Nuclear Cardiology: Basic and Advanced Concepts in Clinical Practice 3030621944, 9783030621940

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Nuclear Cardiology Basic and Advanced Concepts in Clinical Practice Cláudio Tinoco Mesquita Maria Fernanda Rezende Editors

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Nuclear Cardiology

Cláudio Tinoco Mesquita Maria Fernanda Rezende Editors

Nuclear Cardiology Basic and Advanced Concepts in Clinical Practice

Editors Cláudio Tinoco Mesquita Fluminense Federal University Niterói, Rio de Janeiro Brazil

Maria Fernanda Rezende Hospital Vitória Rio de Janeiro, Rio de Janeiro Brazil

ISBN 978-3-030-62194-0    ISBN 978-3-030-62195-7 (eBook) https://doi.org/10.1007/978-3-030-62195-7 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my wife Fernanda and children Júlia and Gabriela. You are my shelter and my love. To Evandro, who made me believe that everything is possible. To my parents, Mário and Célia, who made everything possible. Cláudio Tinoco Mesquita To my parents, Mário and Conceição, my sisters, Márcia and Adriana, and my nephews, Luiz Felipe and Ana Júlia, for understanding and accepting the moments I was absent, for the constant support, and for encouraging me to accept new challenges, because nothing would be possible without them by my side. Maria Fernanda Rezende Most of all, we thank our patients, who need more than never the advances of science and the love of human touch. To them, we dedicate this book. We wish that this book improves the quality of care and ensure better treatment selection, consistent with patient values.

Foreword

The role of nuclear medicine has expanded into cardiological science and practice to an extension and deepness certainly never expected in the beginnings of cardiac output studies, in the middle of the last century, or even at the beginning of cardiac perfusion images, during the 1970s. In parallel, an ever-growing number of cardiologists got attracted by the amazing ability of the radionuclide techniques to explore the dynamics of physiological and pathophysiological phenomena of the cardiovascular system in a non-invasive way. With the development of electronic and digital technologies since the end of the last century, other medical imaging modalities came along. They also focused on the heart and offered the possibility of non-invasive detailed studies of its anatomy, microanatomy and, to a certain extent, cellular function. These were echocardiography, computed tomography and magnetic resonance. However, nuclear medicine, thanks to the versatility of gamma emitters and positron emitters, continues to hold the unique tools for imaging and quantifying the biology of heart cells in a large spectrum of cardiac diseases. Countless reports of studies, researches, observations and guidelines scattered throughout the literature reflect the potential of this branch of science in cardiology and enlarge continuously its applications in diagnosis, prognosis, prevention and treatment orientation. It has become an almost impossible task to select the essential knowledge from that enormous pool of information and to get the true value of each of the multiple communications. There is a need of a compendium that will bring together the state of the art of nuclear cardiology in a systematic way, filtering the available experiences and extracting the capabilities of each procedure, its range, strength and limitations. This goal has been achieved by Nuclear Cardiology: Basic and Advanced Concepts in Clinical Practice. The book covers practically all heart diseases where nuclear techniques have a particularly important role. These include coronary syndromes, cardiomyopathies and heart failure, inflammatory diseases, adrenergic innervation disturbances, electric conduction disturbances, and also iatrogenic effects caused by the treatment of non-cardiac diseases. vii

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Foreword

The editors, who are leading nuclear medicine physicians and cardiologists in their respective countries and well--known members of the international community of nuclear cardiologists, succeeded in bringing together a multinational team of experts in both fields. Each co-author has deep knowledge and wide experience in the subject of his respective chapter and the capability of a critical appraisal of the latest advances, the possible restrictions and the future insights of the particular studies. None of the multiple facets of today’s applications have been left out. Specialists, clinicians and medical students will find in this book the consolidated practices as well as the most recent advances brought by nuclear medicine to cardiology. Springer Verlag and Drs. Mesquita and Rezende deserve congratulations and thanks for the accomplishment of this outstanding enterprise.

1980

 Archives Instituto Dante Pazzanese de Cardiologia, SP. BR

Foreword

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2010

 Courtesy Soares J., INCOR

Anneliese Rosmarie Gertrud Fischer Thom Clinical Imaging, Section Nuclear Medicine Hospital Israelita Albert Einstein São Paulo, Brazil

Editors’ Personal Note

Nuclear cardiology is part of the history of modern cardiology. Advances made in the last 30 years transformed this field to one of the most exciting subspecialties of cardiovascular care. The understanding of advanced coronary physiology with new PET radiotracers, the discovery of new aspects of an old disease like amyloidosis, and the increased use of hybrid techniques in clinical practice are some of the multiple new aspects of this evolving area. Modern life demands collaboration. To address the great challenge of making this book we could count on the support of contributors from many countries. We must thank them for the great work. This book would not have been possible without the help of many dedicated people from Springer, who worked in many technical aspects. We acknowledge the contribution of Sheik Mohideen, Vanessa Shimabukuro, and Henry Rodgers. We would like to thank our colleagues for the time spent in revising this book. Finally, we are especially grateful for the understanding and support shown by our families, as well as their many sacrifices, during this book’s completion. We hope that we have met the expectations of our publishers and readers. But, above all, we sincerely hope that this book will contribute to improved care benefiting the patients. All our regards to them, who trusted our knowledge for their betterment. Cláudio Tinoco Mesquita Fluminense Federal University Niterói, Rio de Janeiro, Brazil Maria Fernanda Rezende Hospital Vitória Rio de Janeiro, Rio de Janeiro, Brazil

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Preface

“A room without books is like a body without a soul.” (Marcus Tullius Cicero)

This book is the result of a great effort in international collaboration. Physicians, physicists, biologists, engineers, data scientists, and many other specialists working in several areas collaborated to create this book. Their work is dedicated to our patients. When I was a medical student, I had the privilege of meeting Mario Verani and seeing the foundation of the American Society of Nuclear Cardiology in my last year of graduation. Mario Verani was born in Rio de Janeiro, Brazil, and was a medical intern at the Antonio Pedro University Hospital, Universidade Federal Fluminense (1967), where I work today as a professor of medicine. Mario Verani was inspirational for many to embrace nuclear cardiology. His work on risk stratification by myocardial perfusion and function imaging after acute myocardial infarction was very important to promote nuclear cardiology in cardiology practice. During my cardiology training, a special friend, Marcílio Henrique de Souza, gave me a seminal book edited by Dr. Mario Verani and Dr. Ami Iskandrian, Nuclear Cardiac Imaging, Principles and Applications (1996). I have read that book many times and it convinced me to specialize in nuclear cardiology. I sincerely hope that this book we are presenting here, Nuclear Cardiology, Basic and Advanced Concepts in Clinical Practice (2020), could be an inspiration for many others to follow this path. One of the most significant parts of medicine for me is to teach. Dr. Maria Fernanda Rezende was one of the best fellows in nuclear medicine that I have had the opportunity to train. She stood out for her dedication, patience, and medical skills in caring for patients. Rapidly she gained widespread recognition and now she coordinates a very successful and busy nuclear medicine department. To work with her in this book was very important and gratifying. Her friendship is one of the greatest’s gifts that I have received. I had the opportunity to meet many of the collaborators of this book during activities of the International Atomic Energy Agency (IAEA). The IAEA is the world’s center for cooperation in the nuclear field and promotes the safe, secure, and peaceful use of nuclear technologies. Dr. Diana Paez, Dr. Enrique Estrada, Dr. Maurizio xiii

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Dondi, and many others must be honored by the great contribution of IAEA’s work in nuclear cardiology. During the IAEA’s activities, I got the opportunity meet Prof. Raffaele Giubbini, a scientist-physician-teacher who became a friend and a role model. His devotion to the field of nuclear cardiology is impressive, and I have to thank him for it. I have also understood and respect the importance of the multidisciplinary approach to get best results in clinical practice. This book can be defined as a multidisciplinary international collaborative initiative. I am extremely grateful to all the authors across the world for their contributions. I am also especially grateful to the Springer Nature Team represented by Vanessa Shimabukuro and Sheik Mohideen. This book covers relevant concepts in nuclear cardiology, combining imaging techniques and clinical data to do so. Today, nuclear cardiology is a worldwide discipline connected to the broader field of cardiovascular imaging. The combination of clinical aspects (symptoms, medications, previous cardiac procedures), ancillary exams, and nuclear images is key to decision-making in clinical practice. The chapters cover a comprehensive range of topics in current cardiology practice, such as ambulatory patients, patients in emergency settings, patients after complex cardiac procedures, and patients during and after the use of cancer therapies that are potentially toxic for the heart (cardio-oncology). As such, multiple clinical scenarios are also presented: patients with suspected coronary disease, patients with heart failure of unknown origin, patients with acute chest pain in the emergency department, patients with suspected pulmonary embolism, and patients with complications of the left ventricular assist device. Furthermore, the book describes nuclear cardiology procedures and techniques, discusses the main clinical indications and scenarios for each procedure, presents new technological advances in the field (machine learning and artificial intelligence tools), and mentions the coronavirus disease 2019 (COVID-19) pandemic. Given its scope, the book offers a valuable guide and videos for various medical professionals, especially cardiologists and nuclear physicians. Niterói, Rio de Janeiro, Brazil

Cláudio Tinoco Mesquita

Contents

1 Cardiac PET Procedure: Perfusion, Coronary Flow, Viability, Inflammation, and PET/MR ������������������������������������������������������������������    1 José Soares Junior 2 SPECT Procedures����������������������������������������������������������������������������������   73 Rafael Willain Lopes and Elry Medeiros Vieira Segundo Neto 3 Evaluation of Myocardial Blood Flow and Myocardial Flow Reserve by Radionuclide Imaging������������������������������������������������  107 Raffaele Giubbini and Elisa Milan 4 Radiation Protection and Exposure in Nuclear Cardiology����������������  125 Tadeu Takao Almodovar Kubo 5 Non-nuclear Cardiac Imaging Modalities: CT and MRI��������������������  145 Carlos Eduardo Rochitte and Ariane Binoti Pacheco 6 Coronary Physiology: From Basic Concepts to FFR and iFR������������  183 Valérie E. Stegehuis, Tim P. van de Hoef, and Jan J. Piek 7 Coronary Artery Calcium and Hybrid Imaging in Ischemic Heart Disease��������������������������������������������������������������������������������������������  203 Adriana Cecilia Puente Barragán and Verónica Vanesa Gómez Leiva 8 Coronary Blood Flow Reserve and Myocardial Ischemia��������������������  225 Fernanda Erthal and Ronaldo Lima 9 Nuclear Cardiology and Coronavirus Disease 2019 (COVID-19) Pandemic��������������������������������������������������������������������������������������������������  247 Cláudio Tinoco Mesquita and Maria Fernanda Rezende 10 Nuclear Imaging in Stable Ischemic Coronary Disease ����������������������  265 Paola Emanuela Poggio Smanio and Fernanda Ambrogi Barbosa da Luz

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11 Nuclear Imaging in Acute Coronary Syndromes����������������������������������  291 Amalia Peix 12 Nuclear Techniques Before and After Coronary Revascularization ������������������������������������������������������������������������������������  331 Fernando Mut, Miguel Kapitan, and Mario Beretta 13 Physiologic and/or Anatomic Assessment of CAD: Patient-Centered Approach��������������������������������������������������������������������  347 João V. Vitola, Marcello Zapparoli, Rodrigo Julio Cerci, and Miguel Morita Fernandes-Silva 14 Evidence-Based and Nuclear Cardiology����������������������������������������������  361 Gabriel Blacher Grossman, Lara Terra Carreira, Victoria Schmidt Ramos, and Thaís Rossato Arrais 15 Pathophysiology, Diagnosis, and Management of Heart Failure����������������������������������������������������������������������������������������  383 Antonio Jose Lagoeiro Jorge and Evandro Tinoco Mesquita 16 PET and SPECT Evaluation of Viable Dysfunctional Myocardium ��������������������������������������������������������������������������������������������  399 Christiane C. Wiefels, Riina Kandolin, Gary Small, and Rob S. Beanlands 17 Bone Tracers for the Diagnosis of Cardiac Amyloidosis����������������������  419 Priscila Cestari Quagliato 18 Adrenergic Nervous System Imaging in HF Management������������������  437 Euclides Timóteo da Rocha, Marcelo José dos Santos, Derk O. Verschure, and Hein J. Verberne 19 Takotsubo Cardiomyopathy and Nuclear Imaging������������������������������  451 Lara Terra Carreira and Gabriel Blacher Grossman 20 PET and SPECT in Inflammatory Diseases: Sarcoidosis, Myocarditis, and Vasculitis ��������������������������������������������������������������������  461 Marcelo Livorsi da Cunha, Ricardo Cavalcante Quartim Fonseca, and Júlio César Silveira Oliveira 21 Cardiovascular Risk Stratification Prior to Non-cardiac Surgery������  495 Teresa Massardo Vega and Rodrigo Jaimovich Fernández 22 Exercise and Pharmacologic Stress Testing������������������������������������������  517 Alan Yazaldy Chambi Cotrado and Wilter dos Santos Ker 23 Evaluation of Ventricular Function by Nuclear Imaging��������������������  545 Nilton Lavatori Corrêa and Isabella Caterina Palazzo

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24 123I-mIBG in the Risk Stratification of Sudden Cardiac Death in Chronic Heart Failure ������������������������������������������������������������������������  567 Derk O. Verschure, K. Nakajima, and Hein J. Verberne 25 Nuclear Image-Guided Methods for Cardiac Resynchronization Therapy��������������������������������������������������������������������  587 Zhuo He, Ernest V. Garcia, and Weihua Zhou 26 Nuclear Imaging in the Management of Infective Endocarditis���������  609 Hossein Jadvar and Patrick M. Colletti 27 PET and SPECT in the Evaluation of Cardiac Implantable Electronic Devices������������������������������������������������������������������������������������  619 Raphaella da Silva and Renata Moreira 28 The Clinical Aspects of Heart Damage by Chemotherapy and Radiotherapy������������������������������������������������������������������������������������  675 Wolney de Andrade Martins, Marcos José Pereira Renni, and Aurora Felice Castro Issa 29 Nuclear Medicine Tools for Cardiac Damage Diagnosis in Oncology ����������������������������������������������������������������������������������������������  691 Luca Terracini Dompieri, Mayara Laís Coêlho Dourado, and Simone Cristina Soares Brandão 30 Acute Coronary Syndrome Evaluation with Nuclear Medicine in the Emergency Setting������������������������������������������������������������������������  709 Jader Cunha de Azevedo, Fernanda Salomão Costa, and Cláudio Tinoco Mesquita 31 Diagnosis of Pulmonary Embolism��������������������������������������������������������  723 Barbara Juarez Amorim, Marcel Yanagihara Rigolon, and Celso Dario Ramos 32 Deep Learning and Artificial Intelligence in Nuclear Cardiology������  741 Erito Marques de Souza-Filho and Fernando de Amorim Fernandes 33 Programmes of the International Atomic Energy Agency for Nuclear Cardiology and Quality Management ������������������������������  763 Maurizio Dondi, Diana Paez, and Sugitha Sureshkumar Index������������������������������������������������������������������������������������������������������������������  781

Contributors

Barbara  Juarez  Amorim, MD, PhD  Division of Nuclear Medicine, State University of Campinas (UNICAMP)-Brazil, Campinas, SP, Brazil Thaís Rossato Arrais, MD  Hospital Moinhos de Vento, Porto Alegre, Brazil Adriana  Cecilia  Puente  Barragán, MD  Department of Nuclear Cardiology, National Medical Center “20 de Noviembre”, ISSSTE, Mexico City, Mexico Rob S. Beanlands, MD, FRCPC, FACC, MASNC, FCCS  University of Ottawa Heart Institute, Ottawa, ON, Canada Mario  Beretta, MD  Department of Nuclear Medicine, Spanish Association Hospital, Montevideo, Uruguay Simone Cristina Soares Brandão, MD, PhD  School of Medicine, Hospital das Clínicas – Universidade Federal do Pernambuco, Recife, Brazil Lara  Terra  Carreira, MD  Clínica CNC, Cardiologia Nuclear de Curitiba, Curitiba, Brazil Rodrigo Julio Cerci, MD  QUANTA Diagnostico por Imagem, Curitiba, Brazil Patrick M. Colletti, MD  Division of Nuclear Medicine, Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Nilton  Lavatori  Corrêa, MD, MsC  Department of Nuclear Medicine, Hospital Pró-Cardíaco, Rio de Janeiro, RJ, Brazil Fernanda Salomão Costa, MD  Nuclear Medicine, Hospital Pró-Cardíaco, Rio de Janeiro, Brazil Alan Yazaldy Chambi Cotrado, MD  Hospital Pró-Cardíaco and Hospital Vitoria, Nuclear Medicine Department, Rio de Janeiro, Brazil Marcelo  Livorsi  da Cunha, MD  Nuclear Medicine and PET-CT Department, Hospital Israelita Albert Einstein, São Paulo, Brazil xix

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Contributors

Fernanda  Ambrogi  Barbosa  da Luz, BSc  Nuclear Medicine Department, Instituto Dante Pazzanese de Cardiologia e Fleury Medicina e Saúde, São Paulo, Brazil Euclides  Timóteo  da Rocha, PhD  Department of Nuclear Medicine, Barretos Cancer Hospital, Barretos, São Paulo, Brazil Raphaella  da Silva, MD  Department of Radiology, PET-CT Division, CDPI Clinics, DASA, Rio de Janeiro, Brazil Fernando de Amorim Fernandes, MSc  Nuclear Medicine Department, Hospital Universitário Antônio Pedro/Ebeserh – Federal Fluminense University, Niteroi, Rio de Janeiro, Brazil Wolney  de Andrade  Martins, MD, MSc, PhD  Cardiology Department, Fluminense Federal University, Niterói, Brazil Jader Cunha de Azevedo, MD, PhD  Radiology Department, Nuclear Medicine Section , Hospital Universitário Antônio Pedro – Universidade Federal Fluminense, Niterói, Brazil Erito  Marques  de Souza-Filho, MD, PhD  Federal Fluminense University and Federal Rural University, Niteroi, Rio de Janeiro, Brazil Luca Terracini Dompieri  Scientific Initiation Scholarship Medical School, Hospital das Clínicas  – Universidade Federal do Pernambuco, Recife, Brazil Maurizio  Dondi, MD  Nuclear Medicine and Diagnostic Imaging, Division of Human Health, International Atomic Energy Agency, Vienna, Austria Marcelo José dos Santos, PhD  Department of Nuclear Medicine, Barretos Cancer Hospital, Barretos, São Paulo, Brazil Wilter  dos Santos  Ker, MSc, MD  Hospital Pró-Cardíaco and Hospital Vitoria, Nuclear Medicine Department, Rio de Janeiro, Brazil Mayara  Laís  Coêlho  Dourado, MD, MSc  Internal Medicine, Hospital das Clínicas – Universidade Federal do Pernambuco, Recife, Brazil Fernanda Erthal, MD  Diagnosticos da America SA, Clínica de Diagnóstico por Imagem, Rio de Janeiro, Brazil Miguel  Morita  Fernandes-Silva, MD, MPH, PhD  QUANTA Diagnostico por Imagem, Curitiba, Brazil Rodrigo Jaimovich Fernández, MD  Nuclear Medicine Department, Clínica Las Condes, Santiago, Chile Ricardo  Cavalcante  Quartim  Fonseca, MD  Nuclear Medicine and PET-CT Department, Hospital Israelita Albert Einstein, São Paulo, Brazil Ernest V. Garcia, PhD  Department of Radiology and Imaging Sciences, Emory University Hospital, Atlanta, GA, USA

Contributors

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Raffaele  Giubbini, MD  Chair of Nuclear Medicine, University of Brescia, Brescia, Italy Gabriel Blacher Grossman, MD, PhD  Serviço de Medicina Nuclear do Hospital Moinhos de Vento, Porto Alegre, Brazil Clínica Cardionuclear, Porto Alegre, Brazil Zhuo  He, BS  College of Computing, Michigan Technological University, Houghton, MI, USA Aurora  Felice  Castro  Issa, MD, MSc, PhD  Cardiology Department, National Institute of Cardiology, Rio de Janeiro, Brazil Hossein  Jadvar, MD, PhD, MPH, MBA  Division of Nuclear Medicine, Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Division of Nuclear Medicine, Department of Radiology, University of Southern California, Los Angeles, CA, USA Antonio  Jose  Lagoeiro  Jorge, MD, PhD  Department of Cardiologia, Hospital Universitário Antonio Pedro, Niteroi, Brazil José  Soares  Junior, MD, PhD  Nuclear Medicine Department, The Heart Institute(InCor)-University of Sao Paulo Medical School (FMUSP), São Paulo, SP, Brazil Riina Kandolin, MD, PhD  Helsinki University Hospital, Heart and Lung Center, Helsinki, Finland Miguel  Kapitan, MD  Department of Nuclear Medicine, Italian Hospital, Montevideo, Uruguay Tadeu  Takao  Almodovar  Kubo, MSc, MBA  Nuclear Medicine, Physrad Assessoria em Física Médica, Rio de Janeiro, Brazil Verónica Vanesa Gómez Leiva, PhD  Department of Nuclear Cardiology, National Medical Center “20 de Noviembre”, ISSSTE, Mexico City, Mexico Ronaldo Lima, MD, PhD  Diagnosticos da America SA, Clínica de Diagnóstico por Imagem, Rio de Janeiro, Brazil Department of Cardiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Fonte Imagem, Rio de Janeiro, Brazil Rafael  Willain  Lopes, MD, PhD  Nuclear Medicine Department, Hospital do Coração – Hcor, São Paulo, Brazil Cláudio Tinoco Mesquita, MD, MSc, PhD, FESC, FACC  Radiology Department, Hospital Universitário Antônio Pedro  – Universidade Federal Fluminense, Niterói, Brazil

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Contributors

Evandro Tinoco Mesquita, MD  Department of Cardiologia, Hospital Universitário Antonio Pedro, Niteroi, Brazil Elisa Milan, MD  Nuclear Cardiology Laboratory, Ospedale Cà Foncello – Treviso ULSS2, Treviso, Italy Renata Moreira, MD  Department of Radiology, PET-CT Division, CDPI Clinics, DASA, Rio de Janeiro, Brazil Fernando  Mut, MD  Department of Nuclear Medicine, Spanish Association Hospital, Montevideo, Uruguay K.  Nakajima, MD, PhD  Department of Functional Imaging and Artificial Intelligence, Kanazawa University, Kanazawa, Japan Elry  Medeiros  Vieira  Segundo  Neto, MD  Nuclear Medicine Department, Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil Júlio César Silveira Oliveira, MD  Nuclear Medicine and PET-CT Department, Hospital Israelita Albert Einstein, São Paulo, Brazil Ariane Binoti Pacheco, MD  Department of Cardiovascular Imaging, University of São Paulo, São Paulo, Brazil Diana Paez, MD  Nuclear Medicine and Diagnostic Imaging, Division of Human Health, International Atomic Energy Agency, Vienna, Austria Isabella Caterina Palazzo, MD  Department of Nuclear Medicine, Hospital Pró-­ Cardíaco, Rio de Janeiro, RJ, Brazil Amalia  Peix, MD, PhD, FACC, FASNC  Department of Nuclear Medicine, Institute of Cardiology, La Habana, Cuba Jan J. Piek, MD, PhD  Department of Cardiology, Amsterdam UMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands Priscila  Cestari  Quagliato, MD  Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil Celso Dario Ramos, MD, PhD  Division of Nuclear Medicine, State University of Campinas (UNICAMP)-Brazil, Campinas, SP, Brazil Victoria Schmidt Ramos, MD  Hospital Moinhos de Vento, Porto Alegre, Brazil Marcos José Pereira Renni, MD, MSc, PhD  Cardiology Department, National Institute of Cancer, Rio de Janeiro, Brazil Maria  Fernanda  Rezende, MD, MSc  Nuclear Medicine, Hospital Vitória, Rio de Janeiro, Brazil Marcel Yanagihara Rigolon, MD, MSc  Nuclear Medicine Physician, Campinas, SP, Brazil

Contributors

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Carlos  Eduardo  Rochitte, MD, MSc, PhD  Department of Cardiovascular Imaging, University of São Paulo, São Paulo, Brazil Gary Small, MB, BCh, BSc, PhD, MRCP  University of Ottawa Heart Institute, Ottawa, ON, Canada Paola  Emanuela  Poggio  Smanio, MD, PhD  Nuclear Medicine Department, Instituto Dante Pazzanese de Cardiologia e Fleury Medicina e Saúde, São Paulo, Brazil Valérie  E.  Stegehuis, MD  Department of Cardiology, Amsterdam UMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands Sugitha Sureshkumar, MD  Nuclear Medicine and Diagnostic Imaging, Division of Human Health, International Atomic Energy Agency, Vienna, Austria Tim  P.  van de Hoef, MD, PhD  Department of Cardiology, Amsterdam UMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands Teresa  Massardo  Vega, MD  Nuclear Medicine Section, Medicine Department, Hospital Clínico de la Universidad de Chile, Santiago, Chile Hein  J.  Verberne, MD, PhD  Department of Radiology and Nuclear Medicine, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands Derk O. Verschure, MD PhD  Department of Radiology and Nuclear Medicine, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Cardiology, Zaans Medical Center, Zaandam, The Netherlands Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands João  V.  Vitola, MD, PhD, MASNC  QUANTA Diagnostico por Imagem, Curitiba, Brazil Christiane C. Wiefels, MD, MSc  University of Ottawa Heart Institute, Ottawa, ON, Canada Universidade Federal Fluminense, Niterói, Brazil Marcello Zapparoli, MD  QUANTA Diagnostico por Imagem, Curitiba, Brazil Weihua Zhou, PhD  College of Computing, Michigan Technological University, Houghton, MI, USA

Chapter 1

Cardiac PET Procedure: Perfusion, Coronary Flow, Viability, Inflammation, and PET/MR José Soares Junior

PET (Positron Emission Tomography) Procedure Cardiovascular diseases remain the leading cause of morbidity and mortality in Western societies with coronary artery disease (CAD) and associated myocardial infarction being the most common type of disease in the circulatory system. Though multiple noninvasive imaging modalities are available for its evaluation, current clinical imaging techniques are mainly focused on assessing the anatomy and function of the heart. However, the development of new molecular-targeted techniques can increase significantly the information obtained, by better visualization and understanding of the molecular pathways involved in myocardial diseases, and, thus, help clinicians to provide more personalized treatments to their patients. Molecular imaging can be broadly defined as the in vivo characterization and measurement of biological processes at the cellular and molecular levels. Positron emission tomography (PET) is an excellent molecular imaging modality. Cardiac positron emission tomography currently constitutes the reference standard for noninvasive quantitative evaluation of myocardial blood-flow and is the most used modality for cardiac molecular imaging. Indeed, PET is unrivaled as a highly specific and sensitive means for tomographic imaging of molecular interactions and pathways in humans, providing useful information beyond standard methods, offering great utility for translational medicine, as the intrinsic diagnostic and prognostic added value of the modality has been robustly demonstrated. The use of one imaging unit to produce two different image datasets has become known as hybrid imaging. Examples of hybrid imaging devices include single photon emission computed tomography/computed tomography (SPECT/CT), positron emission tomography–computed tomography (PET-CT), and positron emission J. Soares Junior (*) Nuclear Medicine Department, The Heart Institute (InCor) -University of Sao Paulo Medical School (FMUSP), São Paulo, SP, Brazil e-mail: [email protected] © Springer Nature Switzerland AG 2021 C. T. Mesquita, M. F. Rezende (eds.), Nuclear Cardiology, https://doi.org/10.1007/978-3-030-62195-7_1

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J. Soares Junior

tomography/magnetic resonance (PET/MR). Positron emission tomography–computed tomography (PET/CT) is a nuclear medicine technique that combines, in a single gantry, a positron emission tomography (PET) scanner and an X-ray computed tomography (CT) scanner to acquire sequential images from both devices in the same session, which are combined into a single superposed (co-registered) image. Integrated PET with CT in a single unit—PET/CT—has become an established and valued imaging modality in clinical routine. One main advantage of a PET/CT scanner is that it uses the CT images (as transmission images) for attenuation correction (AC) of the PET data, rather than relying on a rotating transmission rod source. PET/CT scanners are able to perform the registration of the transmission images in extremely short times (less than a minute), with the PET study acquisitions performed immediately after CT [1]. PET technology uses coincidence detection of pairs of high-energy photons that are emitted from the annihilation of an emitted positron with a free electron. PET scanner is a full-ring device that simultaneously measures two photons traveling in opposite directions (emitted by PET-­ tracers) at 180° angle from each other from the annihilation process at all angles. PET involves the administration of a specific radiolabeled molecule (radiotracer) to a patient and scanning of the body to measure photon emission after positron decay to localize and quantify the radiotracer. The principles underlying PET, instrumentation, and use of different radionuclide tracers with short half-lives allow the study of many biological processes such as myocardial perfusion and metabolism, and PET has been used extensively for research and clinical applications in cardiology [2–5]. Given the full ring of PET/CT, it permits the advantage of dynamic imaging of rapid alterations or changings in radiotracer passage in the left ventricular cavity and myocardium that enables absolute quantification of important parameters. PET offers  technical advantages over SPECT:  higher counting sensitivity, spatial and temporal resolution, and better attenuation correction, thus providing clearer images. Because of the PET tracers’ short half-life, it allows lower effective doses and faster imaging protocols, as shown in Fig. 1.1 [6]. Functional imaging obtained by PET, which depicts the spatial distribution of metabolic or biochemical activity in the body, can be more precisely aligned or correlated with anatomic imaging obtained by CT scanning. Two- and three-dimensional (2D/3D) image reconstructions may be rendered as a function of a common software and control system. The recent introduction of new detector materials, including lutetium oxyorthosilicate (LSO), lutetium yttrium orthosilicate (LYSO), and gadolinium orthosilicate (GSO), which all have faster timing and higher light output than bismuth germanate (BGO), has enabled improved count rate performance while generally maintaining good detection efficiency and detector systems with reduced detection dead-time as well as the increasing use of three-dimensional rather than two-dimensional acquisitions are important milestones in the development of PET technology and have significantly contributed to its increasing use in nuclear cardiology [7]. Cardiac PET allows a noninvasive evaluation of myocardial perfusion, myocardial blood flow (MBF), function, and metabolism, using physiological substrates labeled with positron-emitting radionuclides, such as oxygen-15, nitrogen-13,

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PET Advantages

ADVANTAGE

APLICATION INSTRUMENTATION

 Attenuation Correction Accurate

High Diagnostic Specificity

 No Collimator

High Counts Sensitivity

 High Spatial and Contrast Resolution

High Diagnostic Sensitivity

 High Temporal Resolution

Absolute Quantification Myocardial Blood Flow (MBF) PET Radiotracers

 Short Half-life  Higher Extraction Fraction

Fast Sequential Images Low Radiation Exposure Higher Contrast Resolution

Fig. 1.1  Main benefits of PET technology derived from effective instrumentation and radiotracer characteristics

carbon-11, fluorine-18, and rubidium-82. Positron-emitting radionuclides are produced either using a cyclotron, such as fluorine-18, nitrogen-13, carbon-11, and oxygen, or using a generator such as rubidium-82 (Rb-82). In this chapter, we will introduce the applications of PET for evaluation of perfusion, coronary flow, and inflammation. The cardiac PET tracers used for these purposes are O-15-H2O with a half-life of 2.06 min, N-13 ammonia with a half-life of 9.8 min, Rb-82 with a 76-s half-life, and fluorine-18 fluorodeoxyglucose (18F-FDG) with a 110-min half-life. With the exception of 18F-FDG, these tracers are not widely available, as they require either an onsite cyclotron or a costly generator for their production. PET myocardial perfusion imaging (MPI) with various tracers such as Rb-82, N-13 ammonia, and O-15-H2O has higher sensitivity and specificity than myocardial perfusion SPECT for the detection of coronary artery disease (CAD). Advances in positron emission tomography technology have expanded the application of cardiac PET myocardial perfusion imaging – improved count rate performance, data handling, and computing power of current-generation PET systems have enabled routine quantification of absolute myocardial blood flow (MBF) and coronary flow reserve (CFR). Prognostic data from several recent studies have suggested an important clinical role for MBF quantification and have motivated increased interest in this area [8]. In particular, quantitative PET measurements of myocardial

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perfusion help identify subclinical coronary stenosis, better define the extent and severity of CAD, and detect ischemia when there is balanced reduction in myocardial perfusion due to three-vessel or main-stem CAD [9]. Fusion images of PET perfusion and CT coronary artery calcium scoring or CT coronary angiography provide additional complementary information and improve the detection of CAD. 18F-FDG-PET imaging has high sensitivity for the detection of hibernating/ viable myocardium and detection of cardiac infection and inflammation.

Perfusion Positron Emission Tomography Myocardial Perfusion Imaging Coronary artery disease is a major cause of mortality worldwide. It also presents an enormous societal burden with respect to morbidity, health care expense, and personal hardship. Multiple noninvasive imaging modalities are available for its evaluation and the extension and severity of ischemia is an important parameter for clinical decision-making. Myocardial perfusion scintigraphy single photon emission computed tomography (SPECT) with technetium-99  m-labeled tracers still remains the most widely used noninvasive technique for detecting myocardial ischemia. Myocardial perfusion imaging plays a key role in diagnosing cardiovascular disease, establishing prognosis, assessing the effectiveness of therapy, and evaluating viability [10]. Although SPECT myocardial perfusion scintigraphy is considered an excellent method for detection of ischemia, with 87% sensitivity and 70% specificity in several meta-analyses including a systematic review and meta-analysis of 86 studies (Department of Health Quality of Ontario in Canada) [11] and of 88% and 74%, respectively, in several other series of patients, the technique presents some limitations, such as artifacts caused by the physiological elimination pathways of radiopharmaceuticals labeled with technetium-99m, patient motion artifacts, the absence of attenuation correction on most of the equipment used for the acquisition of the images, and lack of ability to measure quantitatively myocardial perfusion [12]. In addition, the interpretation of the images is made mainly through visual analysis of relative radiopharmaceutical distribution on the walls of the left ventricle (LV) and the contrast of the myocardial tissue sick/normal (hypo/normoperfusion) is determined by the retention fraction of the tracer, which decreases not linearly with increased blood flow caused by cardiovascular stresses. Decreased tissue perfusion, resulting in decreased tracer retention, and the severity of perfusion defects are usually underestimated at 20–40%. This fact can lead to false-negative findings, that is, underestimation of ischemia in the presence of multivessel CAD, in the so-called balanced lesions, or even in left main coronary lesions. Furthermore, although the importance of physiological evaluation of ischemic heart disease is well recognized in the literature, surely SPECT myocardial perfusion scintigraphy may also

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Myocardial Perfusion Imaging SPECT X PET SPECT

PET

Diagnostic Accuracy 78 – 85 %

Diagnostic Accuracy 90 %

 Longer Exam Time Patient Discomfort More susceptible to Movement Artifacts during acquisition  No attenuation correction (in general)  Relative Perfusion

 Short Exam Time Comfortable Less susceptible to Movement Artifacts during acquisition  Attenuation Correction Accurate  Relative Perfusion (Higher Diagnostic Accuracy)

 No absolute quantification (in general)

 Absolute quantification (MBF/CFR)

 Post-stress LVEF

 Peak-stress LVEF

 Higher Radiation Exposure 5 ~ 12 mSv

 Lower Radiation Exposure 3 ~ 4 mSv

 Physical and pharmacological stress

 Pharmacological stress

Fig. 1.2  Comparison between SPECT and PET myocardial perfusion imaging

underestimate the detection of diffuse coronary atherosclerosis and coronary microvascular disease. Positron emission tomography/computed tomography (PET/CT) myocardial perfusion imaging provides superior accuracy and consistent high-­ quality images allowing higher interpretive certainty, low-radiation exposure, and short acquisition protocols; is able to quantify noninvasively myocardial blood flow in absolute terms and coronary flow reserve; has strong prognostic power; and allows for capturing left ventricular ejection fraction (LVEF) close to peak pharmacologic action of cardiovascular stressor agent. Figure 1.2 summarizes some important differences between SPECT and PET myocardial perfusion assessment. These parameters provide additional information over conventional modalities with decreased radiation exposure and shorter acquisition time, as mentioned [13–15]. Post-stress decrease in left ventricular ejection fraction (LVEF) is an important additional finding, which implies higher risk of cardiovascular events. However, as SPECT stress images are acquired several minutes (usually 30–40 min) after the completion of cardiovascular stress, there is an interval between the completion of stress that caused ischemic changes and acquisition of the post-stress images. During this interval, hemodynamic and functional changes in the left ventricle that occurred during stress can partially or fully recover, causing a negative impact on the detection of LV functional post-stress abnormalities. The images of LV function obtained with PET tracers present great advantage compared to SPECT in detecting

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stress-induced left ventricle functional abnormalities, since the acquisition of the images is made during or very close to the peak of action of cardiovascular stressor agent, which allows to evaluate changes in LV wall motion and ejection fraction in real time [16, 17]. PET/CT myocardial perfusion imaging implies the intravenous (IV) injection of a positron-emitting perfusion tracer, for dynamic acquisition of images of the radiotracer passing through the central circulatory system to its extraction and retention in the LV myocardium. As mentioned before, a number of exciting advances in PET/CT technology and improvements in methodology have converged to enhance the feasibility of routine clinical quantification of myocardial blood flow and coronary flow reserve. The acquisition of relative perfusion images, function images, and absolute quantification of myocardial blood flow is named dynamic cardiac PET or dynamic PET, which involves simultaneous tracer injection and image acquisition of short-lived radionuclides. “List-mode” acquisition is performed to reconstruct static, dynamic, and gated images with a single radiotracer injection, generally conducted in a two-phase acquisition—during rest and during stress (either pharmacological or physical). Static data generally reconstructed from the final frame are used for visual and semi-quantitative interpretation of relative perfusion. Myocardial perfusion absolute quantification (myocardial blood flow at rest and stress) is derived from the sequential dynamic first-pass images, which, synchronized with electrocardiogram (ECG), permit evaluation of LV function. Three-­ dimensional (3D) mode acquisition and iterative reconstructions deliver images with better contrast and resolution, with added improved temporal resolution. As such, due to sensitivity and nature of the detection, PET has superior image quality and therefore better diagnostic accuracy over SPECT. The following parameters are obtained: relative perfusion images at rest and stress; LV volumes at rest and stress; LV global and regional function at rest and stress (LVEF); myocardial blood flow quantification in mL/min/g (global and regional) at rest and stress; and the coronary flow reserve (CFR), which is the relation between hyperemic myocardial blood flow (during pharmacological stress) and resting myocardial blood flow. Radiotracers A pivotal property of perfusion tracers is a high first-pass extraction fraction at different flow rates. Low extraction at high flow rates leads to decreased accuracy of ischemia detection, which represents an error source of underestimation. While O-15 water offers the benefit of free diffusion with 100% extraction fraction, N-13 ammonia and especially Rb-82 are extracted by a decreasing rate at higher flow values [18]. Another important characteristic of PET perfusion tracers is the positron range in tissue. The radionuclide emits a positron with kinetic energy. The positron annihilates on contact with electrons after traveling a short distance and produces two 511-keV photons in opposite directions. Since PET systems detect these 511-keV photons and not the original positron, the distance the

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Table 1.1  Radiotracer characteristics and image acquisition for PET perfusion and MBF O-H20 Onsite cyclotron 15

Production

N-ammonia Onsite/nearby cyclotron 9.96 min ≈80%

82

Rb Generator

18

76 s ≈65%

109 min ≈94%

8.6 mm Soluble, microsphere like Dynamic, static, gated Lowest

1.03 mm Soluble, microsphere like, metabolically trapped Dynamic, static, gated Highest

13

F-flurpiridaz Regional cyclotron

Half-life Extraction fraction Positron range Mechanism

2.06 min ≈100%

Data acquisition

Dynamic

Perfusion defect contrast Image quality Pharmacologic stress protocol Treadmill exercise protocol

Intermediate

2.53 mm Soluble, microsphere like, metabolically trapped Dynamic, static, gated Intermediate

N/A Feasible

Excellent Feasible

Good Feasible

Excellent Feasible

Not feasible

Feasible but not practical

Not feasible

Feasible

4.14 mm Freely diffusible, metabolically inert

PET positron emission tomography, MBF myocardial blood flow, N/A not applicable

positron travels prior to annihilation will affect the spatial resolution of PET imaging. High-­energy positrons have long travel distances prior to annihilation and thus demonstrate decreased spatial resolution in comparison to low-energy positrons. In this regard, F-18 has the shortest positron range in comparison with Rb-82, O-15, and N-13, and is expected to obtain the highest spatial resolution (Table 1.1) [19]. Radiolabeled water (15O-H2O) is a metabolically inert and freely diffusible perfusion tracer. Consequently, myocardial uptake is linearly related to MBF, which allows accurate quantification of MBF over a wide range of values. However, since 15 O-H2O is not retained in the myocardial compartment, it rapidly reaches an equilibrium between myocardium and blood pool, without enough myocardial contrast to generate appropriate perfusion images. Quantitative assessment of MBF with 15 O-H2O requires complex mathematical processing to separate myocardial and blood pool and create anatomical images of the left ventricle [18, 20]. These radiokinetic features have limited the ample use of 15O-H2O for clinical PET perfusion imaging. For research purposes, however, this tracer has gained wide popularity. Indeed, 15O-H2O is the ideal radiotracer for flow quantification due to its free diffusion through the cell membrane and tissue uptake proportional to flow. Remarkably, its extraction fraction is 100%. 15O-H2O has an intermediate positron range (4.14 mm) and the very short physical half-life of the 15O isotope (2 min) allows repeated measurements of MBF under different biological conditions in the same session. This radiotracer requires an on-site production. Pharmacologic stress imaging protocol is feasible but treadmill exercise imaging protocol is not [21].

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N-ammonia (13N-NH3) has a high first-pass extraction rate of up to 80% and myocardial uptake is linear over a wide range of MBF, except at very high flow rates. Upon internalization, 13N-NH3 is trapped in the intracellular compartment after metabolic conversion into 13N-glutamine, thereby creating high myocardial contrast images. However, its short physical half-life (10 min) requires an on-site cyclotron for production and immediate administration. The favorable positron range (2.53 mm) and 80% myocardial extraction fraction allow acquisition of intermediate- to high-quality images. A similar performance of 13N-NH3 compared to 15 O-H2O for quantification of MBF has been demonstrated in experimental animal and human studies [22, 23]. Its ability to provide high-quality perfusion images and allow quantification of regional MBF simultaneously has advanced this compound as an excellent clinical perfusion tracer in diagnostic centers with an on-site cyclotron, and an increasing number of publications underline its clinical diagnostic and prognostic value. It is important to mention that for obtaining cardiac images with 13 N-ammonia, pharmacological stress imaging protocol is feasible and treadmill exercise is feasible as well but not practical. Rubidium-82 (82Rb) is an analogue of the potassium cation and undergoes cellular uptake by the Na/K-ATPase. It was one of the first-introduced PET tracers. Unlike other positron-emitting compounds that are cyclotron products, 82Rb can be obtained from commercially available 82Sr/82Rb generator, which has a 5-week shelf life, by decay from 82Sr attached to an elution column (Fig. 1.3). Downsides of 82Rb are the lower myocardial extraction rate (65%), its nonlinear relationship between myocardial tracer uptake and MBF [24, 25], the high positron range of 8.6  mm (which allows the positron to travel for several millimeters before annihilation and thereby lowers spatial resolution), and the ultrashort half-life of 76  s, leading to detector oversaturation at the beginning of the acquisition (particularly with three-­ dimensional acquisition protocols) and low-count statistics and increased image noise in later phases. Since 82Rb is currently the most widely applicable radiotracer for clinical MBF quantification, and has some limitations as a myocardial perfusion PET tracer, some aspects related to dynamic PET with 82Rb acquisition and processing will be addressed later in this chapter. 13

PET Acquisition PET images can be acquired in 2D or 3D mode. Most new PET scanners have 3D images, which improves sensitivity and allows for a reduction in radiation exposure but has increased scatter, dead time, and random events compared with 2D imaging. PET imaging modes can be static, gated, or dynamic. • Static PET acquisition produces myocardial perfusion images that allow relative assessment of tracer uptake on a regional basis. • Gated images: electrocardiographic (ECG)-gated images are acquired in 8 or 16 frames per R-R cycle, in a manner similar to SPECT-gated perfusion studies but at higher spatial resolution.

1  Cardiac PET Procedure: Perfusion, Coronary Flow, Viability, Inflammation… 82Rb

Generador

9

Automatic infusion system

Fig. 1.3  Strontium-82 (82Sr)/rubidium-82 (82Rb) generator and automatic infusion system

• Dynamic acquisition: it is strongly recommended that the data be acquired in dynamic mode/list mode (simultaneous dynamic and ECG-gated) beginning at radionuclide injection, which permits to obtain myocardial perfusion rest and stress images, functional rest and stress images (gated images), plus quantitative images (absolute MBF rest and stress measurements and CFR). From now on, we will present and discuss the dynamic acquisition protocol (Fig. 1.4). PET Imaging Protocols Quantitative perfusion begins with a topogram acquisition for patient positioning. Then, a CT transmission is acquired. The radiotracer is injected (25–50 millicuries [mCi] of 82Rb, 10–20  mCi of 13N-ammonia, and 10–30  mCi of 15O-H2O) and

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J. Soares Junior Horizontal Long Axis

RA/RV Blood Pool

LV Myocardium

Time after Injection

Short Axis

LV Blood Pool

LV Myocardium

Fig. 1.4  PET myocardial perfusion dynamic acquisition. The first sign of activity is in the right atrium/right ventricle (RA/RV blood pool), and then the activity is present in the left ventricle (LV blood pool), and finally the activity is seen in the myocardial wall surrounding the left ventricle (LV myocardium)

dynamic resting imaging acquisition is initiated simultaneously (10  min for 13 N-ammonia and 5–6 min for 15O-H2O or 82Rb). In the second phase, stress induced by pharmacologic stressor—adenosine or dipyridamole—can be performed without delay when using 15O-H2O or 82Rb. With 13N-ammonia the second study is routinely delayed 30 min after the first acquisition, to allow for radiotracer decay. A second dose of radiotracer is injected and the stress imaging acquisition is performed [26]. A schematic diagram of dynamic PET acquisition protocol using 82Rb and 13 N-ammonia is presented in Figs. 1.5 and 1.6, respectively. However, it is possible to conduct a three-phase scan that incorporates cold pressor testing (CPT) through sympathetic stimulation, and CPT takes place after rest and before stress. The ratio of CPT myocardial blood flow to rest myocardial blood flow is known as the endothelial-­dependent vasodilatory index (EDVI) [27]. The ratio of stress myocardial blood flow (MBF) to rest myocardial blood flow is known as the coronary flow reserve (CFR) or myocardial perfusion reserve (MPR). Stress MBF and CFR are used to evaluate the vasodilatory capacity of the coronary artery tree globally as well as regionally, and due to great importance will be addressed in detail in the following pages.

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Schematic acquisition protocol for dynamic PET- myocardial perfusion imaging Using 82Rb 82Rb Pharmacologic 82Rb 30s infusion stress 30s infusion Aminophylline CT-AC CT-AC Rest phase 6 min Gated

Stress phase 6 min

No delay between rest and stress

a

Gated

(min) 30-45 min

b

Right and Left Ventricular Blood Pool Dynamic

Left Ventricular Myocardium

Time after injection

Fig. 1.5  Schematic diagram of dynamic PET acquisition protocol using IV injection of 82Rb at rest and during pharmacological stress (dipyridamole, adenosine, or dobutamine). Note that no delay is necessary between rest and stress acquisitions (due to the ultrashort half-life of 82Rb), and the total procedure time is around 30–45 min. Dynamic PET myocardial perfusion imaging (MPI) used in conjunction with tracer kinetic modeling (1–3 compartments) enables the quantification of absolute myocardial blood flow (MBF). Cardiac perfusion PET data can be reconstructed as a dynamic sequence and kinetic modeling performed to quantify myocardial blood flow, or reconstructed as static gated images to quantify function. (a) Right ventricular blood pool (yellow arrows) and left ventricular blood pool (red arrows). (b) Left ventricular myocardium (red arrows). CT-AC computed tomography-based attenuation correction

Patient Preparation and Protocols Inherently with PET, physical exercise procedures are difficult to perform owing to the temporal proximity of tracer injection and image acquisition. Therefore, pharmacological stress (with vasodilators or dobutamine) is preferred. Patient preparation should be the same used for pharmacological stress. All stress procedures should be supervised by a qualified physician with knowledge of the available pharmacological stress agents and expertise in advanced life support techniques. Due to the importance of quantification of myocardial flow, above and beyond relative perfusion imaging, as 13N-ammonia CFR increases diagnostic sensitivity and has a strong association with prognosis and 82Rb MBF and CFR correctly detect three-vessel CAD and predict adverse cardiovascular events, absolute quantification of MBF and CFR has been well established and is progressively entering routine

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J. Soares Junior Schematic acquisition protocol for dynamic PET-myocardial perfusion imaging Using 13N-Ammonia Pharmacologic 13N-NH Aminophylline stress 3

13N-NH 3

CT-AC

Rest phase 10 min Gated

Stress phase 10 min Gated

CT-AC (min) 60-80 min

~ 30 min delay between rest and stress

LV blood pool Myocardium Myocardium-modeled

Dynamic

Time after injection

Fig. 1.6 Schematic diagram of dynamic PET acquisition protocol using IV injection of 13 N-ammonia at rest and during pharmacological stress (dipyridamole, adenosine, or dobutamine). Note that a 30-min delay is necessary between rest and stress acquisitions, and the total duration of the procedure is around 60–80 min. Dynamic PET myocardial perfusion imaging (MPI) used in conjunction with tracer kinetic modeling (1–3 compartments) enables the quantification of absolute myocardial blood flow (MBF). Cardiac perfusion PET data can be reconstructed as a dynamic sequence and kinetic modeling performed to quantify myocardial blood flow, or reconstructed as static gated images to quantify function. Operational equations are applied to correct for physical decay of the radiotracer, partial volume, and spillover of radioactivity between the left ventricular blood pool (yellow arrow) and myocardium (red arrow). Data obtained through region of interest (ROI) analysis of dynamic images produce a tissue time-activity-curve: in red, blood pool of left-­ ventricle (left ventricular blood pool); and in blue, the tracer concentration after corrected for partial volume and spillover of the radioactive blood in the myocardium. (CT-AC computed tomography-­based attenuation correction)

clinical practice. Because of these evidences, imaging protocols for Myocardial Perfusion with PET tracers include dynamic acquisitions that permit to obtain perfusion images, LV function images, and absolute quantification of MBF, all at rest and during pharmacological stress. Patient Positioning Patient should be placed in the supine position, with the arms out of the PET field of view.

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Dose Considerations • • •

Rb: 25–50 mCi (at rest and at stress) N-ammonia: 10–20 mCi (at rest and at stress) 15 O-H2O: 10–30 mCi (at rest and at stress) 82 13

Rb considerations  For an automated elution/infusion, the system is provided with 82Sr/82Rb generators, which measure the delivered dose using a beta probe, as shown in Fig. 1.3. The recommended weight-based dose of rubidium Rb-82 chloride to be administered per rest or stress component of a PET myocardial perfusion imaging (MPI) procedure is between 10 and 30 megabecquerels (MBq)/kg (0.27–0.81 mCi/kg). Do not exceed a single dose of 2220 MBq (60 mCi). In general, 82Rb dose is infused over 20–30 s, using a constant flow or constant activity mode. Therefore, this time can be enlarged in some types of equipment in order to avoid crystal block saturation. For example, in some 3D time-of-flight (TOF) PET, the timing window (time resolution) for pairs of detectors are not short enough (4–6 nanoseconds), especially in high count rate dynamic studies, and thus detector block saturation occurs causing reduction in the accuracy of MBF quantification. In our experience with a 3D TOF-PET/CT, our group of The Heart Institute in Brazil used an extended Rb-82 infusion (60 s) to avoid detector block saturation and demonstrated that using a 60  s prolonged Rb-82 infusion, MBF and CFR measures could be successfully obtained [28]. Use the lowest dose necessary to obtain adequate cardiac visualization and individualize the weight-based dose depending on multiple factors, including patient weight, imaging equipment, and acquisition type used to perform the procedure. For example, 3D imaging acquisition may require doses at the lower end of the recommended range compared to 2D imaging. For dynamic PET, administer the single dose at a rate of 15–30 mL/min through a catheter inserted into a large peripheral vein; do not exceed an infusion volume of 60 mL. 82

The cardiovascular stress should be provoked by a pharmacological stressor, in general adenosine or dipyridamole, as the evaluation of myocardial blood flow requires the acquisition of dynamic images that represent the arrival of radiotracer in the myocardium of the left ventricle and, therefore, the radiotracer administration must be done with the patient previously positioned in the equipment PET/ CT. Exercise stress is feasible with 13N-NH3 but is associated with increased personnel radiation exposure, must be timed to account for radiotracer decay, and immediate post-exercise imaging may be compromised by patient motion. For dynamic acquisition, PET data are acquired in multiple time-sequenced frames, and the acquisition protocols for 82Rb and 13N-ammonia include CT topogram/Scout for heart localization, CT transmission for attenuation correction (80–140  kVp, 10–20  mA, 4–5  mm slice thickness, ungated to ECG), radiotracer injection at rest, rest emission scan, stress test, radiotracer injection, stress emission scan, CT transmission. Typical flow of a PET myocardial perfusion imaging using 82 Rb and 13N-ammonia is schematically described in Figs. 1.5 and 1.6. Specific 82Rb

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rest/stress myocardial perfusion imaging guideline for BGO, LSO (LYSO), and GSO-PET imaging systems are described in the ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures [29]. Dipyridamole Stress Test Procedure Mechanism of action  Dipyridamole is an indirect coronary artery vasodilator that increases the tissue levels of adenosine by preventing the intracellular reuptake and deamination of adenosine. Dipyridamole-induced hyperemia lasts for more than 15 min. Patient preparation includes nothing to eat for at least 4  h and no caffeine-­ containing beverages or medication at least 12–24  h prior to testing; methylxanthines such as aminophylline, caffeine, or theobromine block the effect of dipyridamole and should be held for at least 12 h prior to the test. Dipyridamole dose  Dipyridamole is administered at 0.56  mg/kg intravenously over a 4-min period (142 μg/kg/min). Clinical and electrocardiographic monitoring is needed; heart rate (HR), blood pressure (BP), and ECG obtained every minute. Presence or absence of symptoms should also be noted every minute. After dipyridamole infusion is finished, click recovery on the monitor and the stress radiotracer is injected IV 3–5  min post-infusion (4  min). Aminophylline (125–250 mg) may be given if the patient develops side-effects from dipyridamole. Ideally, this should be given 2–3  min post stress radiotracer administration. Figure 1.7 shows patient position for dynamic 82Rb MPI acquisition. Adenosine Stress Test Procedure Adenosine is a direct coronary arterial vasodilator and results in a 3.5- to 4-fold increase in myocardial blood flow. Adenosine is given as a continuous infusion at a rate of 140 μg/kg/min over a 4-min period. Maximum dose is 60 mg. Radiotracer infusion should be between 2 min after the start of the adenosine infusion. The infusion of adenosine should not be interrupted for the radiotracer injection. The ECG, heart rate, and symptoms should be monitored continuously during and 5 min upon completion of the adenosine infusion. The half-life of adenosine is less than 10 s. Thus, the adverse effects are generally rapidly self-limiting. If symptoms persist, administer aminophylline, 125 mg, IV, by slow infusion (1 min). Aminophylline administration should be delayed for at least 1 min post radiotracer administration.

1  Cardiac PET Procedure: Perfusion, Coronary Flow, Viability, Inflammation…

a

c

15

b

d

Fig. 1.7  Patient positioning during dynamic 82Rb-MPI acquisition in a hybrid PET/CT (a and b). (c) Venous injection system with no-reflow device. (d) Dipyridamole stress test preparation

Although the clinical use of Regadenoson has not been widely spread yet, this A2A-selective adenosine receptor agonist is administered as a 0.4 mg bolus injected over 15–20 s and followed by a 10-mL saline flush before radiotracer injection. Image Processing Data are reconstructed using filtered back projection or iterative (e.g., ordered subsets expectation maximization [OSEM]), as recommended by each manufacturer. Scatter and random events as well attenuation corrections are applied. Matched resolution and reconstructed pixel size (2–4 mm) between rest and stress are noted. Static images are reconstructed with a prescan delay to minimize blood pool activity on static and gated images: 13N-ammonia (90–180 s); 82Rb (70–90 s if LVEF >50% and 90–130 s if LVEF 35 kg/ m2 perform a two-step exam to optimize the dose received by the radiopharmaceutical [17]. The IAEA document recommends the activity to be administered to patients following the BMI rule [17]: • • • •

Patients with BMI less than 25 kg/m2 – 300 MBq of 99mTc Patients with BMI between 25 and 30 kg/m2 – 340 MBq of 99mTc Patients with BMI between 30 and 35 kg/m2 – 380 MBq of 99mTc Patients with BMI greater than 35 kg/m2 or large chest – 440 MBq of 99mTc

One of the strategies associated with BMI is dose reference levels. In a paper published in 2018 between the European Association of Cardiovascular Imaging (EACVI), the Cardiovascular Committee of European Association of Nuclear Medicine (EANM), and the European Society of Cardiovascular Radiology (ESCR), some boundaries adopted between activity and dose were published (Fig. 4.11). Another strategy is to always check the clinical possibility of performing the stress-only protocol, which will reduce the patient’s radiation exposure by at least 50 %. Avoid protocols with more than one radionuclide, and avoid Tl-201 as radionuclide for MPI examinations. When using hybrid equipment for attenuation correction, always check whether or not a diagnostic image is required for the protocol to deliver the lowest dose required to the patient. Image acquisition protocol and reconstruction software have to be optimized by applying available iterative reconstructions, resolution recovery, and noise reduction. Equipment with solid-state detectors enables list-mode acquisition that combined with a cardiac phantom can do an optimization for image reconstruction and activity protocols [22]. Table 4.3 is from the study of Dorbala et al. where equipment with solid detectors using low dose was evaluated. These devices are still costly to be implemented in many institutions but bring many benefits to the patient’s dose exposure chain by reducing the effective dose and reducing manipulated Fig. 4.11 (White bar) Recommended radiotracer doses for MPI conventional scanners and (gray bar) for scanners with new software and/or hardware [20, 21]

139

4  Radiation Protection and Exposure in Nuclear Cardiology Table 4.3  Radiation dose from low-dose protocols for novel SPECT scanners [20] No. of Rest Study dosea Stress dosea patients 717 24 296–481 462.5; (8–13) 925–1332 (12.5; 25–36)

61

185 (5)

555 (15)

131

62

640 (17.29)

320 (8.65)

50

52

185–222 370–444 (5–6) (10–12) 222 (6) 740 (20)

137

129.5 (3.5)

101

51 48

NA

285

Radiotracer 99m Tc-­ sestamibi

Study Protocol radiation dose (mSv) (1 d) LD stress 4.2 only

BMI,   400 had inducible ischemia on MPI.  In another study, Moser et  al. [16] evaluated CAC score and MPI in asymptomatic patients and found rates of ischemic MPI of 5%, 24%, and 53% in patients with CAC scores of ≤  100, 101 to 400, and ≥ 400, respectively. Berman et al. evaluated 1195 consecutively tested patients without a prior CAD diagnosis who underwent both CAC scanning and MPI [17]; they observed that inducible myocardial ischemia during MPI occurred with low frequency, not only among patients with a CAC score of 400 (Fig. 7.1). Later, Rozanski et al. [18] assessed the relationship between CAC and ischemia according to the patient’s chest pain symptoms. Whereas the threshold CAC score for ischemia is very high among both asymptomatic patients and those with non-­ anginal chest pain, data in a small number of patients suggest that very low CAC scores may be associated with ischemia among patients with typical angina. The frequency rose substantially when the score exceeded 400, confirming this

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25

Ischemia >10%

* 19.9

20 15

*

%

8.9

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CAC = 0 (n = 250)

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> 1000 (n = 151)

*p 5% of the myocardium (dotted bars) and  >  10% of the myocardium (stripped bars). SPECT, single-­ photon emission computed tomography; CAC, coronary artery calcium. (Modified from Berman et al. [17])

threshold for general use in determining the need for subsequent ischemia testing. In concordance with these findings, the 2009 Appropriate Use Criteria for Cardiac Radionuclide Imaging [14] proposes two indications for MPI that are considered to be appropriate following abnormal CAC: (1) patients with a high cardiovascular heart disease (CHD) risk who have an Agatston CAC score of between 100 and 400 and (2) any patient with an Agatston score > 400.

Prognostic Applications of CAC Score Along with MPI CAC score and MPI have been used in combination with risk assessment. With technological advances, hybrid scanners PET and CT are becoming widely available. These hybrid scanners have enabled data acquisition from both modalities in a single session and allow performance of combined MPI and CAC scanning with minimal increase in time, effort, and radiation dose to the patient. Schenker et al. [19] evaluated the incremental prognostic value of simultaneously measured CAC combined with PET-MPI among 621 intermediate-risk patients and a mean follow­up of 1.4  years. The frequency of abnormal scans among patients with a CAC score ≥ 400 was higher than that in patients with a CAC score of 1 to 399 (48.5% vs. 21.7%, P  90 days after scanning), nonfatal myocardial infarction, and all-­ cause mortality. The frequency of abnormal SPECT increased with higher CAC scores from 12% in patients with CAC scores of 0 to 19%, 32%, 37%, and 50% among those with CAC scores of 1 to 99, 100 to 399, 400 to 999, and  ≥  1000, respectively (P  _ 1000

Fig. 7.3  Prevalence of abnormal SPECT according to CAC score. The frequency of abnormal SPECT increased with higher CAC scores from values of 0 to  ≥  1000. SPECT, single-photon emission computed tomography; CAC, coronary artery calcium. (Modified from Engbers et al. [9])

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Part II: Hybrid Cardiac Imaging – SPECT/CT Recently, additional integrated SPECT/CT devices have become available, including systems combining a state-of-the-art multi-head-gated camera and multi-­ detector CT scanner side by side with a common imaging. Some studies have demonstrated that the information obtained by SPECT/CT is more accurate in evaluating patients than that obtained from either SPECT or CT alone. SPECT and CT are proven diagnostic procedures, and fusion imaging in only one could give more important and complete information. Hybrid imaging is the registration of SPECT and CT image sets. The fusioned images typically are displayed with the SPECT data color coded to the CT data in gray scale [21]. The definition of functional relevance of a coronary stenosis by purely morpho-­anatomical criteria has remained controversial, despite many technical advances over the past decades. A coronary stenosis > 50% is generally perceived to confer hemodynamic relevance, although many parameters which cannot be fully elucidated by documenting coronary anatomy alone may determine whether a given lesion may eventually cause stressinduced ischemia or not. Therefore, according to evidence-based guidelines, the proof of ischemia is essential for best clinical practice prior to any revascularization procedure, because a revascularization in a non-­flow-­limiting stenosis is not of benefit to the patient in terms of prognostic or symptomatic improvement [22]. The recent introduction of cardiac hybrid imaging integrating morphological information obtained from noninvasive CCTA with the functional information from the MPI allows a comprehensive noninvasive assessment of CAD. The initial experience on the added clinical value of hybrid imaging has provided encouraging results. In fact, these studies support that hybrid images offer superior diagnostic information with regard to the identification of the culprit vessel and may potentially allow an improved risk stratification. [23–25].

CT for Myocardial Perfusion Imaging: Attenuation Correction Nonhomogeneous photon attenuation in the thorax is one of the most important drawbacks of MPI, limiting the diagnostic accuracy, interpretive confidence, quantification, and laboratory efficiency. On the one hand, attenuation artifacts may reduce MPI specificity, since nonuniform, regional perfusion distribution may be misinterpreted as a perfusion defect; it may also reduce MPI sensitivity when images are improperly scaled to regions suppressed by attenuation, potentially masking true perfusion defects. To overcome this problem, MPI images are corrected by determination of photon attenuation from intervening tissue in the volume of interest; attenuation correction uses CT transmission with SPECT data. Unfortunately, cardiac imaging poses a particular difficulty for AC because of respiratory and cardiac motion. AC using the integration of CT components was a major step forward, improving the specificity of SPECT MPI to 80–90%. AC images

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improve the confidence of the final interpretation by the physician [25, 26]. SPECT/ CT studies have shown that low-dose CT acquisitions are feasible for AC [27]. However, a potential misalignment between emission and transmission data poses the risk of incomplete correction, and thus artificial perfusion defects and requires careful quality control to avoid reconstruction artifacts. SPECT/CT studies show misalignment is quite frequent and the its consequences are clinically significant if they are not corrected [28].

Integration of MPI with CCTA Sato el al. [29] reported superior performance of side-by-side interpretation of 201-­ Tl SPECT/64-row multi-detector computed tomography (MDCT) for detecting > 50% stenosis on invasive coronary angiography (ICA) than alone in patients with suspected CAD. Most of the patients had an intermediate pretest likelihood of the disease. Some arteries were non-evaluable by CCTA (due to severe calcifications, motion artifacts, and/or poor opacification) but were considered positive on the basis of an intention-to-diagnose analysis. Compared to CCTA alone, the combination of SPECT and CCTA resulted in a significant increase in specificity (from 80 to 92%) and PPV (from 69 to 85%) without any change in sensitivity (95%) and NPV (97%). Most recently, Pazhenkottil et  al. [30] classified and followed 428 patients according to hybrid imaging findings into groups: matched those with stenosis of 50% or greater (at CCTA) with ischemia (at SPECT) in subtended territory, unmatched those with CCTA and/or SPECT findings in unrelated territories, and normal those with normal findings at both. End points were all-cause death or MI (“hard events”) and a composite of MACEs. During a median follow-up of 6.8 years, the annual hard event rate was more than fivefold higher for patients with matched findings and was threefold higher for patients with unmatched findings compared with the normal ones. The MACE rates were 21.8%, 9.0%, and 2.4% for matched, unmatched, and normal findings, respectively (Fig. 7.4). A matched hybrid SPECT/ CCTA pattern is associated with a high annual cardiac event rate and is an independent predictor for MACE and hard events (Fig. 7.5). Hybrid fusion imaging findings have shown an independent prognostic value by revealing both coronary stenosis and its functional relevance; this hybrid approach allows improved risk stratification and provides comprehensive information to guide management decisions in CAD patients [31]. A corresponding matched hybrid image finding was associated with a significantly higher death/MI incidence (P, 0.005) in a median follow-up of 2.8 years and proved to be an independent predictor for MACE. The specificity and positive predictive value (PPV) of stand-alone CCTA are particularly suboptimal in the presence of motion artifacts or severe coronary calcifications. Non-evaluable vessels with motion artifacts particularly in the right coronary (RC) artery territory do not usually have hemodynamic significance.

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25 21.8%

Matched

20

% / year

Unmatched Normal

15

10

9.0% 7.0%

5 2.4%

4.6%

3.7%

2.9% 1.2%

0.8%

0 MACE

Hard events

Death

Fig. 7.4  Major annual hard event rate in patients with matched findings in hybrid SPECT/CCTA imaging. Bars show increase in annual event rates of MACE, hard events, and death, in the group of patients with matched findings. SPECT, single-photon emission computed tomography; CCTA, coronary computed tomography angiography; MACE, major adverse cardiac events. (Modified from Pazhenkottil et al. [30])

Fig. 7.5  Cardiac hybrid SPECT/CCTA in a patient with a matched cardiac hybrid imaging demonstrated a matched perfusion defect in the territory of the left anterior descending artery. (a) Multi-planar CCTA reconstruction shows a stenosis of the proximal left anterior descending artery (grilled arrow). (b) Stress imaging, dotted arrow indicates a stress-induced anterior ischemia, and (c) rest imaging, stripped arrow demonstrates the reversibility of the anterior defect. SPECT, single-­photon emission computed tomography; CCTA, coronary computed tomography angiography. Modified from Pazhenkottil et al. [30]

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Image fusion is of particular value in lesions of distal segments, diagonal branches, RC artery, and left circumflex artery (LCX) [24, 25]. Integration of dual imaging appears to improve both the identification of the culprit vessel and the diagnostic confidence for categorizing intermediate lesions and equivocal perfusion defects, and provides added diagnostic information in almost one third of patients as compared to side-by-side analysis, and thus optimizing management decisions.

Part III: Hybrid Imaging – PET/CT Instrumentation and Technical Aspects of Hybrid Imaging A hybrid scanner is integrated with a special gantry that includes both, a PET scanner and a CT scanner, using a common bed to move the patient sequentially through both (Fig. 7.6). Fig. 7.6  PET/CT 64-slide hybrid scanner. The hybrid scanner integrates both systems, PET and CT, in one. PET, positron emission tomography; CT, computed tomography. (Contribution from Nuclear Medicine Department, National Medical Center “20 de Noviembre,” ISSSTE, Mexico City)

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Cardiac imaging may be performed in the two-dimensional or three-dimensional mode, using any of the available crystals (bismuth germanate, gadolinium oxyorthosilicate, lutetium oxyorthosilicate, or lutetium yttrium orthosilicate). Ideal CT configuration should be at least ≥  64-slice multi-detector row, to obtain a better image capability [32, 33]. After acquisition images, the processing and fusion of both images need a dedicated workstations integrated with a special platform for reviewing the respective MPI and CT images; dedicated software for fusion of the MPI and CT images is also needed. Hybrid images in PET/CT can be used for evaluation of ischemia or viability. For evaluation of ischemia, acquisitions of MPI rest-stress images with PET can be usually made with rubidium-82 chloride (82Rb) or nitrogen-13 ammonia (13N-ammonia); for viability evaluation, fluorine-18-2-­ fluoro-2-deoxy-D-glucose (18F-FDG) should be used. General standards and procedures should be done accordingly to the (1) SNMMI/ASNC/SCCT Guideline for Cardiac SPECT/CT and PET/CT [32], (2) ACR-SPR-STR Practice Parameter for the Performance of Cardiac Positron Emission Tomography-Computed Tomography Imaging [34], and (3) Hybrid cardiac imaging: SPECT/CT and PET/CT—a joint position statement by the European Association of Nuclear Medicine (EANM), the European Society of Cardiovascular Radiology (ESCR), and the European Council of Nuclear Cardiology (ECNC) [35]. In the hybrid imaging, the evaluation of MPI imaging with PET and coronary anatomy with CCTA is recommended to realize an initial detailed review of each independently and then use an image fusion technique (hybrid imaging) that includes an integrated anatomic and functional evaluation. Typically, they are acquired sequentially as a part of the same study using hybrid equipment. A sequential diagnostic approach is often applied in clinical practice, with an additional scan (CCTA or MPI) performed only if the results of the initial modality are equivocal. However, when CCTA is performed first, about 50% of the patients will need MPI. The CCTA images overlay on the volume-rendered rest or stress MPI allowing localizing the perfusion defects. The fusion images are typically used to map the abnormal territory on MPI corresponding to the diseased vessel on CCTA. Hybrid imaging can accurately allocate the culprit lesion in multivessel disease [32, 35]. Hybrid imaging with PET/CT combination is a promising tool for evaluation of coronary artery disease since it allows visualization of coronary atherosclerotic lesions and their hemodynamic consequences. A single study appears to offer superior diagnostic accuracy when compared with stand-alone imaging. In some cases, coronary artery anatomy varies considerably among individuals and may disagree with standardized vascular territories in up to 72% of patients referred to MPI; these cases are particular when perfusion defects are present in the inferior and inferolateral wall, which are traditionally those territories with the largest variability in coronary anatomy. Hence, the incremental value of hybrid cardiac imaging resides in the accurate spatial localization of myocardial perfusion defects and subtending coronary arteries (Fig. 7.7) [36].

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Fig. 7.7  Hybrid fusion cardiac PET/CT imaging. (a) Hybrid stress myocardial perfusion volume-­ rendered PET-CT: white arrow demonstrates an antero-apical perfusion defect (ischemia) supplied by the occluded left anterior descending artery. (b) CCTA: triangles show a complete occlusion of the proximal left anterior descending artery. PET/CT, positron emission tomography/computed tomography; CCTA, coronary computed tomography angiography. (Modified from Gaemperli O et al. [36])

Clinical Applications of Hybrid PET/CT Functional and anatomic assessments are necessary and complementary in specific clinical scenarios and enriched the diagnostic value of the hybrid method. Multivessel and subclinical atherosclerosis can be diagnosed accurately with an anatomic evaluation by CCTA and the functional diagnostic value of MPI-PET. The diagnostic value of hybrid images is very high. CCTA has an excellent negative predictive value (NPV) (96–99%) to exclude obstructive significant pericardial CAD (> 70%), indicating that CCTA can be used as a reliable screening tool for CAD. In another way, PPV of CCTA for identifying functional significant ischemia in different anatomic territories is only modest; also the stenosis severity can be overestimated, especially in patients with beam-hardening artifacts (blooming) from very calcified coronaries; in those cases is when the evaluation of MPI obtained from PET added value to the anatomical evaluation. Integration of both techniques in a hybrid imaging has a complementary role in the evaluation of patients with suspected CAD, with improved specificity and PPV as compared to CCTA alone to detection of >  50% stenosis CAD (sensitivity/specificity 96%/100%; PPV/NPV 100%/91%) [35, 37]. One added value was reported by Mouaz H et al. [38], referring the utility of MPI in the evaluation of left ventricular ejection fraction that increments the prognostic value of hybrid imaging. Therefore, combined gated PET-MPI and CCTA can provide better risk stratification by characterization of the extent and severity of underlying CAD and facilitate potential benefit from revascularization.

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The relationship between CCTA and stress perfusion imaging assessed by integrated PET/CT imaging has been published before by Di Carli et  al. [39]. The results indicated that only 47% of significant angiographic stenosis was associated with ischemia and about half of the patients with normal MPI results had evidence of non-flow-limiting CAD. Discordant findings on MPI and CCTA can result from (1) microvascular dysfunction (abnormal blood flow without obstructive pericardial CAD), (2) calcified and nonobstructive CAD with normal perfusion, or (3) obstructive CAD that is not flow-limiting (due to hemodynamic or collateral changes). One advantage of hybrid imaging combining anatomy and function is the power of localizing the guilty vessel of ischemia. Coronary artery anatomy varies considerably among some individuals. Discordances could exist with standardized vascular territories in a significant proportion of patients, particularly in the vascular territories of the LCX and RC arteries. In 72% of all patients, a disagreement in at least one myocardial segment was found. Most frequently, standard RC segments were reassigned to the LCX territory (39% of reassigned segments), and standard LCX segments were reassigned to the left anterior descending (LAD) territory (30%). The validity of segmental assignment with hybrid PET/CCTA has had an excellent agreement (kappa 0.80). Clinical information with fusion images can be enhanced in almost one third of patients. Current evidence suggests that hybrid imaging may be particularly useful in the following subgroups: (1) patients with multiple perfusion defects or perfusion defects involving the inferior and lateral wall and (2) in which either CCTA or MPI results are inconclusive or equivocal [40]. A new radiotracer fluorine-18 flurpiridaz (18F flurpiridaz) has been evaluated with very high-resolution multi-slice CT component (> 128 slices) hybrid scanner and demonstrated increased diagnostic accuracy for the detection of obstructive disease compared with simple techniques (NPV 100%, specificity 100%) [41]. Another potential value of hybrid imaging with PET/CT is the allowance of myocardial blood flow (MBF) quantification. A complete normal CCTA can rule out pericardial CAD but requires information of normal hyperemic MBF and coronary flow reserve (CFR) to rule out coronary microvascular dysfunction. In this context, hybrid PET/CT is useful in circumstances in which maximal MBF is globally reduced and difference must be made between (1) severe pericardial triple vessel disease, (2) diffuse coronary atherosclerosis without focal significance stenosis, and (3) diffuse microvascular disease. This is commonly encountered in patients with heart failure, generally with left ventricle (LV) dilation and reduced left ventricle ejection fraction (LVEF); in this patient, it could be better to plan a hybrid exam with PET/CT to exclude abnormalities in MBF [42]. Hybrid PET/CT study is the best exam to perform in heart failure patients with low to intermediate prior probability of CAD, in whom the primary purpose of the procedure is to exclude extensive CAD as the etiology of heart failure, and thereby avoid the risks and expense of invasive coronary angiography. It also should be noted the functional information gained regarding maximal dilator capacity of the coronary circulation carries important prognostic information which may be more predictive of cardiac death than either left ventricular ejection fraction or extent of pericardial CAD [43]. Therefore, hybrid imaging with PET/CT is a diagnostic tool

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• Improves diagnostic performance to detect CAD compared with CCTA alone. • Allows to identify flow limiting coronary lesions (‘culprit lesions’) in one or multivessel disease. • Adding diagnostic information in approximately one third of patients. • Provides independent prognostic information through combination of morphological and functional criteria.

Fig. 7.8  Incremental clinical value of hybrid imaging PET/CT. Combined perfusion imaging with PET and anatomic coronary evaluation with CCTA provides high diagnostic and prognostic value information in patients with CAD.  PET, positron emission tomography; CCTA, coronary computed tomography angiography. (Modified from Knaapen P. et al. [44])

that brings important information that increments clinical value in patients with suspected CAD (Fig. 7.8) [44]. Rizvi et al. [45] recently demonstrated in an important meta-analysis an improved diagnostic of hybrid methods for detection of obstructive CAD (luminal diameter reduction of >50% or > 70% detected in invasive coronary angiography). Compared with stand-alone CCTA, sensitivity of hybrid imaging and CCTA was compared (91% vs. 90%; p = 0.28); however, specificity was higher for hybrid imaging than CCTA (93% vs. 66%; p  2 usually exclude the presence of high-risk epicardial CAD (negative predictive value > 95%). Oppositely, global MFR  threefold from the basal level in response to an increased demand (exercise, neurohumoral, or pharmacology stimuli) [14–16]. The difference between the baseline and the maximal flow is the coronary flow reserve. The blood flow is autoregulated by a complex cascade in which the vessel diameter and resistance, the myocardial oxygen demand, and the adenosine metabolism have an important role [14–16]. Coronary circulation tree is composed by epicardial vessel (R1), small arteries and arterioles (R2), and intramyocardial capillaries (microvascular circulation) (R3) [15]. Adenosine plays a pivotal role in the coronary flow regulation at the arterioles (R2) level by promoting vasodilation through the A2A receptor in response to increased oxygen demand [17]. R1 resistance is mostly affected by epicardial atherosclerosis (coronary stenosis) and R3 flow may be impaired in conditions that affect the microvasculature (diabetes, left ventricle hypertrophy) [16] (Fig.  8.1). MBF measured by PET or SPECT accounts for all three levels of the resistance (is a measure of both epicardial and microvascular flows), and this is a major difference from the fractional flow reserve measured during coronary angiography (which only accounts for the epicardial vessel). Myocardial ischemia invariably occurs when CBF is insufficient to maintain myocardial contractile function and metabolism. Inadequate blood supply can be Fig. 8.1 Coronary vascular tree representation. A2A (receptor A2A for adenosine), R (resistance)

R1

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Adenosine

A 2A Ateroscherosis

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caused by anatomical and/or functional abnormalities in any of the compartments of the coronary circulation. In addition, extravascular factors, such as decreased diastolic time and elevated extravascular pressure affecting the coronary microcirculation, can also contribute to the development of myocardial ischemia. For over 200 years now, atherosclerotic disease of the epicardial coronary arteries has been recognized as the main cause of myocardial ischemia. CFR gradually diminishes as atherosclerosis causes the vascular lumen to narrow, thus progressively impairing tissue perfusion, all of which lead to ischemia. Data based on positron emission tomography (PET) for noninvasive quantification of regional myocardial blood flow have shown how dysfunction of the coronary microcirculation can occur in numerous clinical settings even in the absence of demonstrable evidence of stenosis on the large epicardial arteries. The term coronary microvascular dysfunction (CMD) covers a wide spectrum of clinical scenarios, including evidence of reduced CFR, and ischemia that is not attributable to epicardial stenosis. And as a further prognostic factor, CMD has also been seen to coexist with CAD. Similar to obstructive epicardial disease, CMD can lead to myocardial ischemia by impairing the ability of the coronary circulation to increase coronary blood flow in response to increased myocardial oxygen demand. CMD can result from an abnormal vasodilatory ability of the microvasculature, compressive external forces affecting the intramural microvessels, or microvascular spasm. CMD is typically the cause of myocardial ischemia in individuals with angina despite completely normal coronary arteriograms (primary microvascular angina), but it can also trigger myocardial ischemia in several other clinical conditions, including in patients with cardiomyopathies and those with obstructive coronary artery disease.

Ischemia-Stenosis Relationship There is a curvilinear relationship between reductions in myocardial blood flow and percent coronary stenosis such that a reduction in coronary blood flow is observed in the setting of a high-grade stenosis [18]. These statements reflect the general relationship between blood flow and obstructive CAD.  However, we can also observe that a high-grade stenosis may not be ischemic (i.e., stenosis without ischemia [SWOI]) [19]. Nearly half of high-grade stenosis may not be ischemic and are undetected with functional imaging alone, as currently undertaken within the current diagnostic evaluation algorithm. Care should be taken when interpreting no ischemia in patients with an elevated risk of obstructive CAD as being equivalent to a statement that the patient does not have CAD. Integration of non-perfusion, exercise, and symptom findings into test interpretation can help to improve risk detection for these patients and should be used whenever available. In addition to SWOI, lesion-specific ischemia has also been reported in the setting of a mild or intermediate coronary stenosis (ischemia without stenosis [IWOS]). Whether this occurs in the setting of high-risk plaque features or diffuse atherosclerosis remains unclear.

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This understanding of IWOS should revolutionize our diagnostic evaluation and result in an elimination of the term “false positive” findings for this patient subgroup. First, patients with mild to intermediate stenosis or for those with evidence of atherosclerotic plaque should be treated as having a diagnosis of CAD. Secondly, the presence of ischemia should prompt intensification of anti-ischemic therapy in addition to implementing CAD preventive therapies. However, data suggest that these patients often do not receive guideline-directed posttest changes in medical management, as they should [20]. As such, imagers should guide referring physicians to make changes in patient management, especially for the subgroup of patients with evidence of atherosclerosis and non-obstructive CAD.

Rationale and Clinical Value of MBF Quantification PET and SPECT MPI studies are based on relative perfusion image, and thus patients with multivessel or left main disease may be underdiagnosed by these methods [21]. Although the addition of gated evaluation has significantly improved the detection of the high-risk population [22], MBF quantification by PET, an absolute measurement in mL/min/g, has proved superior diagnostic accuracy [12, 23] (Fig. 8.2). Ziadi et al. studied a cohort of 120 patients with suspect who underwent 18Rb PET and coronary angiography within 6 months and showed that 88% of patients with severe three-vessel CAD had impaired myocardial flow reserve (MFR = stress/ rest MBF)