta or a new aortic insufficiency in the setting of an acute type A aortic dissection. Nienaber et al reported low sensitivity of about 59% but higher specificity of 83% for the detection of thoracic aortic dissection by transthoracic echocardiography [11]. Echocardiography can visualize thrombi in the right-sided cardiac chambers, main pulmonary artery, or proximal main pulmonary artery branches and lead to diagnosis of pulmonary embolism. Echocardiographic findings of right ventricular dilatation and hypokinesis are helpful in the evaluation of patients with known or suspected acute pulmonary embolism to guide thrombolytic therapy or thrombectomy. However, echocardiogram is not recommended for a routine initial evaluation of patients to establish the diagnosis of acute pulmonary embolism [6,12]. The regional wall motion abnormality on the echocardiogram is less often detected with small infarcts due to tethering of the infarcted area to the surrounding, normally contracting myocardium. When wall motion abnormality is detected, it can be difficult to differentiate between acute and chronic MI, unless a baseline pre-event echocardiogram is available for comparison. Chronic MI tends to be associated with wall thinning, whereas acute MI can display increased wall thickness due to myocardial edema and inflammation.

Post-MI Complications In patients with acute decompensation post-MI or unstable hemodynamics, echocardiography is a valuable tool to assess for post-MI mechanical complications such as ventricular septal defect, free wall rupture/tamponade, ventricular pseudoaneurysm, acute mitral regurgitation, right ventricular involvement or ventricular aneurysm, and thrombus [6] (Figures 3.1 and 3.2). Acute mitral regurgitation post-MI can be due to papillary muscle dysfunction or rupture or

3 . 1 â•… Post–myocardial infarction mechanical complication following a left anterior descending coronary artery infarct. There is a ventricular septal defect with left to right flow located in the distal interventricular septum (arrow).

FIGURE


F I G U R E 3 . 2 â•… Giant left ventricular aneurysm (arrowheads) in a patient

A

with nonreperfused anterior myocardial infarction. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

due to acute systolic anterior motion of the mitral valve. Because the posteromedial papillary muscle is supplied by a single coronary artery, rupture of the posteromedial Â�papillary muscle is more common than rupture of the anterolateral papillary muscle that has a dual blood supply (Figure 3.3). Another possible mechanical post-MI complication is an acute dynamic LV outflow tract obstruction with systolic anterior motion of the mitral valve and mitral regurgitation. This complication is seen more commonly after an acute anterior MI in elderly females with preexisting upper septal hypertrophy. The compensatory hyperdynamic motion of the inferolateral wall leads to altered geometry of the mitral valve apparatus and systolic anterior motion resulting in dynamic LVOT obstruction and mitral regurgitation [2].

Transesophageal Echocardiography Transesophageal echocardiogram (TEE) is an important imaging tool in difficult clinical situations where transthoracic images are nondiagnostic, for example, in intubated postoperative patients in the critical care unit. In patients with acute decompensation, post-MI TEE is considered superior to transthoracic echo to diagnose acute severe mitral regurgitation due to papillary muscle rupture where the timely diagnosis and urgent surgical treatment are crucial for survival. TEE is also commonly employed in assessment of patients with suspected acute aortic dissection (Figure 3.4). The advantage of the TEE over chest computed tomography (CT) or magnetic resonance imaging in the evaluation for aortic dissection is its portability and no need for contrast administration. TEE is usually the preferred modality in hemodynamically unstable patients or in patients with significant renal impairment when both the iodinated contrast and gadolinium administration are undesirable.

B F I G U R E 3 . 3 â•… Post–myocardial infarction mechanical complications.

Ruptured posteromedial papillary muscle head (arrow) prolapsing into the left atrium (A) with associated severe eccentric mitral regurgitation (B).

Risk Stratification and Prognosis Revascularization of the culprit epicardial coronary artery is necessary for myocardial salvage in acute STEMI. However, a successful revascularization of the epicardial coronary artery does not always translate into successful reperfusion of the myocardium at the microvascular level. Using the wall motion abnormalities to assess the extent of myocardial damage, acutely post-MI is confounded by the presence of dysfunctional but viable myocardium due to myocardial stunning. In the reperfused stunned myocardium, improvement in regional contractility starts 1 to 2 days postreperfusion and continues over several weeks to months [2].

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epicardial coronary artery have shown that approximately one-third of patients lack myocardial reperfusion as evidenced by the presence of myocardial no-reflow zones. Absence of the no-reflow zone shortly after revascularization was predictive of an improvement in global and regional myocardial function and lack of adverse ventricular remodeling [15–17]. Lepper et al used intravenous myocardial contrast just prior to primary coronary angioplasty in patients with acute STEMI to define the myocardial area at risk and then at 24 hours after angioplasty to define the no-reflow regions. Authors concluded that the area ratio (no-reflow area divided by area at risk) of 50% was associated with improvement in regional wall motion abnormalities and regional coronary flow reserve [18]. Galiuto et al used myocardial contrast echo to assess the extent of microvascular damage in patients 1 day after successfully reperfused STEMI. At multivariable analysis, the thrombolysis in myocardial infarction flow grade ,3 after percutaneous intervention and the endocardial length of contrast defect .25% were independent predictors of adverse left ventricular remodeling at 6-month follow-up [19] (Figure 3.5).

Low-Dose Dobutamine Echocardiography

B F I G U R E 3 . 4 â•…Transesophageal echocardiogram showing type A aor-

tic dissection with a dissection flap (arrow) in the ascending thoracic aorta (A) and color flow in the true lumen (B).

Myocardial Contrast Echocardiography This technique uses an injection of sonicated microbubbles to image myocardial perfusion. One can look at the replenishment of myocardial opacification after a destruction pulse that eliminates microbubbles in the imaging field. Myocardial contrast signal intensity is considered to reflect microvascular integrity and it has been shown to Â�correlate directly with capillary density and indirectly with collagen content in the biopsied myocardium [13]. Contrast Â�perfusion assessed at 10 to 15 seconds during destructionreplenishment imaging has been shown to correlate well with infarct size in an animal model of acute MI [14]. Studies performed using an intracoronary myocardial contrast injection after successful recanalization of the culprit

Another method for the detection of dysfunctional but Â�viable myocardium early post-MI is the demonstration of contractile improvement with low-dose dobutamine. Hillis et al Â�compared the myocardial contrast echo and low-dose Â�dobutamine Â�echocardiography (DE) early post-MI for Â�predicting LV Â�functional recovery. In their study, normal contrast opacification predicted myocardial functional recovery with a positive predictive value of 63% and a negative Â�predictive value of 73%. Residual contractility during low-dose DE had a Â�positive predictive value of 82% and a negative predictive value of 72%. The authors concluded that the low-dose DE was superior to myocardial contrast echo in predicting functional recovery of dysfunctional myocardium early after acute MI [20].

Post-MI Prognosis Following an acute MI, there are many established prognostic indicators such as the degree of systolic dysfunction, LV dilatation, mitral regurgitation, extent of coronary artery Â�disease, and presence of heart failure [2]. In addition, prognostic value of myocardial viability detected early post-MI was evaluated. In a study by Swinburn and Senior using dobutamine stress echo in stable post-MI patients, the independent predictors of death and nonfatal MI were age and systolic wall thickening index at low-dose dobutamine. The low-dose dobutamine response also provided incremental value over clinical information and LV systolic function at rest [21]. Dwivedi et al demonstrated that the extent of myocardial viability by myocardial contrast echo was a powerful independent predictor of cardiac death or nonfatal MI in a cohort of stable patients early post-MI [22]. In addition, other echocardiographic parameters such as a noninvasive

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A

F I G U R E 3 . 6 â•…Myocardial late gadolinium enhancement in the basal short-axis view in a patient with transmural myocardial infarction in the posterior descending artery territory (white arrowheads) with evidence of left ventricular thrombus (black arrow).

Delayed-enhancement CMR is a more sensitive technique than echocardiography for the detection of LV thrombus [25,26] (Figure 3.6). CMR findings early after acute MI can provide information about infarct size, viable myocardium, and an overall prognosis. Diagnosis and Management B F I G U R E 3 . 5 â•…A, Myocardial contrast echocardiography in 4-chamber

view shows a large endocardial contrast defect in the lateral wall (between arrows) with normal end diastolic volume. B, Two-dimensional echocardiogram at 6-month follow-up shows enlarged left ventricle. Adapted from Ref. 19.

estimation of LV filling pressure using E/E' ratio or persistent restrictive mitral inflow pattern were shown to be predictive of survival after acute MI [23,24].

jâ•… CARDIAC MAGNETIC RESONANCE In patients with clinical suspicion of acute STEMI and diagnostic ECG or elevated biomarkers of acute myocardial injury, there is usually little incremental value of additional diagnostic workup since this would only further delay timely revascularization. Nevertheless, if clinical presentation does not add up, cardiac magnetic resonance (CMR) tissue characterization can offer important additional clues to guide the appropriate patient management. CMR images can also be used to diagnose conditions that can mimic acute MI such as aortic dissection, myocarditis, pericarditis, or acute pulmonary embolism.

Late Gadolinium Enhancement Gadolinium chelates such as gadolinium–diethylenetriamine-pentaacetic acid (Gd-DTPA) are thought to passively diffuse throughout the extracellular space. The proposed mechanism of late gadolinium enhancement (LGE) acutely after MI involves an increase in extracellular volume of distribution in the myocardial tissue after myocyte death (loss of cell membrane integrity) and altered washin and washout kinetics in the infarct zone. In the setting of chronic MI, myocytes have been replaced by collagenous scar with increased interstitial space and therefore increased extracellular volume of distribution when compared to tightly packed myocytes of the normal myocardium [27]. Kim et al [28] studied the relationship of LGE to myocardial injury and infarct age in dogs with experimental MI and after transient myocardial ischemia. The authors used T1-weighted inversion recovery fast gradient echo pulse sequences, acquired 20 to 30 minutes after an intravenous injection of Gd-DTPA, to image canine hearts in vivo and ex vivo. The images were also compared with histopathology using triphenyltetrazolium chloride (TTC) staining for necrosis. They demonstrated that the spatial extent of LGE on CMR images closely correlated with the spatial extent of myocardial necrosis by TTC staining

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at 1 and 3 days post-MI and with the extent of collagenous scar at 8 weeks. The wall thickening at 3 days was impaired in both, regions with infarcted myocardium and transiently ischemic myocardium; however LGE was present only in regions with infarcted myocardium. At 8 weeks postevent, the wall thickening in regions of transient ischemia normalized. The authors concluded that both acute and chronic myocardial infarcts showed LGE; however, myocardial injury without necrosis did not hyperenhance despite the presence of myocardial stunning. The absolute volume of hyperenhanced regions at day 3 postevent had decreased approximately by a factor of 3.4 by 8 weeks postevent, suggesting that spatial extent of collagenous scar at 8 weeks was smaller than spatial extent of acute myocardial necrosis likely due to infarct shrinkage. Similar findings were previously described by Reimer and Jennings, who found about a 4-fold decrease in infarct volume between day 4 and day 28 postevent on histology [29].

T2-weighted Techniques Acute MI is accompanied by myocardial edema [30]. In edematous tissues, hydrogen protons are more frequently bound in free water and display longer transverse relaxation time (T2 time). Higgins et al first demonstrated good linear correlation between T2 relaxation time and myocardial water content in a dog model of acute MI [31]. More than 20 years ago McNamara et al imaged patients early after an acute MI using spin echo pulse sequence and observed that infarcted regions had significantly prolonged T2 relaxation time (∼81 milliseconds) compared to normal myocardium (∼42 milliseconds) [32]. T2-weighted pulse sequences display edematous myocardium as having higher signal intensity than the remote myocardium. The T2-weighted technique has been used to image myocardial edema in conditions such as acute MI, acute myocarditis, or acute rejection after heart transplant [33,34]. Abdel-Aty et al studied 15 dogs with transient coronary occlusion and after reperfusion using T2-weighted inversion recovery fast spin echo sequences with blood and fat suppression. They observed that function in the affected segments deteriorated very early after the coronary artery occlusion. This was followed by the onset of myocardial edema that was visually apparent as high T2 signal intensity areas in ∼28 minutes after coronary occlusion. Myocardial edema was detected in the dysfunctional segments even in dogs without evidence of concurrent myocardial necrosis on LGE images [35]. It has been known that both acute and chronic infarctions exhibit LGE regardless of infarct age [28]. T2-weighted techniques were used to differentiate acute from chronic MI. In another study by Abdel-Aty et al, the addition of T2-weighted images to LGE examination yielded a specificity of 96% to differentiate acute from chronic MI [36]. The ability to localize and differentiate acute from chronic MI can be helpful in clinical situations

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where the biomarkers or ECG are equivocal or when a patient has a history of prior infarct and presents with a possible new event. Infarct-associated edema is thought to persist for 2 to 3 weeks after an acute event, so it can also be used as a tissue memory marker of recent MI [37]. Acute stress-induced cardiomyopathy (Takatsubo cardiomyopathy) can clinically present very similar to acute STEMI or acute coronary syndrome. It is characterized by a typical pattern of wall motion abnormalities with apical ballooning. However, there is no angiographic evidence of obstructive coronary stenosis and no evidence of irreversible myocardial injury by LGE technique [38]. Abdel-Â�Aty et al performed CMR in 7 patients with stress-induced Â�cardiomyopathy and found T2-hyperintense areas matching with areas of myocardial dysfunction, suggesting the presence of myocardial edema in dysfunctional segments. Both abnormalities resolved at follow-up. No significant LGE was observed in the dysfunctional segments. Combination of T2-weighted images and LGE can also be helpful in differentiating acute MI from acute myocarditis. The pattern of myocardial involvement in myocarditis often proceeds from focal to global pattern. The LGE is mostly subepicardial or midwall and often multifocal [33,39,40].

Risk Stratification and Prognosis

Areas at Risk and Infarct Size It has been suggested that T2-hyperintense regions with myocardial edema after acute MI represent areas at risk and correlate well with the extent of acute hypokinesis. The spatial extent of regions with increased T2 signal intensity is larger than the extent of irreversible injury by LGE [41,42] (Figure 3.7). It has been observed that the increase in myocardial T2 signal intensity after acute coronary occlusion develops approximately 1 day postevent and resolves in few months [43,44]. The difference between the area at risk and LGE area is the amount of salvageable myocardium [45]. In other words, the T2-hyperintense regions without LGE represent dysfunctional but viable myocardium [41,42,45,46]. When compared to single photon emission computed tomography for quantification of area at risk and infarct size, advantages of CMR include no radiation exposure, Â�better spatial resolution, and easier logistics. CMR is becoming an attractive imaging technique for evaluating the effectiveness of different adjunctive therapies in acute MI. Good Â�reproducibility [47] and higher image resolution [48] and therefore better ability to detect small infarcts would Â�translate into smaller number of patients needed for clinical trials. Another potential clinical application is in patients presenting late after the onset of MI symptom. Assessment of area at risk compared to area of irreversible injury can help to differentiate between patients who have completed their infarct and patients with potentially salvageable myocardium at risk who would benefit from revascularization [49].

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F I G U R E 3 . 7 â•… Cardiac magnetic resonance in acute nontransmural myocardial infarction. T2-weighted and postcontrast T1-weighted late gadolinium enhancement images showing infarction related transmural edema but only subendocardial necrosis. Modified from Ref. 33.

Improvement of Function, LV Remodeling, and Prognosis Post-MI The main goal of successful reperfusion therapy in acute MI is myocardial salvage with reestablishment of contractile function and improvement in prognosis. Ventricular wall motion at rest cannot be used early post-MI to predict myocardial viability because both necrotic and stunned myocardium have impaired contractile function. Choi et al investigated the utility of LGE in patients within 7 days from an acute MI to predict recovery of regional and global myocardial function. The authors found that the improvement in segmental contractile function on the follow-up scan 8 to 12 weeks post-MI was inversely related to the transmural extent of LGE on the initial scan. For example, 77% of segments with no late enhancement or 67% of segments with 1% to 25% transmural extent LGE showed improved function, but only 5% of segment with .75% transmural extent enhancement improved on follow-up. The best predictor for improvement in global LV systolic function was the amount of dysfunctional but noninfarcted myocardium on the initial scan [50]. Changes in ventricular architecture post-MI with LV dilatation (LV remodeling) depend on infarct size as well as rate of infarct healing and wall stress [51]. A study by Ito et al [16] used an intracoronary injection of echo contrast to image microvascular obstruction or no-reflow zone following successful percutaneous coronary intervention for acute anterior MI. The results indicated that the presence of microvascular obstruction adversely affects LV remodeling perhaps by attenuating the beneficial effect of early reperfusion. At the center of the infarct, there is an area of microvascular obstruction also called no-reflow zone where capillaries become injured and occluded by dying blood cells and debris. Despite restoration of blood flow in the epicardial coronary artery, these areas of no-reflow do not reperfuse. Several studies have validated the microvascular obstruction imaging by CMR against pathology and angiographic myocardial blush score [52,53].

Wu et al looked at patients who underwent CMR examination early after acute MI and then were followed up clinically for a mean of 16 6 5 months. Microvascular obstruction was defined as subendocardial hypoenhancement surrounded by hyperenhanced areas of infarcted myocardium seen 1 to 2 minutes after the gadolinium contrast injection on myocardial perfusion images. The risk of adverse events (cardiac death, reinfarction, heart failure, stroke, or rehospitalization for unstable angina) increased with increasing extent of LGE. Nonetheless, even after infarct size was controlled for, the presence of microvascular obstruction remained predictive of postinfarction complications [54]. Similarly, in the study by Hombach et al in patients imaged early after acute MI, presence of microvascular obstruction on late enhancement images was a significant predictor of major adverse cardiac events (death, MI, rehospitalization for cardiac failure, unstable angina, or revascularization) as was LV end-diastolic volume and LV ejection fraction. The infarct size, microvascular obstruction, and amount of transmural scar were predictive of adverse LV remodeling [55] (Figure 3.8).

jâ•… CARDIAC CT The role of CT in the setting of acute MI is limited to situations with atypical clinical presentation and nondiagnostic ECG findings when noncoronary etiologies of chest pain are suspected (eg, aortic dissection, acute pulmonary embolism). Cardiac CT can be used for the detection of post-MI complications and for the assessment of infarct size and early post-MI viability. Diagnosis and Management Clinical features of acute MI can overlap with other acute conditions such as pulmonary embolism, aortic dissection, or dissecting aortic hematoma. Contrast-enhanced CT is a fast and reliable tool for detection of aortic dissection

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F I G U R E 3 . 8 â•… Basal short-axis slice late gadolinium enhancement in a

patient with inferolateral myocardial infarction with manual quantification of enhanced myocardium and persistent microvascular obstruction (dark central zone within the myocardium with high signal intensity). Adapted from Ref. 55.

with pooled sensitivity of 100% and specificity of 98% in recent meta-analysis by Shiga et al [56]. CT pulmonary angiogram is evolving into a primary imaging modality for the detection of acute pulmonary embolism, especially in the era of multidetector-raw CT with submillimeter spatial resolution [57]. Contrast-enhanced CT scans are commonly performed for the evaluation of symptoms suggestive of acute pulmonary embolism or aortic dissection but can incidentally detect areas of myocardial hypoenhancement that could trigger consideration of an acute MI [58,59]. CT can also detect complications of acute MI such as LV thrombus or pericardial effusion. Based on the CT attenuation coefficient (Hounsfield units), one can differentiate simple fluid from hemorrhagic pericardial effusion. Risk Stratification and Prognosis Similar to CMR, multidetector CT (MDCT) can detect areas of irreversible myocardial injury on delayed postcontrast images using iodinated contrast. Areas of delayed enhancement are thought to reflect an increased interstitial space due to myocyte damage in the acute phase or an increased extracellular volume of distribution due to collagenous scar in the chronic phase of the infarct. Both animal and human studies comparing the 2 techniques reported good agreement for the detection of hyperenhanced regions [60,61]. Lardo et al compared the delayed enhancement on MDCT to histopathology in an animal model and concluded that the spatial extent of acute and

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chronic MI can be accurately determined and quantified with contrast-enhanced MDCT [62]. Contrast-enhanced cardiac CT is also able to detect areas of hypoenhancement on the early postcontrast images that correlate with areas of hypoenhancement on first-pass perfusion CMR [60,63]. Areas of hypoenhancement on early postcontrast images are thought to represent underperfused myocardial regions due to obstructed infarct-related artery and microvascular obstruction in the setting of acute MI or decreased capillary density of the myocardial scar in the setting of chronic MI [62]. Habis et al evaluated the usefulness of 64-slice CT delayed enhancement without iodinated contrast reinjection immediately after coronary angiography in a cohort of acute MI patients where 94% of patients had STEMI. Mean delay between the coronary angiography and CT was 24 6 11 minutes and the viability by CT was defined as no or ,50% subendocardial delayed enhancement. Authors Â�compared the CT viability results with low-dose DE performed 2 to 4 weeks post-MI. On segmental analysis, agreement was noted in 97% of segments; the sensitivity, specificity, positive, and negative predictive values were 98%, 94%, 99%, and 79%, respectively, for detecting Â�viable segments very early post-MI [64] (Figure 3.9). Similarly, Sato et al performed no reinjection CT delayed enhancement immediately following coronary stenting in patients with acute STEMI. Patients with 75% transmural extent of delayed enhancement had significantly higher incidence of adverse LV remodeling at 6-month Â�follow-up and were more often rehospitalized for heart failure Â�compared to patients with ,75% enhancement [65]. Both these studies suggest that CT delayed-Â�enhancement Â�patterns early after STEMI may provide important information about myocardial viability. Limitations of MDCT include the need for iodinated contrast and radiation exposure, especially of concern when both early and delayed postcontrast images are acquired. Development of new imaging protocols and better technology aims to minimize the radiation dose. Examples include lower dose CT angiography with prospective ECG gating in step and shoot mode, retrospective ECG gating with tube current modulation or acquisition of the whole heart volume in a single rotation in one R-R interval with 320-slice CT [66–69].

jâ•… NUC LEAR TECH NIQUES Radionuclide imaging has limited clinical application for diagnosis of acute MI and should be restricted to limited situations where the initial diagnosis of acute MI is not clear. Application of nuclear imaging techniques for assessment of area at risk, infarct size, myocardial salvage, and inducible ischemia after acute MI will be discussed.


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F I G U R E 3 . 9 â•… (A) 64-slice computed tomography (CT) scan 51 Â�minutes

after a primary angioplasty for acute myocardial infarction showing hyperenhancement of the inferolateral wall (arrows). LowÂ� subendocardial dose dobutamine echocardiography confirmed myocardial viability of these segments. (B) 64-slice CT scan 21 minutes after left anterior descending artery reperfusion showing transmural hyperenhancement (arrows) in mid short axis (a) and 4-chamber (b) views. This patient was confirmed to have no viability by low-dose dobutamine echo in all involved segments. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Modified from Ref. 64.

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Diagnosis and Management

Infarct Avid Imaging First attempts to directly visualize areas of MI were based on hot spot imaging agents such as 99mTc-pyrophosphate and 111In-antimyosin. 99m Tc-pyrophosphate is mostly used for bone scanning. The exact mechanism for its affinity to myocardial necrosis is not entirely understood, but it has been proposed that 99mTc-pyrophosphate targets calcium phosphate in the mitochondria of severely injured myocytes. Maximum uptake occurs in 24 to 72 hours after acute infarction and lasts for 6 to 10 days. The shortcomings include 2 to 3 days of accumulation delay in nonreperfused MI, low sensitivity for subendocardial infarcts, and superimposed bone activity that limits reliable image interpretation. Falsepositive results can be seen due to the presence of cardiac

B

calcifications (eg, valvular calcifications, calcified LV aneurysm), cardiac amyloidosis, myocarditis, cardiac metastasis, or secondary hyperparathyroidism. There is reduced sensitivity for detecting small or nontransmural infarcts. Infarct avid scintigraphy can be also performed using 111 In-antimyosin antibody fragments that bind to the exposed intracellular myosin heavy chain after loss of cell membrane integrity. The image acquisition is recommended at about 48 hours after injection to minimize the blood pool activity. 111In-antimyosin antibody imaging of MI has better specificity when compared to 99mTc-pyrophosphate imaging. None of the infarct avid tracer described is currently being used in practice for diagnosis of MI. There is a significant delay in tracer accumulation in the infarct zone or delay required for imaging, making their use not practical [70,71].

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Myocardial Perfusion Imaging

jâ•… REF ERENCES

After an intravenous injection of 99mTc-sestamibi or 99m Tc-tetrofosmin, the radiotracer enters myocytes proportionally to myocardial blood flow. Once it becomes intracellular, it has a very slow washout rate, independent of myocardial blood flow. Because of its pharmacokinetic properties, 99mTc-sestamibi or 99mTc-tetrofosmin can be injected during acute presentation to the hospital and imaged few hours later after stabilization or revascularization, and the images will reflect tracer uptake at the time of injection [72]. Myocardial perfusion imaging at rest using these 99m Tc-labeled radiotracers can be used for the diagnosis of acute MI in patients with chest pain in whom the conventional measures are nondiagnostic. Findings of prior studies show high sensitivity and high negative predictive value of resting perfusion for acute MI [73–75]. The perfusion defects at rest, however, do not distinguish between acute ischemia, acute MI, or prior MI. Myocardial stress and rest perfusion imaging with 99m Tc-sestamibi, 99mTc-tetrofosmin, or 201Thallium chloride tracers can be used to assess the presence and extent of residual inducible ischemia after STEMI following successful fibrinolytic therapy for further risk stratification and to determine the need for cardiac catheterization prior to discharge. Other accepted indications for nuclear imaging after STEMI include evaluation of functional significance of coronary lesion previously identified on angiography, assessment of left ventricular function, or assessment of right ventricular function in suspected right ventricular infarction using a first-pass or equilibrium radionuclide angiography [76].

â•‡ 1. Antman EM, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation. 2004;110(5):588–636. â•‡ 2. Libby P, Braunwald E. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia: Saunders/Elsevier;2008. â•‡ 3. Cannon CP, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol. 2001;38(7):2114–2130. â•‡ 4. Larson DM, et al. “False-positive” cardiac catheterization laboratory activation among patients with suspected ST-segment elevation myocardial infarction. JAMA. 2007;298(23):2754–2760. â•‡ 5. Wang K, Asinger RW, Marriott HJ. ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med. 2003;349(22):2128–2135. â•‡ 6. Douglas PS, et al. ACCF/ASE/ACEP/ASNC/SCAI/SCCT/SCMR 2007 appropriateness criteria for transthoracic and transesophageal echocardiography: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American Society of Echocardiography, American College of Emergency Physicians, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and the Society for Cardiovascular Magnetic Resonance. Endorsed by the American College of Chest Physicians and the Society of Critical Care Medicine. J Am Soc Echocardiogr. 2007;20(7):787–805. â•‡ 7. Matetzky S, et al. Significance of ST segment elevations in posterior chest leads (V7 to V9) in patients with acute inferior myocardial infarction: application for thrombolytic therapy. J Am Coll Cardiol. 1998;31(3):506–511. â•‡ 8. Spodick DH. Acute pericarditis: current concepts and practice.â•‡ JAMA. 2003;289(9):1150–1153. â•‡ 9. Imazio M, et al. Day-hospital treatment of acute pericarditis: a management program for outpatient therapy. J Am Coll Cardiol. 2004;43(6):1042–1046. 10. Salisbury A, et al. Frequency and predictors of urgent coronary angiography in patients with acute pericarditis. Mayo Clin Proc. 2009;84(1):11–15. 11. Nienaber CA, et al. The diagnosis of thoracic aortic dissection by noninvasive imaging procedures. N Engl J Med. 1993;328(1):1–9. 12. Cheitlin MD, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation. 2003;108(9):1146–1162. 13. Shimoni S, et al. Microvascular structural correlates of myocardial contrast echocardiography in patients with coronary artery disease and left ventricular dysfunction: implications for the assessment of myocardial hibernation. Circulation. 2002;106(8):950–956. 14. Coggins MP, et al. Noninvasive prediction of ultimate infarct size at the time of acute coronary occlusion based on the extent and magnitude of collateral-derived myocardial blood flow. Circulation. 2001;104(20):2471–2477. 15. Ito H, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. 1992;85(5):1699–1705. 16. Ito H, et al. Clinical implications of the “no-reflow” phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation. 1996;93(2):223–228.

Risk Stratification and Prognosis Myocardial perfusion defect at the time of initial presentation reflects the myocardium at risk. Subsequent perfusion defect after reperfusion therapy predischarge reflects final infarct size. The difference between these 2 measurements is the amount of myocardium salvaged. Multiple studies demonstrated the value of 99mTc-sestamibi in the quantification of infarct size and myocardial salvage with reperfusion therapy in the setting of acute MI [77]. The end points of infarct size and myocardial salvage have also been used to compare effectiveness of different treatment strategies in MI [78]. Infarct size measured by 99mTc sestamibi imaging shows a close correlation with directly measured infarct size in pathology specimens, left ventricular ejection fraction, regional wall motion, and myocardial enzyme release [79–83]. The infarct size, myocardial salvage index, extent and severity of stress-induced defects, and reversibility score on myocardial perfusion imaging in patients after acute MI were shown to predict short-term and long-term patient outcome [84–87].

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17. Kenner MD, et al. Ability of the no-reflow phenomenon during an acute myocardial infarction to predict left ventricular dysfunction at one-month follow-up. Am J Cardiol. 1995;76(12):861–868. 18. Lepper W, et al. Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve after primary percutaneous transluminal coronary angioplasty [correction of angiography] in patients with acute myocardial infarction. Circulation. 2000;101(20):2368–2374. 19. Galiuto L, et al. The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of postinfarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study. J Am Coll Cardiol. 2008;51(5):552–559. 20. Hillis GS, et al. Comparison of intravenous myocardial contrast echocardiography and low-dose dobutamine echocardiography for predicting left ventricular functional recovery following acute Â�myocardial infarction. Am J Cardiol. 2003;92(5):504–508. 21. Swinburn JM, Senior R. Myocardial viability assessed by dobutamine stress echocardiography predicts reduced mortality early after acute myocardial infarction: determining the risk of events after myocardial infarction (DREAM) study. Heart. 2006;92(1):44–48. 22. Dwivedi G, et al. Prognostic value of myocardial viability detected by myocardial contrast echocardiography early after acute myocardial infarction. J Am Coll Cardiol. 2007;50(4):327–334. 23. Hillis GS, et al. Noninvasive estimation of left ventricular filling pressure by E/e’ is a powerful predictor of survival after acute myocardial infarction. J Am Coll Cardiol. 2004;43(3):360–367. 24. Temporelli PL, et al. Doppler-derived mitral deceleration time as a strong prognostic marker of left ventricular remodeling and survival after acute myocardial infarction: results of the GISSI-3 echo substudy. J Am Coll Cardiol. 2004;43(9):1646–1653. 25. Mollet NR, et al. Visualization of ventricular thrombi with contrastenhanced magnetic resonance imaging in patients with ischemic heart disease. Circulation. 2002;106(23):2873–2876. 26. Srichai MB, et al. Clinical, imaging, and pathological characteristics of left ventricular thrombus: a comparison of contrast-enhanced magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography with surgical or pathological validation. Am Heart J. 2006;152(1):75–84. 27. Mahrholdt H, et al. Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies. Eur Heart J. 2005;26(15):1461–1474. 28. Kim RJ, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999;100(19):1992–2002. 29. Reimer KA, Jennings RB. The changing anatomic reference base of evolving myocardial infarction. Underestimation of myocardial collateral blood flow and overestimation of experimental anatomic infarct size due to tissue edema, hemorrhage and acute inflammation. Circulation. 1979;60(4):866–876. 30. Willerson JT, et al. Abnormal myocardial fluid retention as an early manifestation of ischemic injury. Am J Pathol. 1977;87(1):159–188. 31. Higgins CB, et al. Nuclear magnetic resonance imaging of acute myocardial infarction in dogs: alterations in magnetic relaxation times. Am J Cardiol. 1983;52(1):184–188. 32. McNamara MT, et al. Detection and characterization of acute myocardial infarction in man with use of gated magnetic resonance. Circulation. 1985;71(4):717–724. 33. Friedrich MG. Tissue characterization of acute myocardial infarction and myocarditis by cardiac magnetic resonance. J Am Coll Cardiol Imag. 2008;1:652–662. 34. Marie PY, et al. Detection and prediction of acute heart transplant rejection with the myocardial T2 determination provided by a blackblood magnetic resonance imaging sequence. J Am Coll Cardiol. 2001;37(3):825–831. 35. Abdel-Aty H, et al. Edema as a very early marker for acute myocardial ischemia: a cardiovascular magnetic resonance study. J Am Coll Cardiol. 2009;53(14):1194–1201.


36. Abdel-Aty H, et al. Delayed enhancement and T2-weighted cardiovascular magnetic resonance imaging differentiate acute from chronic myocardial infarction. Circulation. 2004;109(20):2411–2416. 37. Abdel-Aty H, Simonetti O, Friedrich MG. T2-weighted cardiovascular magnetic resonance imaging. J Magn Reson Imaging. 2007;26(3):452–459. 38. Sharkey SW, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation. 2005;111(4):472–479. 39. Friedrich MG, et al. Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation. 1998;97(18):1802–1809. 40. Mahrholdt H, et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation. 2004;109(10):1250–1258. 41. Aletras AH, et al. Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation. 2006;113(15):1865–1870. 42. Dymarkowski S, et al. Value of t2-weighted magnetic resonance imaging early after myocardial infarction in dogs: comparison with bis-gadolinium-mesoporphyrin enhanced T1-weighted magnetic resonance imaging and functional data from cine magnetic resonance imaging. Invest Radiol. 2002;37(2):77–85. 43. Nilsson JC, et al. Sustained postinfarction myocardial oedema in humans visualised by magnetic resonance imaging. Heart. 2001;85(6):639–642. 44. Schulz-Menger J, et al. Cardiovascular magnetic resonance of acute myocardial infarction at a very early stage. J Am Coll Cardiol. 2003;42(3):513–518. 45. Friedrich MG, et al. The salvaged area at risk in reperfused acute myocardial infarction as visualized by cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51(16):1581–1587. 46. Stork A, et al. Comparison of an edema-sensitive HASTE-TIRM sequence with delayed contrast enhancement in acute myocardial infarcts. Rofo. 2003;175(2):194–198. 47. Mahrholdt H, et al. Reproducibility of chronic infarct size measurement by contrast-enhanced magnetic resonance imaging. Circulation. 2002;106(18):2322–2327. 48. Wagner A, et al. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet. 2003;361(9355):374–379. 49. Pennell D. Myocardial salvage: retrospection, resolution, and radio waves. Circulation. 2006;113(15):1821–1823. 50. Choi KM, et al. Transmural extent of acute myocardial infarction predicts long-term improvement in contractile function. Circulation. 2001;104(10):1101–1107. 51. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81(4):1161–1172. 52. Basso C, et al. Morphologic validation of reperfused hemorrhagic myocardial infarction by cardiovascular magnetic resonance. Am J Cardiol. 2007;100(8):1322–1327. 53. Porto I, et al. Relation of myocardial blush grade to microvascular perfusion and myocardial infarct size after primary or rescue percutaneous coronary intervention. Am J Cardiol. 2007;99(12):1671–1673. 54. Wu KC, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation. 1998;97(8):765–772. 55. Hombach V, et al. Sequelae of acute myocardial infarction regarding cardiac structure and function and their prognostic significance as assessed by magnetic resonance imaging. Eur Heart J. 2005;26(6):549–557. 56. Shiga T, et al. Diagnostic accuracy of transesophageal echocardiography, helical computed tomography, and magnetic resonance imaging for suspected thoracic aortic dissection: systematic review and meta-analysis. Arch Intern Med. 2006;166(13):1350–1356.

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57. Schoepf UJ, Goldhaber SZ, Costello P. Spiral computed tomography for acute pulmonary embolism. Circulation. 2004;109(18): 2160–2167. 58. Gosalia A, et al. CT detection of acute myocardial infarction. AJR Am J Roentgenol. 2004;182(6):1563–1566. 59. Lessick J, et al. Diagnostic accuracy of myocardial hypoenhancement on multidetector computed tomography in identifying myocardial infarction in patients admitted with acute chest pain syndrome. J Comput Assist Tomogr. 2007;31(5):780–788. 60. Gerber BL, et al. Characterization of acute and chronic myocardial infarcts by multidetector computed tomography: comparison with contrast-enhanced magnetic resonance. Circulation. 2006;113(6):823–833. 61. Baks T, et al. Multislice computed tomography and magnetic resonance imaging for the assessment of reperfused acute myocardial infarction. J Am Coll Cardiol. 2006;48(1):144–152. 62. Lardo AC, et al. Contrast-enhanced multidetector computed tomography viability imaging after myocardial infarction: characterization of myocyte death, microvascular obstruction, and chronic scar. Circulation. 2006;113(3):394–404. 63. Nieman K, et al. Reperfused myocardial infarction: contrastenhanced 64-section CT in comparison to MR imaging. Radiology. 2008;247(1):49–56. 64. Habis M, et al. Acute myocardial infarction early viability assessment by 64-slice computed tomography immediately after coronary angiography: comparison with low-dose dobutamine echocardiography. J Am Coll Cardiol. 2007;49(11):1178–1185. 65. Sato A, et al. Early validation study of 64-slice multidetector computed tomography for the assessment of myocardial viability and the prediction of left ventricular remodelling after acute myocardial infarction. Eur Heart J. 2008;29(4):490–498. 66. Herzog BA, et al. Accuracy of low-dose computed tomography coronary angiography using prospective electrocardiogram-triggering: first clinical experience. Eur Heart J. 2008;29(24):3037–3042. 67. Husmann L, et al. Feasibility of low-dose coronary CT angiography: first experience with prospective ECG-gating. Eur Heart J. 2008;29(2):191–197. 68. Steigner ML, et al. Narrowing the phase window width in prospectively ECG-gated single heart beat 320-detector row coronary CT angiography. Int J Cardiovasc Imaging. 2009;25(1):85–90. 69. Maruyama T, et al. Radiation dose reduction and coronary assessability of prospective electrocardiogram-gated computed tomography coronary angiography: comparison with retrospective electrocardiogram-gated helical scan. J Am Coll Cardiol. 2008;52(18):1450–1455. 70. Khaw BA. The current role of infarct avid imaging. Semin Nucl Med.1999;29(3):259–270. 71. Flotats A, Carrio I. Non-invasive in vivo imaging of myocardial apoptosis and necrosis. Eur J Nucl Med Mol Imaging. 2003;30(4):615–630. 72. Okada RD, et al. Myocardial kinetics of technetium-99m-hexakis-2methoxy-2-methylpropyl-isonitrile. Circulation. 1988;77(2):491–498. 73. Heller GV, et al. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with

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acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol. 1998;31(5):1011–1017. 74. Kontos MC, et al. Comparison of myocardial perfusion imaging and cardiac troponin I in patients admitted to the emergency department with chest pain. Circulation. 1999;99(16):2073–2078. 75. Varetto T, et al. Emergency room technetium-99m sestamibi imaging to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardiograms. J Am Coll Cardiol. 1993;22(7):1804–1808. 76. Klocke FJ, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation. 2003;108(11):1404–1418. 77. Gibbons RJ, et al. The quantification of infarct size. J Am Coll Cardiol. 2004;44(8):1533–1542. 78. Gibbons RJ, et al. Myocardium at risk and infarct size after thrombolytic therapy for acute myocardial infarction: implications for the design of randomized trials of acute intervention. J Am Coll Cardiol. 1994;24(3):616–623. 79. Dakik HA, et al. Assessment of myocardial viability with 99mTcsestamibi tomography before coronary bypass graft surgery: correlation with histopathology and postoperative improvement in cardiac function. Circulation. 1997;96(9):2892–2898. 80. Medrano R, et al. Assessment of myocardial viability with 99mTc sestamibi in patients undergoing cardiac transplantation. A scintigraphic/pathological study. Circulation. 1996;94(5):1010–1017. 81. Christian TF, et al. Relation of left ventricular volume and function over one year after acute myocardial infarction to infarct size determined by technetium-99m sestamibi. Am J Cardiol. 1991;68(1):21–26. 82. Christian TF, et al. Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarction: identification of myocardial stunning and hyperkinesia. J Am Coll Cardiol. 1990;16(7):1632–1638. 83. Behrenbeck T, et al. Primary angioplasty in myocardial infarction: assessment of improved myocardial perfusion with technetium-99m isonitrile. J Am Coll Cardiol. 1991;17(2):365–372. 84. Miller TD, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation. 1995;92(3):334–341. 85. Burns RJ, et al. The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J Am Coll Cardiol. 2002;39(1):30–36. 86. Miller TD, et al. Usefulness of technetium-99m sestamibi infarct size in predicting posthospital mortality following acute myocardial infarction. Am J Cardiol. 1998;81(12):1491–1493. 87. Ndrepepa G, et al. Prognostic value of myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction. J Nucl Med. 2004;45(5):725–729.

4

Noninvasive Imaging in Patients With Suspected Unstable Angina or Non-ST Elevation MyocardialÂ€Infarction

Benjamin W. Kron Ke vin Wei

Each year in the United States, over 5 million patients present to emergency departments (EDs) complaining of chest pain (CP). The cause of these symptoms may range from benign musculoskeletal problems to life-threatening conditions such as acute myocardial infarction (AMI), aortic dissection, or acute pulmonary embolism. Although most patients end up having minor causes of CP, the significant morbidity and mortality associated with these latter conditions and the inability of physicians to definitively exclude those using simple bedside tools results in most of these patients undergoing prolonged observation and extensive workups prior to discharge. Because of the difficulty in establishing or excluding the presence of a severe cause for a patient’s CP, much attention has been focused on the use of ancillary noninvasive imaging to assist in the triage and risk stratification of these patients. Of the serious causes of CP noted above, cardiac CP is the most frequent [1–3]. An acute coronary syndrome (ACS) is the result of myocardial ischemia (a lack of blood flow to the heart resulting in tissue hypoxia) and encompasses a wide spectrum of presentations from unstable angina (UA) to ST elevation myocardial infarction (STEMI). Patients with new left bundle branch block on the 12-lead electrocardiogram (ECG), 0.2 mV ST elevation in anteroseptal leads, or 0.1 mV elevation in other leads can be classified as STEMI and are candidates for immediate reperfusion therapy with fibrinolysis or percutaneous coronary intervention [4]. Ancillary imaging is not required in such patients to make a diagnosis and should not be considered in order to facilitate urgent reperfusion. Unfortunately, the majority of patients with an ACS do not present as a STEMI. In a study of 3814 patients presenting with CP to the ED, 93% of the presenting ECGs were called normal or nondiagnostic. In those patients whose presenting ECG showed only early 58

repolarization, nondiagnostic changes, or was normal, the rate of death, AMI, or revascularization at 30 days was as high as 23% [5]. Thus, a benign ECG at the time of presentation does not confer a good prognosis. The history, physical examination, ECG, and serum cardiac biomarkers are currently the main tools used to determine if a patient is presenting with an ACS. These findings are also used to provide initial risk stratification. Features that suggest a high likelihood of ACS include patients whose presenting symptoms are similar to previously documented angina, especially in those with a known history of coronary disease or prior myocardial infarction, findings on examination of hemodynamic compromise or heart failure, ECG abnormalities such as new or dynamic ST segment depression or deep T-wave inversion, or elevated serum cardiac biomarkers [6]. Most patients in whom a definitive diagnosis of ACS is established also do not generally require noninvasive imaging and should be managed according to published guidelines. The majority of patients presenting with an ACS, however, lack the symptoms or ECG findings noted above. Elevated levels of cardiac biomarkers are the gold standard for determining the presence of myocellular necrosis, but their kinetics of release into the serum makes them insensitive until many hours after the onset of symptoms [7]. Single determinations of creatinine kinase (CK) at the time of patient presentation have a sensitivity of only 36% for detecting AMI. The sensitivity increases to 69% at 4 hours, and to 95% to 99% by 15 hours [7]. Likewise, cardiac troponins and myoglobin also have limited sensitivity early after the onset of ischemia. Because of the time-dependent nature of ACS, this delay in the diagnosis and risk stratification of patients may worsen their outcome because definitive treatment is not initiated promptly. Serum cardiac biomarker release is also not specific for ischemic injury and may be abnormally elevated in myocarditis, congestive heart failure, or increased myocardial demand [8–10]. Thus, physicians still depend on unreliable parameters such as a patient’s presenting symptoms and physical findings to determine if they have an ACS.

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Noninvasive Imaging in Patients With Suspected Unstable Angina or Non-ST Elevation Myocardial Infarction

Because the diagnosis or exclusion of an ACS is difficult, the current process is often prolonged and requires monitoring in an ED, CP center, or step-down unit, with repeated sets of blood work for cardiac serum markers. It has been estimated that the cost of excluding ACS in patients with CP is between 8 and 10 billion dollars annually in the United States alone. Despite these huge resources, up to 11% of patients are inadvertently discharged from the ED with a missed AMI (average 2.1%), and UAP is missed in up to 4% [11–13]. This misdiagnosis and inappropriate discharge leads to increased mortality for those patients who have an AMI outside the hospital [13]. A diagnostic tool that could improve our ability to detect or exclude ACS in patients with CP but without definitive ECG changes (ST elevation, ST depression, or deep T inversions on the initial ECG), or elevated cardiac serum markers, would therefore be invaluable. In recent years, 2-dimensional (2D) echocardiography, single photon emission computed tomography (SPECT), cardiac magnetic resonance imaging (CMR), and multidetector computed tomography (MDCT) have been evaluated for this purpose.

jâ•…PATHOPHYSIOLOGY OF ACSS AND IMPLICATIONS FOR IMAGING Due to the autoregulatory capacity of the coronary microcirculation, resting myocardial blood flow (MBF) remains constant over a wide range of coronary driving pressures [14]. Consequently, MBF does not fall below normal resting levels until a coronary obstruction exceeds 85% to 90% of the luminal area of an epicardial coronary artery [15]. With such critical stenoses, supply-demand mismatch can result in angina occurring at rest, which is 1 of the 3 principal presentations of UA [6]. Other manifestations of UA include accelerated angina (increased frequency, duration, or onset at a lower threshold) or new-onset angina of at least Canadian Cardiovascular Class III severity [16]. The coronary lesion most commonly associated with the development of an ACS is characterized by erosion or disruption of an atherosclerotic plaque, which brings about a series of pathological processes that decrease MBF. Early atherosclerotic lesions demonstrate upregulation of adhesion molecules on the endothelial cell surface [17], resulting in infiltration of inflammatory cells into the arterial wall. Once there, monocytes develop into macrophages as they ingest oxidized low-density lipoprotein and differentiate into foam cells. Macrophages and lipid-laden foam cells produce cytokines that weaken the fibrous cap of an atherosclerotic lesion through inhibition of collagen production by smooth muscle cells, as well as from the production of matrix metalloproteinases, which degrade collagen [18]. Destabilization of the fibrous plaque and plaque rupture result in exposure of the necrotic lipid core to circulating blood, with resultant thrombus formation. The development

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of a thrombus, which is usually nonocclusive, but is critical enough to reduce resting MBF or severely limit coronary flow reserve leads to an ACS. UA and non-ST elevation MI (NSTEMI) share the same pathophysiology and are part of a continuum, with NSTEMI being a more serious manifestation of the process. An NSTEMI is associated with myocardial injury that will cause the release of detectable quantities of biomarkers. If no biomarker has been released, indicating necrosis, the patient is determined to have UA [6]. There are a number of other pathophysiological mechanisms that can lead to UA and NSTEMI, which are less common than plaque rupture and acute thrombosis. Intense focal spasm of a segment of an epicardial coronary artery caused by endothelial dysfunction and/or hypercontractility of vascular smooth muscle can result in an ACS. Large-vessel spasm can occur on top of nonobstructive plaque as well. Resting perfusion can also be compromised by the development of a coronary artery dissection. Lastly, there is secondary UA, where the precipitating condition is extrinsic to the coronary arterial bed. Patients with secondary UA often have chronic stable angina with an underlying coronary atherosclerotic narrowing, which results in partial exhaustion of coronary vasodilatory reserve. Secondary UA can then be precipitated by conditions that cause an increase in myocardial oxygen requirements, such as tachycardia, severe hypertension, hyperthyroidism, anemia, and so forth.

jâ•…I MAGING METH ODS FOR DETECTION OF ACSS Based on the pathophysiology outlined above, noninvasive imaging techniques have focused on the detection of either anatomically significant coronary artery disease (CAD), reduced perfusion to myocytes, or the consequences of abnormal perfusion (eg, abnormal cardiac function) in order to detect UA or NSTEMI.

jâ•…A SSESSMENT OF WALL THICKENING 2D echocardiography, CMR, computed tomography (CT), and gated SPECT can all be used to evaluate wall thickening (WT), which is closely dependent on resting MBF. Because myocardial contractility is a major determinant of myocardial oxygen consumption, reductions in resting MBF are followed within seconds by the development of hypokinesis. Figure 4.1 illustrates the close coupling that exists between resting MBF and WT [19]. Normal resting MBF (1 mL/kg/min) is associated with WT of approximately 30%. With acute reductions in resting MBF, WT abnormalities develop within seconds. Thus, the assessment of WT provides an indirect measure of the presence of myocardial ischemia.

6 0 Multimodality Imaging in Cardiovascular Medicine

F igure 4 . 1 â•…Relation between resting myocardial blood flow (MF) and wall thickening. Adapted from Ref. 19.

F igure 4 . 2 â•…Relation between myocardial blood flow (MBF) and myocardial uptake of nuclear tracers. Adapted from Ref. 25.

In patients who suffer only transient ischemia, even a brief coronary occlusion (5–15 minutes) results in severely reduced regional systolic function [19]. These functional changes occur briskly and are evident for hours after the initial insult, despite reperfusion, and may take up to 48 hours to normalize [20–22]. The duration and severity of systolic dysfunction (myocardial stunning) directly relate to the duration of ischemic insult, severity of the insult, and the adequacy of reperfusion [20–22].

a contrast agent bolus, ischemic myocardium will demonstrate slow wash-in of contrast and relative hypoperfusion compared to normally perfused tissue [27]. As shown in Figure 4.4, the excellent spatial resolution of CMR can easily delineate the subendocardial location of such defects. The contrast agents that now enable perfusion imaging during echocardiography are composed of microbubbles of high–molecular weight gas (mainly perfluorocarbons currently), encapsulated within a thin shell. Within an ultrasound field, nonlinear oscillation and destruction of microbubbles produces signals that are unique from myocardial tissue. These signals can be selectively received by novel imaging modalities designed specifically for myocardial contrast echocardiography (MCE). Unlike the contrast agents used with CT, CMR, or SPECT, microbubbles remain entirely intravascular, are hemodynamically inert, and have a microvascular rheology identical to that of red blood cells. These properties make microbubbles unique perfusion agents and obviate the need for complex modeling that is required with many other technologies for

jâ•…M YOCARDIAL PERFUSION IMAGING Perfusion imaging with SPECT most often utilizes thallium 201 or 99mTechnetium (99mTc). Thallium 201 is a potassium analog with myocardial uptake that is partly dependent on the Na-K-ATPase pump and is directly proportional to MBF [23]. Following its uptake, there is continued exchange between the myocytes and the extracellular space, resulting in redistribution of thallium over time [23]. 99mTc-sestamibi and tetrofosmin are lipophilic monovalent cations that diffuse passively across plasma and mitochondrial membranes and are sequestered by the large negative membrane potential of mitochondria where they demonstrate no significant redistribution [24]. The relation between MBF and tracer uptake over a wide range of flow rates is shown in Figure 4.2. The uptake of an ideal tracer is completely linear over a wide range of flows (line C), while the uptake of thallium (line B) and 99m Tc-sestamibi (line A) plateau at hyperemic flows [25]. Both thallium and 99mTc-sestamibi, however, demonstrate uptake that is directly proportional to MBF when MBF is reduced below normal resting levels—similar to an ideal tracer [25]. Thus, injection of either tracer in a patient with CP should demonstrate perfusion defects if there is resting ischemia in the setting of an ACS (Figure 4.3). Perfusion CMR uses ultrafast, time-resolved T1-weighted data sets acquired during a bolus injection of gadolinium contrast [26]. Based on first-pass kinetics of

F igure 4 . 3 â•… Horizontal long-axis view of the left ventricle demonstrat-

ing a resting lateral defect (arrow) using emission computed tomography.

Tc-sestamibi single photon

99m

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F igure 4 . 4 â•… Short-axis cardiac magnetic resonance image demonstrating a subendocardial inferior defect (arrow).

quantifying MBF. During a continuous infusion, microbubbles within the myocardial microcirculation can be destroyed using high-power ultrasound, and their subsequent replenishment of tissue is dependent on MBF velocity. Ischemic myocardial segments with low resting flow demonstrate resting perfusion defects (Figure 4.5).

j â•…N ONINVASIVE CORONARY ANGIOGRAPHY Noninvasive assessment of the coronary arteries has been most successful using cardiovascular CT angiography (CCTA). The use of 64-slice MDCT scanners has

F igure 4 . 6 â•… Severe mid right coronary artery stenosis (arrow) detected using 64-slice multidetector computed tomography.

shown excellent accuracy for diagnosing CAD. Newer dual-source 64-slice MDCT and 256-slice detectors may Â�further improve temporal resolution and volume coverage, respectively [28]. Cardiac MDCT offers submillimeter isotropic resolution, typically in the range of 400 μm. A typical CCTA can be performed with 60 to 80 mL of contrast media and a breath-hold spell of ,10 seconds. In order to achieve high contrast enhancement in this short time, a contrast agent with a high concentration of iodine (eg, 370 mgI/mL) should be used, along with a test injection or automated threshold-based bolus to ensure proper timing [28]. A saline flush should be performed immediately after administration of contrast to maintain a tight contrast bolus and decrease the total volume of contrast that is needed for the study [29]. Figure 4.6 shows an example of a patient with suspected cardiac CP who was found to have a severe mid right coronary artery stenosis on CCTA.

jâ•…D IAGNOSTIC AND PROGNOSTIC UTILITY OF NONINVASIVE IMAGING FOR PATIENTS WITH SUSPECTED ACSS Echocardiography

F igure 4 . 5 â•…Apical 3-chamber view showing a dense resting perfusion defect involving the mid to apical septum (arrowheads) using harmonic power Doppler imaging and Definity.

As mentioned above, 2D echocardiography detects a new ACS based on the relationship between MBF and regional WT—a new regional wall motion abnormality is an early manifestation of ischemia. It has been shown that even after a brief coronary occlusion (5–15 minutes), regional systolic function is severely reduced [30]. These functional changes

62 Multimodality Imaging in Cardiovascular Medicine

occur briskly and are evident for hours after the initial insult, despite reperfusion, and may take up to 48 hours to normalize [30–34]. The duration and severity of systolic dysfunction directly relates to the duration of ischemic insult, severity of the insult, and the adequacy of reperfusion [31–35]. In order to have high sensitivity, it is of utmost importance to clearly visualize each myocardial segment, so the use of contrast agents for left ventricular endocardial border delineation is critical for this application of echocardiography. Furthermore, as noted below, myocardial perfusion imaging using MCE can provide incremental prognostic utility. Several studies have evaluated MCE in the evaluation of patients presenting with CP but no ST elevation in the ED. A multicenter, prospective study compared MCE and SPECT to diagnose AMI and risk stratify 203 patients for the development of hard cardiovascular end points (AMI, urgent revascularization, or death) within 48 hours [36]. MCE was found to be equivalent to SPECT in Â�diagnosing AMI but was inferior with respect to predicting other adverse cardiac events. Both MCE and SPECT added significant additional information (17% and 23.5%, respectively) for diagnosis and short-term prognosis over routine clinical methods (ECG, history, and risk factors). This study demonstrated for the first time the incremental value of MCE in the diagnosis and short-term prognosis of AMI. The assessment of myocardial perfusion played a dominant role in the value of MCE. Surprisingly, the evaluation of regional function (RF) was less powerful. The use of bolus administration of the microbubble contrast agent could have resulted in far-field attenuation and affected the assessment of RF. Additionally, UA was not included as an end point, which may have underestimated the diagnostic and prognostic capabilities of MCE in this study. Both wall motion and perfusion with MCE were used to evaluate 100 patients with first-time CP to demonstrate the ability of MCE to detect ACSs (UA, NSTEMI) compared to traditional clinical tests [37]. Those with ST elevation, known CAD, or previous myocardial infarction were excluded. Contrast agents were administered as a slow bolus, and MCE was performed using low mechanical index real-time imaging. Thirty-seven patients were diagnosed with an ACS. An abnormal MCE exam was the most powerful predictor of an ACS (89% sensitivity, 93% specificity, P , .001). Myocardial perfusion was superior to wall motion analysis for detecting an ACS. In 21 patients, MCE was performed before the initial troponin data were available, and 95/98 underwent MCE before follow-up troponins were performed—MCE can thus identify high-risk patients more quickly than the use of serum cardiac markers. In 2 patients with abnormal troponin values, MCE was found to be normal but identified the presence of pericardial Â�effusions. Subsequent angiography was also normal and these individuals were diagnosed with perimyocarditis— demonstrating the excellent negative predictive value of MCE. The use of MCE further strengthened the findings in a prospective study of 114 patients presenting to the

emergency room with suspected cardiac CP [38]. The main study end point was the diagnosis of an ACS. Patients who had Q waves on ECG or a history of myocardial infarction were excluded. All patients underwent MCE and coronary angiography in addition to ECG and serologic testing. Microbubbles were administered using a more contemporary continuous infusion method. An ACS was diagnosed in 87 patients. Myocardial perfusion defects demonstrated 77% sensitivity for the detection of ACS compared to 28% and 34%, respectively, with ECG and troponin, while maintaining similar specificity (89%–96%). Abnormal myocardial perfusion was the only independent variable for diagnosing an ACS (odds ratio 87, P , .001). RF was not as powerful as perfusion for predicting an ACS, but was more sensitive than ST changes or troponin alone (65% compared to 33% and 54%, respectively). This study similarly found incremental benefits for MCE over ECG and cardiac biomarkers in the setting of suspected cardiac CP. The largest study to date evaluating MCE in patients with CP included 1017 patients presenting to the ED who were .30 years of age, with CP lasting at least 30 minutes occurring within the previous 12 hours. Primary end points included all-cause mortality and acute MI. Secondary end points included revascularization or UA (typical CP, dynamic ECG changes, and/or mild troponin elevation). Late prognostic utility was also evaluated and patients were followed up for up to 2 years. MCE was performed with a continuous infusion of microbubbles, and images were interpreted separately for RF and myocardial perfusion by experienced clinicians blinded to all clinical information. In contradistinction to the last few studies presented, patients with a prior MI were not excluded from enrollment. The short-term and long-term prognostic significance of MCE on primary and secondary cardiovascular end points were determined in the study from Rinkevich et al [39]. Total short-term events (48 hours) were noted in 16% of patients, 9% of whom had AMI. Patients with abnormal RF were 6-fold more likely to have an early event compared to those with normal function. Patients with abnormal perfusion were 2.5-fold more likely to have an adverse event, but those with both abnormal RF and myocardial perfusion were 14.3-fold (P , .001) more likely to have events, demonstrating the incremental benefit of combined WT and perfusion data over RF alone in these patients. Similar findings were noted over late follow-up where patients with abnormal RF had a 5-fold increased incidence of an adverse event compared to those with normal function, and the patients with both abnormal perfusion and function were at the highest risk of adverse events (10-fold increase). In clinical practice, it is important not only to diagnose an ACS, but to risk stratify patients appropriately for decisions regarding triage and management. A commonly used clinical tool is the thrombolysis in myocardial infarction (TIMI) risk score [40]. However, because there is an inherent delay in obtaining serum cardiac biomarker data, a full TIMI risk score cannot be derived in patients at the

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time of a patient’s presentation to the ED. MCE may therefore provide better risk stratification early in the assessment of CP patients than even a composite risk score. This hypothesis was evaluated by Tong et al [41]. Normal RF and perfusion on MCE were used to identify a low-risk population (adverse event rate of 0.4%) and were found to have a better negative predictive value than the TIMI score without troponins (2% adverse event rate in patients with a modified TIMI score of 0–1). As shown in Figure 4.7, even when patients are considered low risk by clinical criteria, MCE can further subdivide those patients into low-, Â�intermediate-, and high-risk groups based on their RF and myocardial perfusion findings. The same holds true for patients who are clinically intermediate risk (Figure 4.8). Although the ability of MCE to detect a patient with an ongoing ACS or AMI is excellent, RF and myocardial perfusion abnormalities may resolve in patients with only transient ischemia, especially if there is a significant delay between the

Event-Free Survival

1.0 Nl RF + MCE (n=350)

0.8

Ab RF + Nl MCE (n=91)

0.6

Ab RF + Ab MCE (n=85)

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

18

20

22

24

Follow-up(months) F igure 4 . 7 â•…Risk stratification of chest pain patients who are clinically low risk (modified thrombolysis in myocardial infarction score 0–2) based on results of contrast echocardiography. Nl, normal; Ab, abnormal; RF, regional function; MCE, myocardial contrast echocardiography. Adapted from Ref. 41.

1.0

Event-Free Survival

0.8

Nl RF + MCE (n=114)

0.6

Ab RF + Nl MCE (n=41)

0.4 Ab RF + MCE (n=87)

0.2

0.0

0

2

4

6

8

10

12

14

16

18

20

22

24

Follow-up(months) F igure 4 . 8 â•…Risk stratification of chest pain patients who are clinically intermediate risk (modified thrombolysis in myocardial infarction score 3–4) based on results of contrast echocardiography. Nl, normal; Ab, abnormal; RF, regional function; MCE, myocardial contrast echocardiography. Adapted from Ref. 41.

63

ischemic episode and imaging. The effect of the timing of MCE and patient presentation were evaluated in a study where the patients were divided into 4 quartiles (0, 1, 4, and 12 hours) based on their last episode of CP [42]. The negative predictive value of MCE was found to remain extremely high (94% for the development of any cardiac event) even up to 12 hours after CP had resolved [42]. Thus, even in the setting of Â�spontaneous reperfusion and restoration of normal antegrade flow, the presence of myocardial stunning in patients who have suffered significant ischemia persists for many hours. The cost associated with the performance of echocardiography (especially if contrast is used for every case) is substantial. It has been shown, though, that by reducing the number of unnecessary admissions to hospital and other downstream costs for low-risk patients, MCE is cost-efficient and can even reduce the costs of managing patients with undifferentiated CP by as much as $900 per patient [43]. One of the limitations of echocardiography is that the positive predictive value of MCE was found to be only 34% when patients with prior MI were not excluded, because the presence of existing wall motion abnormalities confounds their evaluation [42]. Since many patients have a history of prior cardiac events, it is unsatisfactory to exclude a significant proportion of patients from potentially beneficial technology. Another way to determine if an abnormality is new is to compare with a previous MCE study, but many patients do not have prior studies for comparison. In the future, it may be possible for microbubbles to detect specific molecular events within the circulation. In ischemiareperfusion injury, inflammation is prominent. By changing the surface of microbubbles, they can be made to stick and accumulate at sites of inflammation by attaching to upregulated molecules there. Specific targeted microbubbles have been developed with robust attachment to activated leukocytes, or even to the endothelial surface itself. Strategies that have been used include the addition of phosphatidylserine to the lipid shell to increase complement deposition [44] or the conjugation of specific ligands (such as monoclonal antibodies or peptides) to the microbubble surface [45,46]. This technique has been used to specifically image the molecular mediators of leukocyte recruitment such as the selectins, ICAM-1, VCAM-1, and MAdCAM-1. The ability of MCE to detect regional Â�myocardial Â�inflammation was tested in an animal Â�experimental model of left anterior descending coronary artery occlusion for 90 Â�minutes followed by reperfusion [44]. Phosphatidylserinelipid–shelled microbubbles targeted to activated leukocytes were injected 60 minutes after reperfusion followed by imaging 15 Â�minutes later. Figure 4.9 shows the MCE images (Panel A), and a 2,3,5- Â�triphenyltetrazolium chloride–stained slice of Â�myocardium (to delineate infarction, panel B). The short-axis background-subtracted color-coded MCE image demonstrates an area of contrast enhancement (green and red) from retained targeted microbubbles. The location and spatial extent of inflammation on MCE includes not only the area of Â�myocardial Â�necrosis (panel B) but also


F igure 4 . 9 â•…Myocardial contrast echocardiography using microbubbles targeted to P-selectin (panel A, yellow arrowheads), and the corresponding triphenyltetrazolium– stained myocardium denoting subendocardial infarction (panel B, black arrowheads). Adapted from Ref. 44.

the surrounding ischemic myocardium that was salvaged by reperfusion. Even up to 120 Â�minutes after reperfusion, such MCE images of ischemic memory should be able to define the presence of recent ischemia, but significant delays between the event and imaging may limit the sensitivity of even MCE. Such issues still require further study. Real-time 3D echocardiography is an emerging technique that has the potential to enhance cardiac functional assessment [47,48]. 2D echocardiography and MCE can be limited by the inability to visualize all wall segments, and the necessity of mentally reconstructing multiple images in the 2D plane. 3D echocardiography makes it possible to instantly obtain 3D imaging of the heart. This technique ensures identification of all wall segments and is potentially more sensitive in identifying small wall motion abnormalities. The role of 3D echo and its benefits over MCE have not been evaluated in patients with CP. Some advantages of MCE over other potential modalities are its cost, its speed, and its transportability. It is smaller and portable, compared to SPECT, CMR, and CT. Echo is also relatively cheap compared to these other Â�methods. No image processing is required. Limitations would include Â�operator-dependent image quality, lack of Â�quantitative Â�variables for evaluation, and inadequate acoustic Â�windows in some patients despite using contrast. In the last year, the safety of ultrasound contrast agents was brought into Â�question by the US Food and Drug Administration (FDA). A number of large database reviews have now shown that ultrasound contrast agents are extremely safe, even in critically ill patients [49,50]. Currently, the FDA still recommends 30 minutes of observation with ECG and O2 saturation monitoring in acutely ill patients who have received ultrasound contrast agents. Single Photon Emission Computed Tomography Because SPECT relies on the principal that a reduction in resting MBF is associated with a proportionate decrease in the uptake of nuclear perfusion tracers, the detection of acute cardiac

ischemia with this technique makes pathophysiologic sense. With 99mTc-based agents, patients can be imaged at a later time point after injection, because the lack of redistribution after initial injection still reflects MBF at the time of injection. Therefore, this technique provides an assessment of reduced resting MBF, through detection of these tracers. Reduced resting MBF is the underlying cause of myocardial ischemia so this technique effectively evaluates myocardial ischemia. Table 4.1 shows a list of studies utilizing nuclear imaging in patients with CP, along with their overall sensitivity, specificity, and negative predictive value for diagnosing AMI in the ED [51–57]. The sensitivity for detecting AMI ranged from 90% to 100% with negative predictive values of 99% to 100%. The limited specificity is a result of an inability of 99mTc-SPECT to distinguish between new and old infarctions. Although the studies above confirmed the diagnostic potential of SPECT, they did not address the impact of SPECT on clinical decision making. This issue was evaluated in a large randomized study where patients were randomized to either usual care or a scan strategy that incorporated results derived from immediate resting 99m Tc-SPECT perfusion imaging [57]. All patients presented with symptoms suggestive of acute cardiac ischemia within 3 hours of consent and had a normal or nondiagnostic initial ECG. In patients eventually diagnosed with ACS, there was no difference in appropriate hospital admission rates between the 2 groups. However, in patients without ACS, the number of unnecessary admissions to the CCU, telemetry ward, or CP unit was reduced from 52% to 42% (20% relative reduction, P , .001) [57]. SPECT was also found to risk stratify patients appropriately in this study—the incidence of AMI was 0.6%, 0.8%, and 10.3% in patients with normal, equivocal, and abnormal scans, respectively [57]. In addition to detecting perfusion defects, 99mTcsestamibi SPECT using gated acquisition and reconstruction have the added advantage of assessing regional and global ventricular functions [58,59]. The evaluation of ventricular function also provides prognostic as well as diagnostic information in patients. A multicenter study showed that the evaluation of wall motion and perfusion together

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65

jâ•… Table 4.1â•…Nuclear imaging in patients presenting to the emergency department with chest pain and a nondiagnostic ECG Study

Agent

N

Sensitivity (%)

Specificity (%)

NPV (%)

End Point

Varetto et al [51]

MIBI

â•‡â•‡ 62

100

92

100

CAD

Hilton et al [52]

MIBI

â•‡ 102

â•‡ 94

83

â•‡ 99

CAD/AMI

Tatum et al [53]

MIBI

â•‡ 438

100

78

100

AMI

Kontos et al [54]

MIBI

â•‡ 532

â•‡ 93

71

â•‡ 99

AMI

Heller et al [55]

Tetrofosmin

â•‡ 357

â•‡ 90

60

â•‡ 99

AMI

Kontos et al [56]

MIBI

â•‡ 620

â•‡ 92

67

â•‡ 99

AMI

Udelson et al [57]

MIBI

1215

â•‡ 96

–

â•‡ 99

AMI

AMI, acute myocardial infarction; CAD, coronary artery disease; ECG, electrocardiogram; MIBI, 99mTc-sestamibi; Tetrofosmin, 99mTc-tetrofosmin; NPV, negative Â�predictive value.

provided greater diagnostic and prognostic value than perfusion alone [60]. Their data showed that patients who had both abnormal wall motion and perfusion defects were significantly more likely to have an AMI compared to those with perfusion defects alone. Although SPECT is an expensive technology, the use of SPECT in patients with acute CP in the ED could be cost effective. Similar to echo, if SPECT imaging leads to a patient not needing to be admitted, this will ultimately save money. As discussed above, the high negative predictive value of SPECT allows the identification of low-risk patients with noncardiac CP and results in a higher rate of direct discharge from the ED. It has been estimated that despite the added cost of imaging in all patients with CP, there can be an average reduction of costs of $70 per patient [61]. There are limitations of SPECT as well. Most of the studies enrolled mainly low-risk patients with a low incidence of events in this population, and so estimating the negative predictive value of SPECT may be overoptimistic. Secondly, most of these studies used CK or CK-MB as the gold standard for diagnosis of AMI rather than the more sensitive cardiac troponins. It is known that around 3% to 4% of the left ventricular myocardium must be ischemic for a perfusion defect to appear on SPECT [58]; thus, smaller ischemic events detectable only with troponins may not be detected by SPECT, making sensitivity lower. One study showed normal SPECT perfusion in 34% of CP patients who were eventually diagnosed with an ACS [55]. This study highlighted the limited ability of SPECT to detect UA and milder ischemic events that are troponin positive but CK-MB negative. Some of these milder events, however, may be detectable using abnormal WT from gated SPECT [60]. SPECT has many obvious advantages such as timetested durability, high sensitivity, combined benefits of evaluating both perfusion and ventricular function, standardized

imaging protocols, and well-established quantitative methods. From a logistic standpoint, though, an expert panel recently outlined the difficulties of nuclear perfusion imaging, which included decay and license issues, the need for isotope preparation, relative inaccessibility of nuclear laboratories in many hospitals, difficulties with single-image interpretation rather than the usual stress/rest images for comparison, and low spatial resolution [62]. Ongoing developments in nuclear imaging may continue to address some of the limitations currently associated with imaging for the detection of ACS. For example, many patients continue to present to the ED late after their onset of CP. The detection of myocardial ischemia may not be possible with the assessment of MP if spontaneous reperfusion and restoration of normal MBF has occurred, or with RF if stunning has resolved. In the setting of Â�myocardial ischemia, however, the myocardium shifts high-energy ATP production from fatty acid metabolism (which is the preferred metabolic pathway) to glucose utilization [63]. Studies have shown that imaging of an iodinated fatty acid analog, 15-(p-[iodine-123]iodophenylÂ� -3-(R,S)Â�methylpentadecanoic acid (BMIPP) using SPECT can identify previous severe ischemia as areas of reduced tracer uptake. BMIPP is trapped in cardiomyocytes with limited catabolism [64] and can be imaged clinically with labeling using 123I. Myocardial uptake of BMIPP after an ischemic insult is diminished due to reduced activation of fatty acids by coenzyme A and less fatty acid metabolism [63]. The ability of BMIPP SPECT to identify recent Â�ischemia in patients presenting with CP was evaluated in 111 patients [65]. BMIPP SPECT was performed 1 to 5 days after the disappearance of the last episode of CP. Abnormal BMIPP had greater sensitivity than tetrofosmin SPECT for identifying patients with ischemia due to fixed CAD, or vasomotor spasm. Thus, ischemic memory imaging may be one method of identifying patients with acute


cardiac causes of CP but no MI. It may also be a method that allows the differentiation of acute ischemia from remote events in the same patient. Cardiac Magnetic Resonance Imaging CMR has recently shown promising results in the evaluation of patients with CP. This technology does not expose the patient to ionizing radiation or iodinated contrast agents and has excellent spatial and temporal resolution, as well as intrinsic blood-tissue delineation without the need for administration of an exogenous agent, thus allowing the evaluation of global and regional wall motion abnormalities [66]. Valve structure and function, as well as regurgitant lesions can be assessed with dynamic cine (bright blood) imaging, and the severity of regurgitation can be semiquantitatively assessed from jet appearance or quantified volumetrically using velocity phase maps [67]. GadoliniumDTPA can be utilized to assess myocardial perfusion, and the introduction of delayed enhancement can determine the presence of viable versus infarcted myocardium [68–70]. The spatial distribution of delayed enhancement may also assist in differentiating ischemic heart disease from other cardiac pathologies. Newer pulse sequences (T2 fast spin echo) allow imaging of myocardial edema, which is particularly useful when evaluating patients with acute CP. The presence of myocardial edema in a patient presenting with acute CP is highly suggestive of ACS [71]. Although not as advanced in development as MDCT, magnetic resonance angiography can assess proximal and mid coronary artery segments and exclude significant CAD [72]. A recent meta-analysis comparing CMR to MDCT showed MDCT to be superior to CMR in evaluating coronary anatomy; however, CMR still provides moderate results including a sensitivity of 72% and specificity of 87% when compared with angiography [72]. It is worth pointing out that as with MDCT, a number of the coronary segments evaluated with CMR were excluded because of motion artifact. Thus, CMR possesses many attributes that make it a potentially excellent method for assessment of patients with suspected ACS. The use of CMR in the acute setting of the ED to evaluate patients with CP has been less well studied than other modalities presented above. In one study, 161 CP patients presenting to the ED with a nondiagnostic ECG underwent CMR within 12 hours of presentation for evaluation of MP and RF. CMR was shown to have a sensitivity of 84% and a specificity of 85% for detection of patients who had an AMI or UA [73]. The study found that the sensitivity and specificity of MRI was greater than an abnormal ECG (80% and 61%, respectively), strict ECG criteria for ischemia (16% and 95%, respectively), peak troponin-I (40% and 97%, respectively), and TIMI risk score >3 (48% and 85%, respectively) [73]. As with other modalities discussed previously, the limitation of using myocardial perfusion and WT with CMR

is an inability to differentiate acute from chronic ischemia. This limitation was recently addressed in a study where the incremental benefit of T2-weighted imaging for myocardial edema and left ventricular wall thickness analysis were added to standard CMR, which included cine wall motion, firstpass myocardial perfusion, and delayed-enhancement imaging [74]. In a cohort of 62 patients, standard CMR had 85% sensitivity, 84% specificity, 58% positive predictive value, and 95% negative predictive value, with overall diagnostic accuracy of 84% for detection of an ACS [74]. The addition of T2-weighted imaging and left ventricular wall thickness to standard CMR increased the positive predictive value to 85% and the overall accuracy to 93%, due to the ability to differentiate new ACS from prior MI and from the detection of UA [74]. The CMR signatures for UA included the presence of signal hyperintensity on T2-weighted images from myocardial edema, without delayed hyperenhancement or necrosis. Only 2 patients with UA were missed [74]. On the other hand, patients with NSTEMI had both T2-weighted hyperintensity as well as delayed hyperenhancement, while those with remote MI demonstrated wall thinning with no myocardial edema, and those with noncardiac CP had none of these abnormalities [74]. In future, phosphorus 31 spectra using nuclear magnetic resonance (31P-NMR) spectroscopy can potentially be used to detect one of the earliest metabolic derangements due to myocardial ischemia. Metabolic derangements develop early in the ischemic cascade, and maintenance of cellular levels of high-energy phosphates is needed to preserve myocardial function. With severe myocardial ischemia, there is a rapid loss of phosphocreatine and a decrease in the ratio of phosphocreatine to ATP [75]. Using CMR, myocardial energy metabolism can be assessed with 31P-NMR spectroscopy. The use of the phosphocreatine-to-ATP ratio to detect ischemia using 31P-NMR spectroscopy was evaluated in women admitted to hospital with CP who were found to have no significant CAD on angiography [76]. The change in Â�phosphocreatine-to-ATP ratio in this group was compared to normal controls, and to patients with known severe stenosis (.70%) of the left anterior descending coronary artery. Isometric handgrip exercise at 30% of maximal grip strength was used as the stressor. In the reference group, the phosphocreatine-to-ATP ratio decreased by 2.6%  10% during stress. The decrease was significantly greater in patients with CAD, where the phosphocreatine-to-ATP ratio dropped by 20%  11%. In patients with CP but normal coronary Â�arteries, 7 of the 35 women had a significant decrease in phosphocreatine-to-ATP ratio of 29%  5.1%, presumably due to diffuse CAD with no focal luminal stenosis or microvascular disease. In the WISE study, the detection of ischemia using the phosphocreatine-to-ATP ratio has been found to predict outcome in women with CP despite the absence of epicardial CAD. Patients with an abnormal ratio had Â�significantly higher rates of hospitalization for angina, catheterization, and treatment costs [77].

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Despite its strengths, a number of obstacles may prevent CMR from becoming as widely accepted a tool as other modalities, such as the inability to image patients with claustrophobia, highly complex and lengthy studies that may be tolerated poorly by acutely ill and symptomatic patients, and contraindications in patients with implanted devices. Some logistical challenges also exist, such as the limited availability of the technology to all hospitals or the limited number of systems in a particular hospital; at least in 1 study, about 5% of eligible patients were excluded because the system was being used for other urgent cases [74]. Computed Tomography The use of CCTA for the evaluation of patients with CP and nondiagnostic ECGs has been increasing as newer technology improves the diagnostic quality of the images. The use of 64-slice MDCT scanners has shown excellent accuracy for diagnosing CAD. Newer dual-source 64-slice MDCT and 256-slice detectors may further improve temporal resolution and volume coverage, respectively [78]. Cardiac MDCT now offers isotropic resolution in the range of 400 μm. These advances allow MDCT to evaluate coronary anatomy, ventricular function, and potentially myocardial perfusion, making it an attractive option for the evaluation of patients with suspected ACS. CT also has the added advantage of having a high sensitivity for detecting other serious causes of CP such as aortic dissection and pulmonary embolism. The ability to detect and quantify the severity of a coronary stenosis gives MDCT an added benefit over the other imaging modalities discussed so far. A recent metaanalysis showed that MDCT had an 85% sensitivity and a 95% specificity for detecting a stenosis .50% in severity [79]. It is important to point out, however, that a significant number of coronary segments were excluded from analysis in many of these studies because of motion artifact or size ,2 mm. Other limitations in MDCT coronary angiography include patients with tachycardia despite the use of beta-blockade and poor visualization of segments with previous stent placement.

67

The use of MDCT in the evaluation of acute CP patients in the ED has been evaluated in only small singlecenter studies at this time. Because little data demonstrating CCTA findings in patients with and without ACS are available, there is the potential for inappropriate use of MDCT from additional testing rather than preventing admissions or cost [80]. The North American Society for Cardiac Imaging and the European Society for Cardiac Radiology therefore convened an expert panel to review the literature, identify areas that require more research, and provide interim summary recommendations in the preparation for development of comprehensive guidelines [80]. As discussed above, most patients with CP are admitted to hospital or undergo prolonged observation prior to discharge, and most will not turn out to have an ACS. The powerful negative predictive value of MDCT makes it an attractive option for exclusion of significant CAD in low-risk patients, who can potentially be discharged expediently from the ED. In 3 recent studies, all of which enrolled adult patients with acute CP that was suspected to be cardiac in etiology, but without initial ECG or serum biomarker evidence of ischemia, significant CAD Â�(stenosis .50%) was excluded in 60% to 71% of patients [81–83]. The negative predictive value of MDCT for ACS was found to range from 97% to 100% [81–83]. Cardiac event rates (cardiac death, AMI, and UAP) over a period of 6 to 15 months were very low in patients with minimal abnormalities on MDCT after discharge from the ED [81–83]. Figure 4.10 shows images from a 43-year-old woman who presented to the ED with atypical CP, normal ECG, and negative serum biomarkers. She was referred to cardiac MDCT from the ED. A curved multiplanar reformat of left anterior descending coronary artery (panel A), and multiplanar reformat of right coronary artery (panel B), demonstrated entirely normal coronary arteries, without evidence of coronary plaque or stenosis. The patient was therefore reassured that her CP was noncardiac in etiology, and she was discharged from the ED without any recommendations for further cardiac testing. Multivariate regression logistic analyses have shown that MDCT can provide independent incremental risk stratification for the development of an ACS over the

4 . 1 0 â•… Cardiovascular computed tomography angiography images from a patient presenting with chest pain.

F igure


clinical evaluation. For every additional segment (total of 17 segments) with plaque, the average increase in odds of having ACS was 1.58 (95% confidence interval 1.18–1.87) [82]. Although patients presenting with acute CP who have significant CAD identified on MDCT are at much higher risk, the positive predictive value of an abnormal CCTA for the development of an ACS is much lower than its negative predictive value (47%–52%) [82,83]. Even though higher noncalcified plaque burden and eccentric remodeling have been found more frequently in patients with ACS, the ability to differentiate acute versus stable coronary lesions by CCTA is limited [84]. Therefore, patients with previously documented CAD or those at high risk probably will not be as suitable for evaluation by CCTA in the ED. Currently, many patients (up to 25%) may be ineligible for MDCT due to renal insufficiency, tachyarrhythmias, asthma, or inability to comply with breath-hold requirements. In a recent study, significant coronary stenosis could not be excluded in approximately 17% of studies due to the presence of a prior stent, severe calcification, poor signal-tonoise ratio, or tachycardia [82]. An important consideration for the use of CT is the exposure to a moderate amount of radiation. This is an increasingly important point of discussion as the implications of the vast amount of radiation we expose our patients to in today’s highly technological world of medicine is further investigated. However, with radiation dose–Â�reducing strategies, such as prospective triggering, radiation dose has been reduced considerably (~3–5 mSv), similar to that of an invasive coronary angiogram. Also, the need for radiographic contrast adds some risk of renal toxicity and hypersensitivity reactions. Similar to SPECT and CMR, there is also some potential danger in transporting a patient who is potentially unstable for an imaging study away from a closely monitored setting.

j â•… SUMMARY The evaluation of a patient presenting with acute CP is challenging, and making a rapid diagnosis of ACS while differentiating it from all other causes of CP is clinically difficult. The use of ancillary imaging including echocardiography, SPECT, CMR, and CT have all been evaluated in their ability to provide incremental diagnostic and prognostic information over simple bedside tools like history, physical examination, and ECG. All the technologies have their own strengths and weaknesses when compared to others. SPECT and echocardiography are well-established Â�technologies that can directly assess the presence of myocardial ischemia and its functional consequence on RF; newer and more expensive techniques such as MDCT and CMR can directly assess coronary anatomy and have just started to be evaluated in the acute CP setting. There

are few studies that directly compare these technologies, and more data are clearly needed before physicians can understand the subsets of patients who may benefit most from anatomic imaging versus perfusion/function imaging. Other comparisons such as relative safety, availability, logistics, and cost-effectiveness between the various technologies are also lacking. Other issues will also influence the choice of the modality to be used, such as the availability of personnel and infrastructure at each institution to accommodate imaging after normal working hours, rapid interpretation of studies, and quick communication of results to the ordering physician. Despite these and other questions that need to be answered before any one technique is used exclusively, the future of noninvasive cardiac imaging remains an exciting and ever changing field. The adaptation of any one of these techniques into their proper role in ED will take considerably more time and effort in terms of research, money, and clinical experience.

jâ•… REFERENCES â•‡ 1. American Heart Association. Heart Disease and Stroke Statistics— 2008 Update. Dallas, TX: American Heart Association; 2008. â•‡ 2. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism. A 25-year population-based study. Arch Intern Med. 1998;158:585–593. â•‡ 3. Tsai TT, Nienaber CA, Eagle KA. Acute aortic syndromes. Circulation. 2005;112:3802–3813. â•‡ 4. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110(5):588–636. â•‡ 5. Forest RS, Shofer FS, Sease KL, Hollander JE. Assessment of the standardized reporting guidelines ECG classification system: the presenting ECG predicts 30 day outcomes. Ann Emerg Med. 2004;44:206–212. â•‡ 6. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with UA/non-ST-Â� elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Writing committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-STElevation Myocardial Infarction): developed in collaboration with the American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2007;50:e1–e157. â•‡ 7. Pope JH, Selker HP. Acute coronary syndromes in the emergency department: diagnostic characteristics, tests and challenges. Cardiol Clin. 2005;23:423–451. â•‡ 8. Lakkireddy DR, Kondur AK, Chediak EJ, Nair CK, Khan IA. Cardiac troponin I release in non-ischemic reversible myocardial injury from acute diphtheric myocarditis. Int J Cardiol. 2005;98:351–354. â•‡ 9. Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005;142:786–791.

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31. Wei K, Le E, Bin JP, Coggins M, Goodman NC, Kaul S. Mechanism of reversible 99mTc-sestamibi perfusion defects during pharmacologically induced coronary vasodilation. Am J Physiol. 2001;280:H1896–H1904. 32. Heyndrickx GR, Baig H, Nellens P, Leusen I, Fishbein MC, Vatner SF. Depression of regional blood flow and wall thickening after brief coronary occlusions. Am J Physiol. 1978;234:H653–H659. 33. Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation. 2001;104:2981–2989. 34. Nixon JV, Brown CN, Smitherman TC. Identification of transient and persistent segmental wall motion abnormalities in patients with unstable angina by two-dimensional echocardiography. Circulation. 1982;65:1497–1503. 35. Ito H, Tomooka T, Sakai N, Higashino Y, Fujii K, Katoh O, et al. Time course of functional improvement in stunned myocardium in risk area in patients with reperfused anterior infarction. Circulation. 1993;87:355–362. 36. Kaul S, Senior R, Firschke C, Wang XQ, Lindner J, Villanueva FS, et al. Incremental value of cardiac imaging in patients presenting to the emergency department with chest pain and without ST-segment elevation: a multicenter study. Am Heart J. 2004;148: 129–136. 37. Korosoglou G, Labadze N, Hansen A, et al. Usefulness of real-time myocardial perfusion imaging in the evaluation of patients with first time chest pain. Am J Cardiol. 2004;94:1225–1231. 38. Kang DH, Kang SJ, Song JM, Choi KJ, Hong MK, Song JK, et al. Efficacy of myocardial contrast echocardiography in the diagnosis and risk stratification of acute coronary syndrome. Am J Cardiol. 2005;96:1498–1502. 39. Rinkevich D, Kaul S, Wang XQ, Tong KL, Belcik T, Kalvaitis S, et al. Regional left ventricular perfusion and function in patients presenting to the emergency department with chest pain and no ST-segment elevation. Eur Heart J. 2005;26:1606–1611. 40. Antman E, Cohen M, Bernink PJL, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000; 284: 835–842. 41. Tong KL, Kaul S, Wang XQ, Rinkevich D, Kalvaitis S, Belcik T, et al. Myocardial contrast echocardiography versus thrombolysis in myocardial infarction score in patients presenting to the emergency department with chest pain and a nondiagnostic electrocardiogram. J Am Coll Cardiol. 2005;46:920–927. 42. Kalvaitis S, Kaul S, Tong KL, Rinkevich D, Belcik T, Wei K. Effect of time delay on the diagnostic use of contrast echocardiography in patients presenting to the emergency department with chest pain and no S-T segment elevation. J Am Soc Echocardiogr. 2006;19:1488–1493. 43. Wyrick JJ, Kalvaitis S, McConnell J, Rinkevich D, Kaul S, Wei K. Cost efficiency of myocardial contrast echocardiography in patients presenting to the emergency department with chest pain of suspected cardiac origin and a non-diagnostic electrocardiogram . Am J Cardiol. 2008;102:649–652. 44. Christiansen JP, Leong-Poi H, Klibanov AL, Kaul S, Lindner JR. Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography. Circulation. 2002;105:1764–1767. 45. Weller GER, et al. Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1. Circulation. 2003;108:218–224. 46. Lindner JR, et al. Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation. 2001;104:210–212. 47. Lang RM, Mor-Avi V, Sugeng L, Nieman PS, Sahn DJ. Threedimensional echocardiography: the benefits of the additional dimension. J Am Coll Cardiol. 2006;48:2053–2069. 48. Hung J, Lang R, Flachskampf F, et al. 3D Echocardiography: a review of the current status and future directions. J Am Soc Echocardiogr. 2007;20:213–233.

70 Multimodality Imaging in Cardiovascular Medicine

49. Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies. J Am Coll Cardiol. 2008;51:1704–1706. 50. Wei K, Mulvagh SL, Carson L, et al. The safety of definity and optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses. J Am Soc Echocardiogr. 2008;11:1202–1206. 51. Varetto T, Cantalupi D, Altieri A, et al. Emergency room technetium-99m sestamibi imaging to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardiograms. J Am Coll Cardiol. 1993;22:1804–1808. 52. Hilton TC, Thompson RC, Williams HJ, et al. Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol. 1994;23:1016–1022. 53. Tatum JL, Jesse RL, Kontos MC, et al. Comprehensive strategy for the evaluation and triage of the chest pain patient. Ann Emerg Med. 1997;29:116–123. 54. Kontos MC, Jesse RL, Schmidt KL, et al. Value of acute rest sestamibi perfusion imaging for evaluation of patients admitted to the emergency department with chest pain. J Am Coll Cardiol. 1997;30:976–982. 55. Heller GV, Stowers SA, Hendel RC, et al. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol. 1998;31:1011–1017. 56. Kontos MC, Jesse RL, Anderson FP, et al. Comparison of myocardial perfusion imaging and cardiac troponin I in patients admitted to the emergency department with chest pain. Circulation. 1999;99:2073–2078. 57. Udelson JE, Beshansky JR, Ballin DS, et al. Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: a randomized controlled trial. JAMA. 2002;288:2693–2700. 58. O’Connor MK, Hammell T, Gibbons RJ. In vitro validation of a simple tomographic technique for estimation of percentage myocardium at risk using methoxyisobutyl isonitrile technetium 99m (sestamibi). Eur J Nucl Med. 1990;17:69–76. 59. Mannting F, Morgan-Mannting MG. Gated SPECT with technetium99m-sestamibi for assessment of myocardial perfusion abnormalities. J Nucl Med. 1993;34:601–608. 60. Kaul S, Senior R, Harrel FE, et al. Incremental value of cardiac imaging in patients presenting to the emergency department with chest pain and without ST-segment elevation: A multicenter study. Am Heart J. 2004;148:129–136. 61. Heller GV, Udelson JE, Ziffer J, et al. Assessing suspected acute cardiac ischemia in the emergency department: logistics, testing modalities, implications for perfusion imaging. J Nucl Cardiol. 2001;8:274–285. 62. Kontos MC, Tatum JL. Imaging in the evaluation of the patient with suspected acute coronary syndrome. Semin Nucl Med. 2003;4:246–258. 63. Dilsizian V, Bateman TM, Bergmann SR, et al. Metabolic imaging with beta-methyl-p-[(123)I]-iodophenyl-pentadecanoic acid identifies ischemic memory after demand ischemia. Circulation. 2005;112:2169–2174. 64. Goodman MM, Kirsch G, Knapp FF Jr. Synthesis and evaluation of radioiodinated terminal p-iodophenyl substituted a- and b-methyl branched fatty acids. J Med Chem. 1984;27:390–397. 65. Cave AC, Ingwall JS, Friedrich J, et al. ATP synthesis during low-flow ischemia: influence of increased glycolytic substrate. Circulation. 2000;101:2090–2096. 66. Wagner S, Auffermann W, Buser P, Semelka RC, Higgins CB. Functional description of the left ventricle in patients with volume overload, pressure overload, and myocardial disease using cine magnetic resonance imaging. Am J Cardiac Imag. 1991;5:87–97. 67. Lotz J, Meier C, Leppert A, Galanski M. Cardiovascular flow measurement with phase-contrast MR imaging: basic facts and implementation. Radiographics. 2002;22:651–671.

68. Kim RJ, Chen EL, Lima JA, Judd RM. Myocardial Gd-DTPA kinetics determine MRI contrast enhancement and reflect the extent and severity of myocardial injury after acute reperfused infarction. Circulation. 1996;94:3318–3326. 69. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999;100:1992–2002. 70. Setser RM, Bexell DG, O’Donnell TP, et al. Quantitative assessment of myocardial scar in delayed enhancement magnetic resonance imaging. J Magn Reson Imag. 2003;18:434–441. 71. Aletras AH, Tilak GS, Natanzon A, et al. Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted CMR imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation. 2006;113:1865–1870. 72. Kaandorp TAM, Lamb HF, Bax JJ, van der Wall EE, de Roos A. Magnetic resonance imaging of coronary arteries, the ischemic cascade, and myocardial infarction. Am Heart J. 2005;149:200–208. 73. Kwong RY, Schussheim AE, Rekhraj S, et al. Detecting acute coronary syndrome in the emergency department with cardiac magnetic resonance imaging. Circulation. 2003;107:531–537. 74. Cury RC, Shash KS, Nagurney JT, et al. Cardiac magnetic resonance with T2-weighted imaging improves detection of patients with acute coronary syndrome in the emergency department. Circulation. 2008;118:837–844. 75. Kawai Y, Tsukamoto E, Nozaki Y, Morita K, Sakurai M, Tamaki N. Significance of reduced uptake of iodinated fatty acid analogue for the evaluation of patients with acute chest pain. J Am Coll Cardiol. 2001:38;1888–1894. 76. Buchthal SD, den Hollander JA, Merz CN, et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med. 2000;342:829–835. 77. Johnson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004:109:2993–2999. 78. Wintersperger BJ, Nikolaou K, von Ziegler F, et al. Image quality, motion artifacts, and reconstruction timing of 64-slice coronary computed tomography angiography with 0.33-s rotation speed. Invest Radiol. 2006;41:436–442. 79. Schuijf JD, Bax JJ, Wijns W, et al. Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography. Am Heart J. 2006;15:404–411. 80. Stillman AE, Oudkerk M, Ackerman M, et al. Use of multidetector computed tomography for the assessment of acute chest pain: a consensus statement of the North American Society of Cardiac Imaging and the European Society of Cardiac Radiology. Int J Cardiovasc Imaging. 2007;23:415–427. 81. Rubinshtein R, Halon DA, Gaspar T, et al. Usefulness of 64-slice cardiac computed tomographic angiography for diagnosing acute coronary syndromes and predicting clinical outcome in emergency department patients with chest pain of uncertain origin. Circulation. 2007;115(13):1762–1768. 82. Hoffmann U, Nagurney JT, Moselewski F, et al. Coronary multidetector computed tomography in the assessment of patients with acute chest pain. Circulation. 2006;114(21):2251–2260. 83. Goldstein JA, Gallagher MJ, O’Neill WW, Ross MA, O’Neil BJ, Raff GL. A randomized controlled trial of multi-slice coronary computed tomography for evaluation of acute chest pain. J Am Coll Cardiol. 2007;49(8):863–871. 84. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol. 2007;50:319–326.

5

Post-MI Risk Stratification

M ARK R. VESELY JAmES A . A RRI GHI GAGANDEEP S . GUR m HARISHA KO mmANA VASKEN D ILSIZIAN jâ•… INTRODUCTION Acute myocardial infarction (MI) is highly prevalent in the United States, occurring every 34 seconds [1]. This results in an estimated 610 000 first-time and 325 000 recurrent MIs annually, many of which are fatal events. A wide variability persists in post-MI mortality based on age, race, and gender. For example, 15% of white men between 40 and 69 years of age and 62% of black women 70 years or older will die within 5 years following a first MI [1]. While annual MI-related death rates declined 34% from 1995 to 2005 [2], there remains an average 15 years of life lost following an MI [3]. Likewise, patients who have survived an MI are at increased risk of future cardiac events such as a subsequent MI and development of heart failure or life-threatening arrhythmias. Predicting who will experience further clinical difficulties following an MI is thus an important endeavor. The characterization of risk for future cardiac events enables management choices to be made at an individualized level, thus matching the utilization of diagnostic and therapeutic modalities to a patient’s risk of future cardiac events or death. The risk for adverse outcome following acute MI is affected by a number of variables. These include historical and demographic factors, markers of clinical stability, and various biomarkers that assess infarct size or heart failure [4–18]. Factors related to the residual structure and function of the post-MI heart play an important role in a patient’s vulnerability for future cardiac events or death. Specifically, the state of LV function, presence of electrical instability, and the amount of ischemic but viable myocardium perfused by stenotic coronary arteries are important prognostic factors [19,20]. The importance of risk assessment using such physiologic measures is highlighted by

experimental and clinical evidence of the great variability in infarct size for a given coronary occlusion [21–23]. The physiologic assessment of patients after MI can be achieved by numerous noninvasive imaging Â�modalities, including transthoracic echocardiography (TTE), Â�cardiac computed tomography, cardiac magnetic resonance imaging (CMR), and radionuclide cardiac Â�imaging with Â�single photon emission computed tomography (SPECT), or Â�positron emission tomography (PET). The selection of which test to perform is based on the specific clinical Â�question, the relative advantages of one test over another in the particular clinical situation, and the availability of local expertise and technology. The goal of this Â�chapter is to review the various imaging modalities utilized in Â�post-MI risk assessment in order to facilitate their Â�appropriate use. The major utility of cardiac imaging in the post-MI population is in assessing several of the most important factors that affect long-term risk. These include (1) left ventricular (LV) function, which may lead to heart failure; (2) the extent of residual myocardial ischemia/viability, which may lead to recurrent MIs; and (3) the likelihood of sudden cardiac death (SCD) based on certain functional parameters.

jâ•…I NI TIAL ACUTE MI MANAGEMENT CONTRIBUTES TO POST-MI RISK STRATIFICATION There are significant differences in the management of acute MI patients based on initial presentation. Acute MI patients with ECG evidence of ST segment elevation (STEMI) are usually treated with prompt revascularization by percutaneous coronary intervention (PCI) during cardiac catheterization or with fibrinolytic therapy [24]. In contrast, patients suffering a non-ST segment elevation MI (NSTEMI) can be managed with either an early invasive strategy (ie, cardiac catheterization) or conservatively with medical therapies [25]. Likewise, patients presenting late in the course of their MI may be managed with invasive or noninvasive strategies, depending on their clinical presentation. There is considerable overlap of the approaches to assessment of risk and management for these clinically different patient populations. 71


72

In STEMI patients initially treated with PCI, early risk stratification for 30-day and 1-year mortality can be completed with multimodality scoring systems such as the Zwolle primary PCI index [26] and CADILLAC risk score [27]. These systems are derived by assessment of both clinical variables and factors obtained by imaging, including left ventricular ejection fraction (LVEF), number of diseased coronary vessels, and post-PCI TIMI flow grade in the infarct-related vessel. STEMI patients treated with fibrinolytic agents are risk stratified using risk scores such as the TIMI risk score, TIMI risk index, and GRACE risk model, which are based on clinical information at initial presentation [28–30]. Many such patients will subsequently undergo cardiac catheterization as part of the initial management and risk stratification process. Patients with STEMI who do not undergo cardiac catheterization and/or reperfusion therapy, however, are most likely to benefit from noninvasive risk stratification, which usually includes assessment of LV function and ischemic burden. Risk stratification in patients with acute NSTEMI begins at the initial presentation, to identify those at immediate high risk. Unstable patients secondary to cardiogenic shock, overt heart failure, ventricular arrhythmias, or mechanical complications should undergo coronary angiography as soon as possible with reperfusion therapy as indicated thereafter. Non–high-risk patients are further assessed to identify patients likely to benefit by an early invasive treatment plan, including cardiac catheterization within 4 to 48 hours. Except for low-risk patients (TIMI

The assessment of LV size and function is an important component of risk stratification after any type of MI. This can be accomplished with invasive or noninvasive imaging techniques. In 1960, biplane left ventriculography was first utilized for calculation of LV volumes during cardiac catheterization [33]. Twenty years later, functional and volumetric data derived from biplane left ventriculography was shown to be useful in predicting post-MI outcome. Among patients with acute MI undergoing cardiac catheterization prior to discharge from the index hospitalization, those with a post-MI LVEF of ,40% had increased risk for death after discharge compared to those with relatively preserved LVEF [34]. Subsequent studies have shown that beyond LVEF, LV end-systolic volume (ESV) independently predicted post-MI mortality (Figure 5.1) [35]. In the

B

100 ESV130ml (n=71)

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