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Cardiac Neurotransmission Imaging*

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Cardiac Neurotransmission Imaging* CONTINUING EDUCATION Cardiac Neurotransmission Imaging* Ignasi Carrio´ Department of Nuclear Medicine, Hospital Sant Pau, Barcelona, Spain though no structural heart disease can be shown by tradi- Cardiac neurotransmission imaging with SPECT and PET allows tional morphologic and functional investigations. In such a in vivo assessment of presynaptic reuptake and neurotransmit- situation, evaluation of abnormalities of the cardiac nerves, ter storage as well as of regional distribution and activity of cardiac ganglia, and neurotransmission process may be clin- postsynaptic receptors. In this way, the biochemical processes ically relevant. In the United States, approximately 300,000 that occur during neurotransmission can be investigated in vivo at a micromolar level using radiolabeled neurotransmitters and sudden cardiac deaths occur each year, and almost 20% of receptor ligands. SPECT and PET of cardiac neurotransmission them are in patients without evidence of coronary artery characterize myocardial neuronal function in primary cardio- disease (2). Nuclear medicine is currently the only imaging neuropathies, in which the heart has no significant structural modality with sufficient sensitivity to offer in vivo visual- abnormality, and in secondary cardioneuropathies caused by ization of cardiac neurotransmission at a micromolar level. the metabolic and functional changes that take place in different Such a unique capability has great diagnostic potential and diseases of the heart. In patients with heart failure, the assess- currently allows noninvasive classification of dysautono- ment of sympathetic activity has important prognostic implica- tions and will result in better therapy and outcome. In diabetic mias, characterization of pathologic myocardial substrate in patients, scintigraphic techniques allow the detection of auto- arrhythmogenic cardiomyopathies, and assessment of neu- nomic neuropathy in early stages of the disease. In conditions ronal status in coronary artery disease. This article will with a risk of sudden death, such as idiopathic ventricular discuss the pathophysiologic basis of cardiac neurotrans- tachycardia and arrhythmogenic right ventricular cardiomyopa- mission and will focus on the main clinical applications, thy, PET and SPECT reveal altered neuronal function when no from those for which only preliminary but compelling data other structural abnormality is seen. In patients with ischemic are available to those that are well established. heart disease, heart transplantation, drug-induced cardiotoxic- ity, and dysautonomias, assessment of neuronal function can help characterize the disease and improve prognostic stratifi- CARDIAC INNERVATION AND NEUROTRANSMISSION cation. Future directions include the development of tracers for new types of receptors, the targeting of second messenger The autonomic nervous system is divided into the sym- molecules, and the early assessment of cardiac neurotransmis- pathetic and parasympathetic subsystems (3,4). The auto- sion in genetically predisposed subjects for prevention and early nomic outflow is controlled by regulatory centers in the treatment of heart failure. midbrain, hypothalamus, pons, and medulla. These regula- Key Words: cardiac neurotransmission; cardiac PET; cardiac tory centers integrate input signals coming from other areas SPECT; cardiomyopathies of the brain as well as afferent stimuli coming from barore- J Nucl Med 2001; 42:1062–1076 ceptors and chemoreceptors distributed in the skin, muscles, and viscera. Subsequently, efferent signals follow descend- ing pathways in the lateral funiculus of the spinal cord that terminate on cell bodies placed in the intermediolateral and Visualization and quantitation with SPECT and PET of intermediomedial columns. The major neurotransmitters of the pathophysiologic processes that take place in the nerve the sympathetic and parasympathetic systems are norepi- terminals, synaptic clefts, and postsynaptic sites in the heart nephrine and acetylcholine, which define the stimulatory can be referred to as cardiac neurotransmission imaging and inhibitory physiologic effects of each system. Sympa- (Fig. 1). Clearly, the nerves are as important as the coronary thetic fibers leave the spinal cord at segments T1 to L2–3. arteries for many of the functions of the heart, particularly Preganglionic sympathetic fibers consist of small myelin- cardiac rhythm, conduction, and repolarization (1). In many ated fibers that come off the spinal roots as white rami clinical circumstances, these processes appear altered al- communicantes and synapse in the paravertebral ganglia. Gray rami communicantes that rejoin the anterior spinal roots and connect with body organs are formed by small Received Dec. 8, 2000; revision accepted Mar. 9, 2001. For correspondence or reprints contact: Ignasi Carrio´ , MD, Hospital Sant unmyelinated postganglionic fibers (5). Adrenergic fibers Pau, Pare Claret 167, 08025-Barcelona, Spain. that innervate the heart originate in the left and right stellate *NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ACTIVITY THROUGH THE SNM WEB SITE (http://www.snm.org/education/ce_online.html) UNTIL ganglia. The left stellate innervates the right ventricle, JULY 2002. whereas the right stellate innervates the anterior and lateral 1062 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 42 • No. 7 • July 2001 guanethidine are also transported by uptake-1, which can be inhibited by cocaine and desipramine. A quantitatively less significant transport protein, uptake-2, removes norepineph- rine from the extracellular space. Free cytosolic norepineph- rine is degraded rapidly to dihydroxyphenylglycol by mono- amine oxidase and passes through the presynaptic cell membrane into the extracellular space by passive diffusion. Adrenergic neurotransmitters bind to the postsynaptic ␤-adrenoceptors. ␤1- and ␤2-receptors are located in the sarcolemma of the myocytes with a proportion of 80%:20%. FIGURE 1. Concept of cardiac neurotransmission imaging. This distribution may vary in the failing human heart, with On left, electron microscopy of cardiac synapse shows postsyn- a higher proportion of ␤2-receptors being expressed (7). aptic concentration of neurotransmitter. On right, methylquinu- ␤1-receptors are occupied by norepinephrine, whereas ␤2- clidinyl benzylate (MQNB) and PET show in vivo visualization of receptors are occupied by epinephrine. ␤ -receptors are cardiac muscarinic receptors in patient with dilated cardiomy- 1 opathy (DCM) and in healthy volunteer (CONTROL). located mainly in the synaptic cleft, whereas ␤2-receptors are located far from the synaptic cleft to protect epinephrine arriving as a hormone or from extracardiac neuronal pro- portions of the heart. The adrenergic fibers travel the sub- duction from neuronal reuptake. ␤-adrenoceptors are cou- endocardium, following the coronary vessels from the base pled to G protein subunits, and stimulation of ␤-adrenocep- to the apex of the heart (6). The parasympathetic innervation tors results in increased adenylyl cyclase activity, of the heart is scarce in comparison; the inferior wall is the subsequently leading to intracellular cyclic adenosine region with a higher density of parasympathetic fibers. monophosphate (cAMP) formation and phosphorylation of Parasympathetic innervation originates from the medulla intracellular proteins, mediated by protein kinases, and in- and follows through the right and left vagus nerves, which fluencing calcium transients and repolarization. When pro- then divide into the superior and inferior cardiac nerves. longed excessive stimulation of adrenergic receptors takes Parasympathetic fibers modulate sinoatrial nodal and atrio- place, the first consequence is desensitization of adrenocep- ventricular nodal function and innervate the atria, whereas tors, followed by downregulation with enhanced receptor vagal fibers to the ventricles are sparse. degradation and decreased receptor synthesis (7,8). The Activation of the sympathetic branch of the autonomic next step is uncoupling of the receptors with overexpression nervous system or a rise in the level of catecholamines may of inhibitory G proteins and ␤-ARK and downregulation of result in cardiac adrenergic stimulation and in subsequent adenylyl cyclase. The final clinical consequence is de- changes in the contractile and electrophysiologic status of the heart. The sympathetic nervous system is a vasoactive creased myocardial reserve and impaired exercise capacity. neurohormonal system that evolved as a primary means of On the other hand, parasympathetic innervation is distrib- preserving circulatory homeostasis during environmental uted throughout the atrial and ventricular walls, with a stress. Increased sympathetic activity, with respect to the gradient from the former to the latter, with acetylcholine cardiovascular system, leads to peripheral vasoconstriction, being the main neurotransmitter. Acetylcholine is synthe- sodium and water retention, and the activation of other sized by transport of choline into the cytosol of the nerve neurohormonal systems. At a cardiac level, sympathetic terminal through the high-affinity choline transporter and activation results in an increased heart rate (chronotropic acetylation by choline acetyltransferase. The transmitter is effect), augmented contractility (inotropic effect), and en- then stored in vesicles and released when nerve stimulation hanced atrioventricular conduction (dromotropic effect). In activates muscarinic receptors. The effects are terminated the heart, an increased
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