REVIEW ARTICLE Autonomic innervation of the heart: Role of molecular imaging Myron C. Gerson, MDa a
Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati
Received Jun 29, 2015; accepted Jun 29, 2015 doi:10.1007/s12350-015-0236-y
Remarkable progress has been made in the diagnosis and treatment of cardiac disease in the last 50 years, and yet the burden of heart failure is growing and the challenge of preventing arrhythmic death remains. The role of the autonomic nervous system in the development and progression of heart failure and in the initiation of sudden cardiac death has been studied extensively. Beta-adrenergic blockade has emerged as a cornerstone in the treatment of both heart failure and cardiac arrhythmias. Nevertheless, the ability to noninvasively measure cardiac autonomic activity, use measures of autonomic activity to guide cardiac therapy, and identify high and low risk patients has met with limited clinical application. Autonomic innervation of the heart: role of molecular imaging provides a broad review of scientific investigation of cardiac autonomic innervation, the accomplishments to date in the development of imaging to characterize autonomic innervation, and the prospects for the use of cardiac autonomic imaging to improve patient outcomes. The authors and editors of autonomic innervation of the heart: role of molecular imaging are to be congratulated for providing a comprehensive and definitive review of the subject. The book begins with a concise chapter reviewing the anatomy and physiology of the autonomic nervous system with a focus on the heart. This includes discussion of sympatho-vagal balance in control of cardiac inotropy and chronotropy, followed by a review of autonomic regulation of coronary blood flow. The second chapter is provided from a wealth of electrophysiologic experience and establishes a detailed foundation for the relationship of the cardiac autonomic nervous system to cardiac electrophysiology. The effects
Reprint requests: Myron C. Gerson, MD, Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati; myron. [email protected] J Nucl Cardiol 1071-3581/$34.00 Copyright Ó 2015 American Society of Nuclear Cardiology.
of sympathetic and parasympathetic nerve activity on the complex origins of ventricular arrhythmias are explored in terms of cellular and clinical mechanisms. Sympathetic and parasympathetic nerves differentially alter cellular effective refractory periods, with sympathetic activation shortening refractoriness and enhancing the potential for early and heterogeneous depolarizations. Parasympathetic activation prolongs refractoriness and increases the potential for other focal pacemakers to take a dominant role. A role of sympathetic innervation on up-regulation of nerve growth factor and related ‘‘nerve sprouting’’ is discussed as a source of innervation heterogeneity. The literature is discussed on the arrhythmogenic interaction of sympathetic heterogeneity in the border regions between myocardial scar and viable ischemic myocardium. This leads to discussion of the future role of imaging in assessing spatial distribution as well as intensity of autonomic innervation. The molecular mechanisms of ventricular arrhythmias arising from the interactions of cardiac innervation and genetic mutations in cellular channels (e.g., congenital long QT syndrome and Brugada syndrome) are reviewed. A section on atrial fibrillation explores the role of triggered activity from atrial locations outside the pulmonary vein ostia, the contribution to atrial fibrillation of ganglionated plexuses, and the role of parasympathetic as well as sympathetic nerve activity in the origin of atrial fibrillation. Indirect assessment of parasympathetic tone with measures of heart rate variability and baroreceptor sensitivity is reviewed leading to a discussion of parasympathetic modulation of sudden cardiac death. The chapter concludes with a discussion of the autonomic aspects of medical and device therapies for arrhythmias and heart failure, and the implications of vagal function for cardiac risk. Chapter 3 begins with a discussion of the role of the autonomic nervous system in normal cardiac function. It then reviews the reduction in vagal function and role of sympathetic nerve hyperactivity in the development and progression of heart failure. Chapter 4 examines the role
Gerson Autonomic innervation of the heart
of the autonomic nervous system in the development of ventricular arrhythmias during acute myocardial ischemia and infarction. Chapter 5 begins a section of the book focused on existing cardioneural radiotracers. The mechanism of tracers utilizing the norepinephrine uptake-1 transporter is presented, along with a detailed consideration of the challenges in quantitating sympathetic nerve activity and distribution. The important area of post-synaptic cardioneural tracers is then reviewed. Chapter 6 begins with a review of the physiology of the parasympathetic nervous system. It reviews the existing parasympathetic radiotracers and the complex compartmental analysis multi-injection protocols required currently to measure receptor density and affinity constants. Chapter 7 details the investigative steps involved in designing, synthesizing, and validating new autonomic radiotracers. The next chapter examines the strengths of positron emission tomography (PET) for autonomic imaging, including quantitation and kinetic data analysis. Chapter 9 defines the fundamentals of planar and tomographic imaging of I-123 MIBG. Standardization of planar imaging of I-123 MIBG has been described in guidelines and the chapter points to some of the essential steps required to provide accurate, reproducible regions of interest over cardiac and background regions of interest. The section on tomographic imaging provides a good discussion of the heterogeneous distribution of I-123 MIBG in the heart. There is no discussion of the differences in heartto-mediastinum ratio calculated from tomographic compared to planar images and no discussion about methods for regional quantitation of sympathetic activity. C-11 metahydroxyephedrine (mHED) has long served as the standard for imaging sympathetic nerve activity with PET. In chapter 10, the flow limitations of C-11 mHED are noted, with the resultant difficulty in early detection of significant sympathetic nerve loss until regional nerve losses approach 40% of control levels. This leads to a discussion of potential future PET tracers with more optimal kinetic properties. New tracers have also provided insights to better understand the various physiologic components of sympathetic nerve terminals. Chapter 11 explores the important area of imaging b-adrenergic receptors in the heart. Heart failure results in a decrease in the density of b-adrenergic receptors. It has been suggested that a mismatch between presynaptic sympathetic innervation and postsynaptic b-adrenergic receptors may lead to major adverse cardiac events. Investigation of this and other hypotheses related to post-synaptic b-adrenergic receptor density imaging has been limited by the sparse availability of short-lived C-11 b-adrenergic receptor tracers and the lack of specificity of many of these
Journal of Nuclear CardiologyÒ
tracers for individual b-receptor subgroups. The future potential for developing F-18 labeled b-adrenergic receptor tracers is likely to bring research with badrenergic receptor radiotracers to the forefront. Both presynaptic and post-synaptic PET imaging have been investigated in patients with dilated and hypertrophic cardiomyopathies, and derangements in autonomic function have been regarded as markers of ventricular remodeling in the course of heart failure. Chapter 12 discusses the role of PET imaging of autonomic innervation in heart failure. Chapter 13 begins by reviewing the underlying physiological principles of I-123 MIBG imaging for assessing autonomic function. I-123 MIBG findings in heart failure patients are then described including improvement in sympathetic neuronal function in response to treatment with b-adrenergic blockade and other guidelines-based therapies. The chapter focuses on the use of I-123 MIBG imaging to establish prognosis in heart failure patients. Specific attention is paid to the use of I-123 MIBG heart-to-mediastinum ratio to assess the risk of life-threatening cardiac arrhythmias. A thoughtful section on the current limitations of I-123 MIBG for cardiac neuronal evaluation contains a discussion of likely areas in which single photon imaging of the sympathetic cardiac innervation will improve in the coming years. The authors point out that selection of heart failure patients for implanted defibrillator placement and for selection of heart failure drugs is largely based on guidelines derived from populations of heart failure patients. Optimized therapy can be improved by consideration of the status of sympathetic innervation in order to provide individualized design of heart failure and arrhythmia treatment. Chapter 14 addresses the role of the sympathetic nervous system in patients with myocardial ischemia, including acute and remote myocardial infarction, stable coronary disease, vasospastic angina, and silent myocardial ischemia. The greater sensitivity to ischemic injury of sympathetic nerve terminals compared to myocytes is discussed, along with the increasing body of evidence suggesting that autonomic imaging may provide important clinical information regarding prognosis and response to therapy in patients with coronary heart disease. Chapter 15 is focused on the autonomic nervous system in patients with diabetes mellitus. The 5-year mortality in diabetics with cardiac autonomic neuropathy is estimated to be fivefold greater than in diabetic patients without evidence of autonomic neuropathy. The authors discuss the limitations of indirect measures of autonomic neuropathy including heart rate variability, citing literature that abnormalities of cardiac sympathetic innervation are detectable by imaging prior to detection by ECG-based methods. They review
Journal of Nuclear CardiologyÒ
literature documenting a nearly threefold increase in heart failure progression in diabetic patients with a reduced I-123 MIBG heart-to-mediastinum ratio (\1.6) and discuss the proposed mechanisms. It is proposed that early identification of autonomic neuropathy by I123 MIBG imaging may facilitate risk factor modification and intensive medical treatment, which may then favorably affect outcome. Chapter 19 explores the potential applications of sympathetic neural imaging in the treatment of heart failure patients. The response of nuclear measures of cardiac sympathetic innervation, along with measures of left ventricular function and clinical status, to guidelinebased medical and device therapy is reviewed. This leads to questions of potential roles for sympathetic imaging in optimizing heart failure medical therapy. It also leads to questions of the future roles of sympathetic innervation imaging to evaluate the effectiveness of an individual heart failure patient’s response to medical management and the likelihood that advanced heart failure therapies including ventricular assist devices or cardiac transplantation that carries increased risk and cost, will be required. Beyond the common clinical cardiac syndromes of ischemic heart disease, non-ischemic cardiomyopathy, and heart disease in patients with diabetes mellitus, the book explores autonomic imaging of less common cardiac and neurologic conditions. This includes cardiac amyloidosis (Chapter 16), cardiac transplantation (Chapter 17), cardiac autonomic involvement in renal disease (Chapter 20), and cardiac dysfunction resulting from cancer chemotherapeutic agents (Chapter 23).
Gerson Autonomic innervation of the heart
Cardiac sympathetic imaging of neurologic diseases and processes is explored in chapters 21 and 22, including the use of sympathetic imaging agents in the evaluation of effects of mental stress on the heart. Chapter 21 reviews cardiac sympathetic imaging as an aid in the classification of various neurodegenerative diseases. This includes I-123 MIBG images illustrating abnormal reduction in myocardial sympathetic nerve activity in Parkinson’s disease and Lewy body dementia, but preserved myocardial activity in multisystem atrophy and Alzheimer’s disease. Autonomic Innervation of the Heart: Role of Molecular Imaging shows many of the advantages of a multi-authored text. The chapters are authored by writers with extensive experience in their assigned topic. The chapters are structured with an abstract and introduction, and end with a conclusion section. As such, each chapter can stand alone as a complete work. The book also has the potential limitation of a multi-authored text, in that there is considerable redundancy and repetition among chapters, resulting in a longer book. Nevertheless, Innervation of the Heart is clearly written, extensively referenced, the material is easy to follow, and provides a definitive reference. It will prove indispensable to clinicians and scientists with a specific interest in the autonomic nervous system of the heart. It will be of broad interest to cardiac imagers, heart failure specialists, and electrophysiologists. With wider adoption of autonomic imaging procedures in the routine practice of cardiology, this excellent book will be of increasing interest for the general cardiology community.
Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati
Received Jun 29, 2015; accepted Jun 29, 2015 doi:10.1007/s12350-015-0236-y
Remarkable progress has been made in the diagnosis and treatment of cardiac disease in the last 50 years, and yet the burden of heart failure is growing and the challenge of preventing arrhythmic death remains. The role of the autonomic nervous system in the development and progression of heart failure and in the initiation of sudden cardiac death has been studied extensively. Beta-adrenergic blockade has emerged as a cornerstone in the treatment of both heart failure and cardiac arrhythmias. Nevertheless, the ability to noninvasively measure cardiac autonomic activity, use measures of autonomic activity to guide cardiac therapy, and identify high and low risk patients has met with limited clinical application. Autonomic innervation of the heart: role of molecular imaging provides a broad review of scientific investigation of cardiac autonomic innervation, the accomplishments to date in the development of imaging to characterize autonomic innervation, and the prospects for the use of cardiac autonomic imaging to improve patient outcomes. The authors and editors of autonomic innervation of the heart: role of molecular imaging are to be congratulated for providing a comprehensive and definitive review of the subject. The book begins with a concise chapter reviewing the anatomy and physiology of the autonomic nervous system with a focus on the heart. This includes discussion of sympatho-vagal balance in control of cardiac inotropy and chronotropy, followed by a review of autonomic regulation of coronary blood flow. The second chapter is provided from a wealth of electrophysiologic experience and establishes a detailed foundation for the relationship of the cardiac autonomic nervous system to cardiac electrophysiology. The effects
Reprint requests: Myron C. Gerson, MD, Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati; myron. [email protected] J Nucl Cardiol 1071-3581/$34.00 Copyright Ó 2015 American Society of Nuclear Cardiology.
of sympathetic and parasympathetic nerve activity on the complex origins of ventricular arrhythmias are explored in terms of cellular and clinical mechanisms. Sympathetic and parasympathetic nerves differentially alter cellular effective refractory periods, with sympathetic activation shortening refractoriness and enhancing the potential for early and heterogeneous depolarizations. Parasympathetic activation prolongs refractoriness and increases the potential for other focal pacemakers to take a dominant role. A role of sympathetic innervation on up-regulation of nerve growth factor and related ‘‘nerve sprouting’’ is discussed as a source of innervation heterogeneity. The literature is discussed on the arrhythmogenic interaction of sympathetic heterogeneity in the border regions between myocardial scar and viable ischemic myocardium. This leads to discussion of the future role of imaging in assessing spatial distribution as well as intensity of autonomic innervation. The molecular mechanisms of ventricular arrhythmias arising from the interactions of cardiac innervation and genetic mutations in cellular channels (e.g., congenital long QT syndrome and Brugada syndrome) are reviewed. A section on atrial fibrillation explores the role of triggered activity from atrial locations outside the pulmonary vein ostia, the contribution to atrial fibrillation of ganglionated plexuses, and the role of parasympathetic as well as sympathetic nerve activity in the origin of atrial fibrillation. Indirect assessment of parasympathetic tone with measures of heart rate variability and baroreceptor sensitivity is reviewed leading to a discussion of parasympathetic modulation of sudden cardiac death. The chapter concludes with a discussion of the autonomic aspects of medical and device therapies for arrhythmias and heart failure, and the implications of vagal function for cardiac risk. Chapter 3 begins with a discussion of the role of the autonomic nervous system in normal cardiac function. It then reviews the reduction in vagal function and role of sympathetic nerve hyperactivity in the development and progression of heart failure. Chapter 4 examines the role
Gerson Autonomic innervation of the heart
of the autonomic nervous system in the development of ventricular arrhythmias during acute myocardial ischemia and infarction. Chapter 5 begins a section of the book focused on existing cardioneural radiotracers. The mechanism of tracers utilizing the norepinephrine uptake-1 transporter is presented, along with a detailed consideration of the challenges in quantitating sympathetic nerve activity and distribution. The important area of post-synaptic cardioneural tracers is then reviewed. Chapter 6 begins with a review of the physiology of the parasympathetic nervous system. It reviews the existing parasympathetic radiotracers and the complex compartmental analysis multi-injection protocols required currently to measure receptor density and affinity constants. Chapter 7 details the investigative steps involved in designing, synthesizing, and validating new autonomic radiotracers. The next chapter examines the strengths of positron emission tomography (PET) for autonomic imaging, including quantitation and kinetic data analysis. Chapter 9 defines the fundamentals of planar and tomographic imaging of I-123 MIBG. Standardization of planar imaging of I-123 MIBG has been described in guidelines and the chapter points to some of the essential steps required to provide accurate, reproducible regions of interest over cardiac and background regions of interest. The section on tomographic imaging provides a good discussion of the heterogeneous distribution of I-123 MIBG in the heart. There is no discussion of the differences in heartto-mediastinum ratio calculated from tomographic compared to planar images and no discussion about methods for regional quantitation of sympathetic activity. C-11 metahydroxyephedrine (mHED) has long served as the standard for imaging sympathetic nerve activity with PET. In chapter 10, the flow limitations of C-11 mHED are noted, with the resultant difficulty in early detection of significant sympathetic nerve loss until regional nerve losses approach 40% of control levels. This leads to a discussion of potential future PET tracers with more optimal kinetic properties. New tracers have also provided insights to better understand the various physiologic components of sympathetic nerve terminals. Chapter 11 explores the important area of imaging b-adrenergic receptors in the heart. Heart failure results in a decrease in the density of b-adrenergic receptors. It has been suggested that a mismatch between presynaptic sympathetic innervation and postsynaptic b-adrenergic receptors may lead to major adverse cardiac events. Investigation of this and other hypotheses related to post-synaptic b-adrenergic receptor density imaging has been limited by the sparse availability of short-lived C-11 b-adrenergic receptor tracers and the lack of specificity of many of these
Journal of Nuclear CardiologyÒ
tracers for individual b-receptor subgroups. The future potential for developing F-18 labeled b-adrenergic receptor tracers is likely to bring research with badrenergic receptor radiotracers to the forefront. Both presynaptic and post-synaptic PET imaging have been investigated in patients with dilated and hypertrophic cardiomyopathies, and derangements in autonomic function have been regarded as markers of ventricular remodeling in the course of heart failure. Chapter 12 discusses the role of PET imaging of autonomic innervation in heart failure. Chapter 13 begins by reviewing the underlying physiological principles of I-123 MIBG imaging for assessing autonomic function. I-123 MIBG findings in heart failure patients are then described including improvement in sympathetic neuronal function in response to treatment with b-adrenergic blockade and other guidelines-based therapies. The chapter focuses on the use of I-123 MIBG imaging to establish prognosis in heart failure patients. Specific attention is paid to the use of I-123 MIBG heart-to-mediastinum ratio to assess the risk of life-threatening cardiac arrhythmias. A thoughtful section on the current limitations of I-123 MIBG for cardiac neuronal evaluation contains a discussion of likely areas in which single photon imaging of the sympathetic cardiac innervation will improve in the coming years. The authors point out that selection of heart failure patients for implanted defibrillator placement and for selection of heart failure drugs is largely based on guidelines derived from populations of heart failure patients. Optimized therapy can be improved by consideration of the status of sympathetic innervation in order to provide individualized design of heart failure and arrhythmia treatment. Chapter 14 addresses the role of the sympathetic nervous system in patients with myocardial ischemia, including acute and remote myocardial infarction, stable coronary disease, vasospastic angina, and silent myocardial ischemia. The greater sensitivity to ischemic injury of sympathetic nerve terminals compared to myocytes is discussed, along with the increasing body of evidence suggesting that autonomic imaging may provide important clinical information regarding prognosis and response to therapy in patients with coronary heart disease. Chapter 15 is focused on the autonomic nervous system in patients with diabetes mellitus. The 5-year mortality in diabetics with cardiac autonomic neuropathy is estimated to be fivefold greater than in diabetic patients without evidence of autonomic neuropathy. The authors discuss the limitations of indirect measures of autonomic neuropathy including heart rate variability, citing literature that abnormalities of cardiac sympathetic innervation are detectable by imaging prior to detection by ECG-based methods. They review
Journal of Nuclear CardiologyÒ
literature documenting a nearly threefold increase in heart failure progression in diabetic patients with a reduced I-123 MIBG heart-to-mediastinum ratio (\1.6) and discuss the proposed mechanisms. It is proposed that early identification of autonomic neuropathy by I123 MIBG imaging may facilitate risk factor modification and intensive medical treatment, which may then favorably affect outcome. Chapter 19 explores the potential applications of sympathetic neural imaging in the treatment of heart failure patients. The response of nuclear measures of cardiac sympathetic innervation, along with measures of left ventricular function and clinical status, to guidelinebased medical and device therapy is reviewed. This leads to questions of potential roles for sympathetic imaging in optimizing heart failure medical therapy. It also leads to questions of the future roles of sympathetic innervation imaging to evaluate the effectiveness of an individual heart failure patient’s response to medical management and the likelihood that advanced heart failure therapies including ventricular assist devices or cardiac transplantation that carries increased risk and cost, will be required. Beyond the common clinical cardiac syndromes of ischemic heart disease, non-ischemic cardiomyopathy, and heart disease in patients with diabetes mellitus, the book explores autonomic imaging of less common cardiac and neurologic conditions. This includes cardiac amyloidosis (Chapter 16), cardiac transplantation (Chapter 17), cardiac autonomic involvement in renal disease (Chapter 20), and cardiac dysfunction resulting from cancer chemotherapeutic agents (Chapter 23).
Gerson Autonomic innervation of the heart
Cardiac sympathetic imaging of neurologic diseases and processes is explored in chapters 21 and 22, including the use of sympathetic imaging agents in the evaluation of effects of mental stress on the heart. Chapter 21 reviews cardiac sympathetic imaging as an aid in the classification of various neurodegenerative diseases. This includes I-123 MIBG images illustrating abnormal reduction in myocardial sympathetic nerve activity in Parkinson’s disease and Lewy body dementia, but preserved myocardial activity in multisystem atrophy and Alzheimer’s disease. Autonomic Innervation of the Heart: Role of Molecular Imaging shows many of the advantages of a multi-authored text. The chapters are authored by writers with extensive experience in their assigned topic. The chapters are structured with an abstract and introduction, and end with a conclusion section. As such, each chapter can stand alone as a complete work. The book also has the potential limitation of a multi-authored text, in that there is considerable redundancy and repetition among chapters, resulting in a longer book. Nevertheless, Innervation of the Heart is clearly written, extensively referenced, the material is easy to follow, and provides a definitive reference. It will prove indispensable to clinicians and scientists with a specific interest in the autonomic nervous system of the heart. It will be of broad interest to cardiac imagers, heart failure specialists, and electrophysiologists. With wider adoption of autonomic imaging procedures in the routine practice of cardiology, this excellent book will be of increasing interest for the general cardiology community.
