CONTINUING EDUCATION Cardiac Neurotransmission Imagingjnm.snmjournals.org/content/42/7/1062.full.pdf · Cardiac Neurotransmission Imaging Ignasi Carrio´ Department of Nuclear Medicine,

CONTINUING EDUCATION

Cardiac Neurotransmission Imaging*Ignasi Carrio´

Department of Nuclear Medicine, Hospital Sant Pau, Barcelona, Spain

Cardiac neurotransmission imaging with SPECT and PET allowsin vivo assessment of presynaptic reuptake and neurotransmit-ter storage as well as of regional distribution and activity ofpostsynaptic receptors. In this way, the biochemical processesthat occur during neurotransmission can be investigated in vivoat a micromolar level using radiolabeled neurotransmitters andreceptor ligands. SPECT and PET of cardiac neurotransmissioncharacterize myocardial neuronal function in primary cardio-neuropathies, in which the heart has no significant structuralabnormality, and in secondary cardioneuropathies caused bythe metabolic and functional changes that take place in differentdiseases of the heart. In patients with heart failure, the assess-ment of sympathetic activity has important prognostic implica-tions and will result in better therapy and outcome. In diabeticpatients, scintigraphic techniques allow the detection of auto-nomic neuropathy in early stages of the disease. In conditionswith a risk of sudden death, such as idiopathic ventriculartachycardia and arrhythmogenic right ventricular cardiomyopa-thy, PET and SPECT reveal altered neuronal function when noother structural abnormality is seen. In patients with ischemicheart disease, heart transplantation, drug-induced cardiotoxic-ity, and dysautonomias, assessment of neuronal function canhelp characterize the disease and improve prognostic stratifi-cation. Future directions include the development of tracers fornew types of receptors, the targeting of second messengermolecules, and the early assessment of cardiac neurotransmis-sion in genetically predisposed subjects for prevention and earlytreatment of heart failure.

Key Words: cardiac neurotransmission; cardiac PET; cardiacSPECT; cardiomyopathies

J Nucl Med 2001; 42:1062–1076

Visualization and quantitation with SPECT and PET ofthe pathophysiologic processes that take place in the nerveterminals, synaptic clefts, and postsynaptic sites in the heartcan be referred to as cardiac neurotransmission imaging(Fig. 1). Clearly, the nerves are as important as the coronaryarteries for many of the functions of the heart, particularlycardiac rhythm, conduction, and repolarization (1). In manyclinical circumstances, these processes appear altered al-

though no structural heart disease can be shown by tradi-tional morphologic and functional investigations. In such asituation, evaluation of abnormalities of the cardiac nerves,cardiac ganglia, and neurotransmission process may be clin-ically relevant. In the United States, approximately 300,000sudden cardiac deaths occur each year, and almost 20% ofthem are in patients without evidence of coronary arterydisease (2). Nuclear medicine is currently the only imagingmodality with sufficient sensitivity to offer in vivo visual-ization of cardiac neurotransmission at a micromolar level.Such a unique capability has great diagnostic potential andcurrently allows noninvasive classification of dysautono-mias, characterization of pathologic myocardial substrate inarrhythmogenic cardiomyopathies, and assessment of neu-ronal status in coronary artery disease. This article willdiscuss the pathophysiologic basis of cardiac neurotrans-mission and will focus on the main clinical applications,from those for which only preliminary but compelling dataare available to those that are well established.

CARDIAC INNERVATION AND NEUROTRANSMISSION

The autonomic nervous system is divided into the sym-pathetic and parasympathetic subsystems (3,4). The auto-nomic outflow is controlled by regulatory centers in themidbrain, hypothalamus, pons, and medulla. These regula-tory centers integrate input signals coming from other areasof the brain as well as afferent stimuli coming from barore-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 thatterminate on cell bodies placed in the intermediolateral andintermediomedial columns. The major neurotransmitters ofthe sympathetic and parasympathetic systems are norepi-nephrine and acetylcholine, which define the stimulatoryand inhibitory physiologic effects of each system. Sympa-thetic fibers leave the spinal cord at segments T1 to L2–3.Preganglionic sympathetic fibers consist of small myelin-ated fibers that come off the spinal roots as white ramicommunicantes and synapse in the paravertebral ganglia.Gray rami communicantes that rejoin the anterior spinalroots and connect with body organs are formed by smallunmyelinated postganglionic fibers (5). Adrenergic fibersthat innervate the heart originate in the left and right stellateganglia. The left stellate innervates the right ventricle,whereas the right stellate innervates the anterior and lateral

Received Dec. 8, 2000; revision accepted Mar. 9, 2001.For correspondence or reprints contact: Ignasi Carrio, MD, Hospital Sant

Pau, Pare Claret 167, 08025-Barcelona, Spain.*NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ACTIVITY THROUGH

THE SNM WEB SITE (http://www.snm.org/education/ce_online.html) UNTILJULY 2002.

1062 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 42 • No. 7 • July 2001

portions of the heart. The adrenergic fibers travel the sub-endocardium, following the coronary vessels from the baseto the apex of the heart (6). The parasympathetic innervationof the heart is scarce in comparison; the inferior wall is theregion with a higher density of parasympathetic fibers.Parasympathetic innervation originates from the medullaand follows through the right and left vagus nerves, whichthen divide into the superior and inferior cardiac nerves.Parasympathetic fibers modulate sinoatrial nodal and atrio-ventricular nodal function and innervate the atria, whereasvagal fibers to the ventricles are sparse.

Activation of the sympathetic branch of the autonomicnervous system or a rise in the level of catecholamines mayresult in cardiac adrenergic stimulation and in subsequentchanges in the contractile and electrophysiologic status ofthe heart. The sympathetic nervous system is a vasoactiveneurohormonal system that evolved as a primary means ofpreserving circulatory homeostasis during environmentalstress. Increased sympathetic activity, with respect to thecardiovascular system, leads to peripheral vasoconstriction,sodium and water retention, and the activation of otherneurohormonal systems. At a cardiac level, sympatheticactivation results in an increased heart rate (chronotropiceffect), augmented contractility (inotropic effect), and en-hanced atrioventricular conduction (dromotropic effect). Inthe heart, an increased presynaptic neuronal release of nor-epinephrine is thought to be accompanied by an impairedneuronal uptake of noradrenaline by the sympathetic nerveendings and by a reduced number of uptake sites. Theseneuronal alterations will increase the norepinephrine con-centration in the synaptic cleft.

The source of synthesis of norepinephrine is the aminoacid tyrosine, which is converted to dihydroxyphenylala-nine and then to dopamine. Dopamine is transported intostorage vesicles by active transport and transformed tonorepinephrine by the enzymeb-hydroxylase. The action ofnorepinephrine in the synaptic cleft is terminated mainly byreuptake into the presynaptic nerve ending by the uptake-1carrier. Other related amines such as epinephrine and

guanethidine are also transported by uptake-1, which can beinhibited by cocaine and desipramine. A quantitatively lesssignificant 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 cellmembrane into the extracellular space by passive diffusion.

Adrenergic neurotransmitters bind to the postsynapticb-adrenoceptors.b1- and b2-receptors are located in thesarcolemma of the myocytes with a proportion of 80%:20%.This distribution may vary in the failing human heart, witha higher proportion ofb2-receptors being expressed (7).b1-receptors are occupied by norepinephrine, whereasb2-receptors are occupied by epinephrine.b1-receptors arelocated mainly in the synaptic cleft, whereasb2-receptorsare located far from the synaptic cleft to protect epinephrinearriving as a hormone or from extracardiac neuronal pro-duction from neuronal reuptake.b-adrenoceptors are cou-pled to G protein subunits, and stimulation ofb-adrenocep-tors results in increased adenylyl cyclase activity,subsequently leading to intracellular cyclic adenosinemonophosphate (cAMP) formation and phosphorylation ofintracellular proteins, mediated by protein kinases, and in-fluencing calcium transients and repolarization. When pro-longed excessive stimulation of adrenergic receptors takesplace, the first consequence is desensitization of adrenocep-tors, followed by downregulation with enhanced receptordegradation and decreased receptor synthesis (7,8). Thenext step is uncoupling of the receptors with overexpressionof inhibitory G proteins andb-ARK and downregulation ofadenylyl cyclase. The final clinical consequence is de-creased myocardial reserve and impaired exercise capacity.

On the other hand, parasympathetic innervation is distrib-uted throughout the atrial and ventricular walls, with agradient from the former to the latter, with acetylcholinebeing the main neurotransmitter. Acetylcholine is synthe-sized by transport of choline into the cytosol of the nerveterminal through the high-affinity choline transporter andacetylation by choline acetyltransferase. The transmitter isthen stored in vesicles and released when nerve stimulationactivates muscarinic receptors. The effects are terminatedby rapid degradation by acetylcholinesterase. Muscariniccholinergic receptors play a role in the regulation of heartrate and contractile function in balance with adrenergicreceptors. The main mechanism of action seems to be inhi-bition of the guanosine triphosphate (GTP)-activated ade-nylate cyclase activity mediated by a GTP-bindinga-regu-latory protein (Gi). Gi inactivates the catalytic subunit ofadenylate cyclase, thereby reducing intracellular cAMP lev-els and exerting an antiadrenergic effect. Therefore, theparasympathetic system acts through muscarinic cholinergicinhibition of b-adrenergic cardiac responsiveness. In thisway, adrenaline is enhanced and inotropic stimulation isinduced by noradrenaline after parasympathetic blockadewith atropine.

FIGURE 1. Concept of cardiac neurotransmission imaging.On left, electron microscopy of cardiac synapse shows postsyn-aptic concentration of neurotransmitter. On right, methylquinu-clidinyl benzylate (MQNB) and PET show in vivo visualization ofcardiac muscarinic receptors in patient with dilated cardiomy-opathy (DCM) and in healthy volunteer (CONTROL).

CARDIAC NEUROTRANSMISSIONIMAGING • Carrio 1063

Cardiac function declines with age. This is a physiologicmultifactorial process in which a decrease in cardiac respon-siveness tob-adrenergic stimulation is one of the mostprominent alterations. Several possible defects can accountfor this age-dependant reduced responsiveness: for exam-ple, reduction in the number ofb-adrenergic receptors be-cause of increased sympathetic activity with aging andsubsequent receptor downregulation, and changes in thefunctional state of the receptors with functional deficits ofG-protein–coupled proteins or post-cAMP defects.

IN VIVO METHODS TO ASSESS SYMPATHETICACTIVITY IN HUMANS

Sympathetic Nervous System at a Presynaptic LevelThe sympathetic neuronal firing rate can be assessed

directly by means of microneurography. However, micro-neurography has significant limitations because it can beapplied only to the nerves of skin and muscles and not to thenerves of internal organs such as the heart. In heart failure,for example, systemic sympathetic activity may be normalwhereas sympathetic activity at a cardiac level is increased.

In myocardial tissue obtained by endomyocardial biopsy,noradrenaline concentrations and the cardiac noradrenalineuptake sites can be quantified in vitro. In addition, cardiacnoradrenaline kinetics can be assessed biochemically invivo. Cardiac neuronal uptake, which is the most importantmechanism for the inactivation of noradrenaline, can beassessed in vivo by 3 techniques. The first is by determiningthe cardiac removal of intravenously infused radioactivenoradrenaline before and after neuronal uptake blockadewith desipramine. The second is by measuring the differ-ence between the fractional extraction of radioactive nor-adrenaline and radioactive isoproterenol, which is not asubstrate for neuronal uptake. The third is by measuringregional arteriovenous differences of radioactive and endog-enous dihydroxyphenylglycol, which is an exclusively in-traneuronal metabolite of noradrenaline.

Noradrenaline spillover is considered the standard mea-surement for global sympathetic nerve firing rate (9) andcan be measured using a radiotracer method. This methodinvolves the continuous intravenous infusion of a tracerdose of radioactive noradrenaline. The spillover rate repre-sents the amount of noradrenaline that enters the plasma.For the infusion rate of radioactive noradrenaline, the fol-lowing relationship holds at a steady state: noradrenalinespillover rate5 infused radioactive noradrenaline/plasmanoradrenaline specific radioactivity.

This technique can be used not only to assess total-bodyspillover of noradrenaline but also to measure spillover inthe heart by intracoronary infusion of radioactive noradren-aline and by sampling of the coronary sinus. The spilloverfrom the heart can be calculated by means of the Fickprinciple: cardiac noradrenaline spillover5 (coronary si-nus2 radioactive noradrenaline)1 (radioactive noradren-aline 3 cardiac noradrenaline fractional extraction)3 cor-onary sinus plasma flow. This method, however, cannot

discriminate between increased neuronal release and re-duced neuronal uptake. Furthermore, because cardiac cath-eterization is needed, the invasive nature of this method is amajor drawback.

Sympathetic Nervous System at a Postsynaptic LevelIndirect information concerning the postsynaptic sympa-

thetic activity can be obtained in vitro by determiningb-adrenoceptor density in an endomyocardial biopsy. Onehypothesis is that the sensitivity of the cardiacb-adreno-ceptors can be measured in vivo by assessing the chrono-tropic and inotropic responses to endogenous and exoge-nous b-adrenoceptor agonists. For example, a bluntedchronotropic response to isoproterenol is often seen in pa-tients with heart failure and is related to unfavorable prog-nosis in these patients (7). However, these methods do notprovide direct information on the density and activity ofpostsynaptic receptors and have limited clinical applica-tions.

Sympathetic Nervous System at the Effector LevelThe autonomic nervous system modulates heart rate vari-

ability. This physiologic effect can be assessed by means ofambulatory recorded electrocardiograms. For example, re-duced heart rate variability has been observed in patientswith chronic congestive heart failure (8). Power spectrumanalysis may be performed to determine the contribution ofsympathetic nerve activity to fluctuations in sinus rhythm.This power spectrum represents the distribution of the totalvariance in the signal over the different constituent frequen-cies. Low-frequency oscillations (0.04–0.15 Hz) are par-tially evoked by the sympathetic nervous system, suggest-ing that they may provide information on sympatheticnervous activity at a postsynaptic level. In chronic heartfailure, tachycardia is usually accompanied by a reductionin total power in the heart rate variability spectrum. Thelow-frequency power expressed as a percentage of totalpower is a good indicator of sympathetic modulation ofheart rate and has been shown to be increased in patientswith chronic heart failure.

However, arrhythmias strongly influence the power spec-trum, and only patients with sinus rhythm can be studiedwith this technique. Furthermore, quantitative assessment ofsympathetic activity by this technique is difficult becauseheart rate variability is an end-organ response, which isdetermined not only by nerve firing and electrochemicalcoupling but also by cardiacb-adrenoceptor sensitivity andpostsynaptic signal transduction. These phenomena mayexplain the frequently observed absence of correlation be-tween heart rate variability and cardiac noradrenaline spill-over.

RADIOPHARMACEUTICALS FOR CARDIACNEUROTRANSMISSION ASSESSMENT

Radiotracers for scintigraphic imaging of cardiac neuro-transmission have been developed by radiolabeling of the


neurotransmitters or their structural analogs or false neuro-transmitters. Binding characteristics, selectivity, and bind-ing reversibility determine the suitability of a given agent.Furthermore, radiochemical purity, and specific activity re-quired to minimize occupation of binding sites by nonla-beled molecules, as well as pharmacologic effects in pa-tients, have to be defined in the process of validation ofneurotransmission radiopharmaceuticals for in vivo imag-ing.

Of the many radiopharmaceuticals that have been de-signed and tested to assess cardiac neurotransmission, themost commonly used are the following (Table 1; Fig. 2): ata presynaptic level,18F-fluorodopamine is available to as-sess norepinephrine synthesis, and11C-hydroxyephedrine,11C-ephedrine, and123I-metaiodobenzylguanidine (MIBG)are available to assess presynaptic reuptake and storage byPET and SPECT; at a postsynaptic level,b-blockers such as11C-CGP and11C-carazolol are available to assessb-adre-noceptor expression and density. The quantification of neu-rotransmitter synthesis and transport by PET requires tracerkinetic modeling. Typically, presynaptic norepinephrine re-uptake function is assessed by calculation of the distributionvolume of tracers using compartment models and nonlinearregression analysis to calculate influx and efflux rate con-stants. Myocardial adrenoceptor density (Bmax) may be mea-sured by injection of different amounts of radioactivity andcold substance, assessment of input function and estimationof metabolites, and graphic analysis.

18F-Fluorodopamine18F-fluorodopamine is taken up in sympathetic nerve ter-

minals and transported into axoplasmic vesicles, where it isconverted into18F-fluoronorepinephrine and stored (10).During sympathetic stimulation,18F-fluoronorepinephrine

is released from sympathetic nerve terminals similarly to3H-norepinephrine. 6-18F-fluorodopamine can be synthe-sized from 6-18F-fluorodopa by enzymatic decarboxylationusing anL-amino acid decarboxylase (11). A direct syn-thesis method using a modification of the high-yieldradiofluorodemercuration used in the synthesis of 6-18F-fluorodopa can also be applied. The specific activities ofthe 6-18F-fluorodopamine obtained by these synthesis meth-ods typically range from 7,400 to 29,600 MBq/mmol(10,11).

Cardiac18F-fluorodopamine images can be analyzed bydrawing regions of interest within the ventricular wall usinga composite of the images for each plane. In computingtime–activity curves, the logs of the concentrations of ra-dioactivity, adjusted for the dose per kilogram of bodyweight, in the left ventricular myocardium and in arterialblood can be expressed as a function of time after injectionof the radiotracer. The specific activity of18F-fluorodopa-mine at the time of injection and the assayed plasma con-centrations of18F-fluorodopamine can be used to estimatethe proportions of the total plasma radioactivity that are dueto 18F-fluorodopamine and its metabolites. Exponentialcurve fitting may be used to describe the relationshipsbetween time and radioactivity concentrations in myocar-dium, blood, and plasma. Differences between estimatedand empiric values can be assessed graphically. The re-ported mean concentration of18F-fluorodopamine in the leftventricular myocardium peaks at 5–8 min after infusion,being 10.26 67 nCi3 kg/mL 3 mCi in healthy volunteers(11).

11C-Hydroxyephedrine and 11C-Epinephrine11C-hydroxyephedrine is a false neurotransmitter that has

the same neuronal uptake mechanism as norepinephrine,

TABLE 1Most Commonly Used Radiopharmaceuticals for Cardiac Neurotransmission Imaging

Targeted process Radiopharmaceutical Imaging and parameters References

Presynaptic uptake-1 and storage 123I-MIBG Planar/SPECTHeart-to-mediastinum ratioWash-out rate

6,17–34,36,38,40,47–53,55–68,78–86

Transport and storage intoaxoplasmic vesicles

18F-fluorodopamine PETPeak myocardial

concentration

10,11,35,72

Presynaptic uptake-1 and storage 11C-HED (hydroxyephedrine) PETRetention fractionVolume distribution

12,13,15,16,37,39,69,70,75,76

Presynaptic uptake-1 and storageand metabolism

11C-EPI (epinephrine) PETRetention fractionVolume distribution

14,15

Postsynaptic adrenoceptor density 11C-CGP (4-(3-t-butylamino-2-hydroxypropoxy)-benzimidazol-1)

PETCardiac Bmax

24–26,42,43,69,70,75–77

Postsynaptic adrenoceptor density 18F-fluorocarazolol PETCardiac Bmax

27,28

Postsynaptic muscarinic receptordensity

11C-MQNB (methylquinuclidinyl benzylate) PETCardiac Bmax

29,30


through neuronal uptake-1, but is not degraded by mono-amine oxidase and catechol methyltransferase, the enzymesresponsible for the metabolism of norepinephrine in theheart (12). The storage and release properties, however,seem to differ from those of the physiologic neurotransmit-ters (13). 11C-epinephrine may be a more physiologic tracerfor the evaluation of presynaptic sympathetic nerve functionregarding uptake mechanism, vesicular storage, and metab-olism (14). 11C-epinephrine is rapidly transported into thepresynaptic nerve terminal through uptake-1 and is stored inthe vesicles similarly to norepinephrine.11C-hydroxyephed-rine and11C-epinephrine can be synthesized with chemicalpurity . 95% and specific activity from 33,300 to 74,000GBq/mmol (15). After correction for the contribution of11C-labeled metabolites, the calculated fraction of intacttracers can be plotted as a function of time. The correctedblood time–activity curve is used as the arterial input func-tion for the calculation of myocardial retention of tracers.The retention fraction (L/min) can be calculated for eachregion by dividing the tissue11C concentration at 60 min bythe integral of the radiotracer concentration in arterial bloodfrom the time of injection to the end of the last scan:retention5 Ct(T1:T2)/*T 2Cb(t)dt, where Ct(T1:T2) is tissueactivity in the image frame between T1 and T2 (MBq/mLtissue), and Cb is blood activity (MBq/mL blood) integratedfrom time 5 0 to time 5 T2. Cardiac images can beanalyzed by volumetric sampling procedures to generatetime–activity curves and polar maps to assess homogeneityof myocardial tracer distribution (14–16). Volume distribu-tion for 11C-hydroxyephedrine in healthy volunteers hasbeen reported to be 716 19 mL/g of tissue. Myocardialretention fractions of11C-hydroxyephedrine and11C-epi-nephrine in healthy volunteers at 5 min after injection havebeen reported to be 0.246 0.02 and 0.296 0.02, respec-tively (15).

MIBGGuanethidine is a potent neuron-blocking agent that acts

selectively on sympathetic nerve endings (17). By the mod-ification of this compound into MIBG, the affinity for neu-ronal uptake sites is increased. MIBG was labeled with123Ito enable scintigraphic visualization of the sympathetic ner-vous system in humans (18), providing the first radiophar-maceutical for the assessment of cardiac neurotransmissionby SPECT. The first clinical application of123I-MIBG wasimaging of the adrenal medulla and neoplasms originatingfrom the neural crest, such as pheochromocytoma and neu-roblastoma (19). 123I-MIBG scintigraphy also showed astriking uptake in the heart, because of its dense sympatheticinnervation. In 1980, the potential use of123I-MIBG inmyocardial imaging was first suggested, although at thattime no information was available on the physiology ofcardiac123I-MIBG uptake and its metabolism under differ-ent conditions in humans (18). Much work has been done toelucidate the mechanism by which the sympathetic nerveendings take up123I-MIBG. MIBG and noradrenaline havebeen shown to have similar molecular structures and to usethe same uptake and storage mechanisms in the sympatheticnerve endings (6,20–22).

Neuronal uptake of123I-MIBG is achieved mainlythrough the sodium- and energy-dependent uptake-1 mech-anism, which is characterized by a temperature dependency,a high affinity (a Km [mmol/L] of 1.226 0.12 for MIBG and1.41 6 0.50 for noradrenaline), and a low capacity (a Vm

[pmol/106 cells/10 min] of 64.36 3.3 for MIBG and 36.667.2 for noradrenaline). Sisson et al. (20,21) showed inanimal experiments that the kinetics of125I-MIBG mim-icked those of3H-noradrenaline under different conditions.In these experiments, yohimbine, ana2-adrenoceptor antag-onist, was used to increase sympathetic nerve function,whereas clonidine was used to induce the opposite effect.

FIGURE 2. Most commonly used radio-ligands for assessment of cardiac pre- andpostsynaptic processes. ATP 5 adenosinetriphosphate; DOPA 5 dihydroxyphenylala-nine; NE 5 norepinephrine.


Sodium-independent neuronal uptake of MIBG has alsobeen reported. This nonneuronal uptake-2 mechanism dom-inates at higher concentrations of the substrate and is prob-ably the result of passive diffusion. The relative role of eachuptake mechanism depends on the plasma concentration ofMIBG. However, neuronal uptake is predominantly deter-mined by the uptake-1 mechanism because an extremelysmall quantity of MIBG is usually injected for diagnosticscintigraphy. Typically, 1 standard dose of 185 MBq con-tains 6.253 10 29 g MIBG. Recently, the use of no-carrier-added MIBG has been reported to improve image quality(23).

11C-CGPLipophilic antagonists ofb-adrenoceptors such as iodo-

pindolol have been used in in vitro studies. Lipophilicmolecules such as11C-propranolol cannot be used to studythe heart in vivo because of high accumulation in the lungs.CGP-12177 (4-(3-t-butylamino-2-hydroxypropoxy)-benzi-midazol-1) is a hydrophilic antagonist that binds to thereceptor with high affinity (0.3 nmol/L) (24). Because ofhigh hydrophilicity, CGP-12177 selectively identifies cell-surfaceb-adrenoceptors that are coupled to adenylate cy-clase. CGP can be labeled with11C using CGP-17704 as aprecursor and11C-phosgene. To quantitatively assess theconcentration of receptor sites, one must use a mathematicmodel (24–26). The model parameters, including the recep-tor concentration and the kinetic rate constants, can bederived from experimental data using a kinetic or graphicmethod. The kinetic method is based on a fitting procedureand needs to measure the input function, which is hamperedby the presence of metabolites. Furthermore, the kineticmethod needs to maintain a balance between the respectivecomplexities of the model structure and of the experimentalprotocol. On the other hand, the graphic methods are basedon simplifying hypotheses. A graphic method based on theinjection of a tracer dose of CGP, followed by injection ofradioligand with a low specific activity and an excess ofunlabeled CGP, which does not require measurement of theinput function, has been proposed (24). With this approach,values of Bmax have been reported to be 106 3 pmol/g oftissue in healthy volunteers, with a dissociation constant of0.0146 0.002 min21.

18F-FluorocarazololCarazolol is a lipophilic, nonselectiveb-adrenoceptor

antagonist to theb-1 andb-2 receptors and can be labeledwith 11C and18F (27). Uptake in the target organs, such asthe heart, is substantial and can be blocked and displaced bypropranolol in a way that suggests that fluorocarazolol andpropranolol compete for binding to the same receptor sites.The in vivo binding is stereoselective because theR-isomerdoes not accumulate in the target organs (28). 18F-fluoro-carazolol can be synthesized by reacting the precursorS-desisopropylcarazolol with18F-fluoroacetone and high-per-formance liquid chromatography purification. The specificactivity may average 55,500 GBq/mmole, with a radio-

chemical purity. 99%. After correction for metabolites inplasma, time–activity curves from the heart and lungs canbe normalized to injected dose and body weight. Myocar-dial tissue-to-plasma concentration ratios of fluorocarazololin healthy individuals reach a plateau of 186 1 in the heartat 45 min after injection of the radiotracer. During the slowkinetic phase, maximal concentrations in the heart rangefrom 0.03 to 0.085 pmol/mL (28).

11C-Methylquinuclidinyl BenzilateMethylquinuclidinyl benzilate (MQNB) is a highly spe-

cific hydrophilic antagonist of muscarinic receptors and canbe labeled with11C. The stimulation of local muscarinicreceptors inhibits norepinephrine release from adrenergicnerve terminals. Although present on sympathetic nerveendings in a prejunctional distribution, muscarinic receptorsplay a role in neurotransmission within the intrinsic cardiacsympathetic nervous system. MQNB can be labeled with11C by methylation of quinuclidinyl benzylate with11C-methyl iodide, with a specific radioactivity ranging from 12to 80 GBq/mmol (29,30). Left ventricular muscarinic recep-tors can be quantified after PET imaging with a mathematicmodel based on a multiinjection protocol of labeled andunlabeled ligand. The input function can be derived from aregion of interest drawn within the left ventricular cavity.Time–activity curves can be generated for different leftventricular regions after correction for decay and expressedas pmol/mL after dividing by specific radioactivity at time0. After compartmental modeling, the Bmax values reportedin healthy volunteers were 256 7.7 pmol/L, with a disso-ciation constant of 2.26 1 pmol/mL without significantdifferences in the septal, anterior, and lateral regions of theleft ventricle (30).

IMAGING TECHNIQUES

Planar and Tomographic Imaging of the Heartwith MIBG

Planar imaging has commonly been used to determinecardiac MIBG uptake. Myocardial uptake and distributionare visually assessed. A semiquantitative measurement ofmyocardial MIBG uptake can be obtained by calculation ofa heart-to-mediastinum ratio (6). However, this techniquehas some limitations: the superposition of noncardiac struc-tures such as the lung and mediastinum may preclude op-timal visualization, and superposition of myocardial seg-ments and motion artifacts interferes with regionalassessment of radioligand uptake. SPECT imaging mayovercome these disadvantages, although in some patho-physiologic conditions, myocardial MIBG uptake may beseverely reduced, hampering the obtention of tomographicslices of the heart.

The standard procedure is as follows. Thirty minutes afterthyroid blockade by oral administration of 500 mg potas-sium perchlorate, approximately 370 MBq123I-MIBG areadministered intravenously. Planar scintigraphic images andSPECT studies of the heart are acquired 20 min (early


image) and 4 h (delayed image) after injection. A 20%window is usually used, centered over the 159-keV123Iphotopeak. Planar images are acquired in anterior and 45°left anterior oblique views of the thorax and stored in a128 3 128 matrix. MIBG uptake is semiquantified bycalculating a heart-to-mediastinum ratio after drawing re-gions of interest over the mediastinum in the anterior viewand over the myocardium in the left anterior oblique view.Average counts per pixel in the myocardium are divided byaverage counts per pixel in the mediastinum. The intraob-server variability of the heart-to-mediastinum ratio is,2%,and the interobserver variability is,5%. A heart-to-medi-astinum ratio. 1.8 is considered normal. The washout ratefrom initial to delayed images is,10% in healthy individ-uals (31,32). SPECT studies can be obtained by a singlepass of 60 steps at 30 s per step (643 64 matrix), startingat the 45° right anterior oblique projection and proceedingcounterclockwise to the 45° left posterior oblique projec-tion. The data are reconstructed in short-axis, horizontallong-axis, and vertical long-axis views, and scatter or atten-uation correction may be applied. For visual evaluation ofSPECT slices, reductions in the MIBG concentration ingiven myocardial segments can be scored using a pointscale. In addition, polar maps can be constructed fromshort-axis images and can be compared with those ofhealthy individuals (Figs. 3 and 4).

Quantitative assessment of the cardiac uptake of MIBG inthe heart, by comparing the cardiac count density with thecount density of a reference region such as the mediastinum,is hampered by several variables. First, tissue attenuation isnonuniform for intrathoracic organs because tissue densityand, therefore, the attenuation coefficient vary. This non-uniform attenuation can be corrected theoretically using aniterative reconstruction algorithm or by constructing indi-vidual attenuation maps during acquisition using a linesource. Second, photons that scatter within the patient are

often indistinguishable from unscattered photons with re-spect to their photon energy. These scattered photons con-tribute to a further loss of spatial resolution. For123I-MIBGSPECT, a limiting factor is the number of counts acquired.Therefore, dose and acquisition time should be maximized.Procedures to limit the effects of these factors will improveimage quality, that is, image resolution and contrast.

Somsen et al. (33) and Somsen (34) have developed amethod in which the count density in the left ventricularcavity is used as a reference. Volumes of the myocardiumand the left ventricular cavity are reconstructed fromSPECT acquisitions. The count density in the left ventric-ular cavity is calibrated by the123I activity in a venous bloodsample drawn at the time of the acquisition. Subsequently,cardiac123I-MIBG uptake can be calculated according to thefollowing equation: cardiac123I-MIBG uptake5 (myocar-dial count density/cavity count density)3 venous bloodsample (Bq/mL).

PET ImagingPET imaging protocols vary according to the radiotracer

characteristics and the available instrumentation. Obtainedvolumetric datasets are realigned according to standardizedaxes. Physiologic parameters can be assessed by applyingtracer kinetic models to quantitative datasets (Fig. 5). Re-gion-of-interest analysis of the activity concentration insidethe left ventricular cavity yields the time–activity curve ofarterial blood and allows assessment of the arterial inputfunction. Continuous thoracic PET scanning is performedfor up to 3 h after18F-fluorodopamine infusion. The totalscanning time is divided into intervals of 5–30 min, and thetomographic results of each interval are assessed. Scan

FIGURE 3. Planar cardiac 123I-MIBG images of cancer patientafter chemotherapy. Intensity of cardiac MIBG uptake can beassessed by comparing activity in heart with activity in medias-tinum. Accelerated washout of MIBG is seen between early (A)and delayed (B) images after chemotherapy. ANT 5 anteriorview; PI 5 postinjection.

FIGURE 4. SPECT MIBG study of healthy volunteer. Short-axis tomograms and reconstructed polar maps show normalMIBG distribution and washout.


sequences may consist of 5 frames3 1 min, 5 frames3 5min, 4 frames3 15 min, and 3 frames3 30 min. PETscanning of11C-hydroxyephedrine and11C-epinephrine usu-ally lasts for 60 min. Scan sequences may consist of 15frames: 63 30 s, 23 60 s, 23 150 s, 23 300 s, 23 600 s,and 13 1,200 s. With11C-CGP, continuous thoracic scan-ning, recording data in list mode, is typically performed for1 h after infusion. With18F-fluorocarazolol, acquisition pro-tocols after infusion may consist of 8 frames3 15 s, 4frames3 30 s, 4 frames3 1 min, 4 frames3 2 min, 6frames3 4 min, and 2 frames3 10 min. For11C-MQNB,data recording starts with the first injection. Sixty sequentialimages may be acquired, using 1 of the cross-sections andreconstruction according to the specific protocol applied.Scan sequences may consist of 22 frames—83 15 s, 4330 s, 23 60 s, and 83 150 s—after each infusion.

CLINICAL APPLICATIONS

Primary CardioneuropathiesDysautonomias.Derangements of sympathetic and para-

sympathetic nervous system function are frequently encoun-tered in neurology and cardiology. Autonomic hypofunctioncan be caused by several drugs and disease-associated poly-neuropathies such as diabetes and amyloidosis. Autonomicfailure may also occur without an identifiable cause orsometimes in relation to a disease in which dysautonomia isunlikely. A consensus statement by the American Auto-nomic Society and the American Academy of Neurologydistinguishes 3 forms of primary disautonomia: pure auto-nomic failure, defined as a sporadic, idiopathic cause ofpersistent orthostatic hypotension and other manifestationsof autonomic failure that occur without other neurologicfeatures; Parkinson’s disease with autonomic failure; andmultiple-system atrophy. However, distinguishing betweenParkinson’s disease with autonomic failure and some formsof multiple-system atrophy is difficult, and physiologic and

neurochemical tests often fail to properly separate the dif-ferent forms of dysautonomia.

Goldstein et al. (10,35) have used PET scanning with18F-fluorodopamine to examine cardiac sympathetic inner-vation in patients with different types of dysautonomia. Inlight of the PET findings, they proposed a new pathophys-iologic classification of dysautonomias in which sympa-thetic neurocirculatory failure results from peripheral sym-pathetic denervation or decreased or absent sympatheticsignal traffic. The results of PET scanning are related tocentral degeneration, to responsiveness to treatment withlevodopa–carbidopa, and to signs of sympathetic neurocir-culatory failure, with orthostatic hypotension and abnormalblood pressure responses associated with Valsalva’s maneu-ver. Patients with pure autonomic failure or parkinsonismand sympathetic neurocirculatory failure have no myocar-dial 18F-fluorodopamine uptake or cardiac norepinephrinespillover, indicating loss of myocardial sympathetic-nerveterminals. Patients with the Shy-Drager syndrome haveincreased levels of18F-fluorodopamine activity, indicatingintact nerve terminals and absent nerve traffic. Patients withdysautonomia without sympathetic neurocirculatory failurehave normal levels of18F-fluorodopamine activity in themyocardium and normal rates of cardiac norepinephrinespillover. 18F-fluorodopamine PET studies in combinationwith neurochemical tests and clinical observations supportthis new clinical pathophysiologic classification of dysau-tonomias, with enhanced diagnostic differentiation betweenmultiple-system atrophy, Shy-Drager syndrome, parkinson-ism with autonomic failure, and peripheral autonomic fail-ure (35).

Heart Transplantation.During orthotopic heart trans-plantation, the entire recipient heart is excised except for theposterior atrial walls, to which the donor atria are anasto-mosed. During the process, the allograft becomes com-pletely denervated. Lack of autonomic nerve supply is as-sociated with major physiologic limitations. The inability toperceive pain does not allow symptomatic recognition ofaccelerated allograft vasculopathy, and heart transplant pa-tients often experience acute ischemic events or left ven-tricular dysfunction or die suddenly. In addition, denerva-tion of the sinus node does not allow adequate accelerationof heart rate during stress and efficient increase in cardiacoutput. Furthermore, loss of vasomotor tone may adverselyaffect the physiologic alterations in blood flow, producealtered hemodynamic performance at rest and during exer-cise, and decrease exercise capacity. Scintigraphic uptake of123I-MIBG and 11C-hydroxyephedrine supports the conceptthat spontaneous reinnervation takes place after transplan-tation (36–39). All studies performed up to 5 y after hearttransplantation suggest that reinnervation is likely to be aslow process and occurs only after 1 y after transplantation(40).

Sympathetic reinnervation, measured by regional distri-bution and intensity of myocardial MIBG uptake, increaseswith time after transplantation, with a positive correlation

FIGURE 5. PET characterization of presynaptic volume distri-bution of neurotransmitter (Vd of 11C-hydroxyephedrine) andpostsynaptic receptor density (Bmax measured by 11C-CGP) inhealthy volunteers (CONTROL) and patients with arrhythmo-genic right ventricular cardiomyopathy (ARVC), right ventricularoutflow tract (RVOT), and hypertrophic cardiomyopathy (HCM).Circles represent mean values; crosses represent SDs.


between heart-to-mediastinum rates and time after trans-plantation. Serial MIBG studies over time show that rein-nervation begins from the base of the heart and spreadstoward the apex (Fig. 6). MIBG uptake is seen primarily inthe anterior, anterolateral, and septal regions. MIBG uptakeis usually not apparent in the posterior or inferior myocar-dial regions, except for some basal posterior localization.Complete reinnervation of the transplanted heart is not seenon scintigraphic studies, even up to 12 y after transplanta-tion. Early vasculopathy may inhibit the process of sympa-thetic reinnervation of the transplanted heart. The relation-ship between reinnervation status and graft vasculopathydeserves further investigation and may help to characterizesubsets of transplant patients with different clinical out-comes.

In a recent PET perfusion and sympathetic reinnervationstudy of heart transplant patients, Di Carli et al. (39) showedthat blood flow increases in response to sympathetic stim-ulation in the territory of the left anterior descending artery.This territory has the highest uptake of11C-hydroxyephed-rine, whereas in other territories, increase in flow and uptakeof 11C-hydroxyephedrine is minor. This study also showedthat basal flow in transplant recipients is similar in allcoronary territories despite differences in sympathetic rein-nervation, suggesting that cardiac-efferent adrenergic sig-nals play an important role in modulating myocardial bloodflow during activation of the sympathetic nervous system.

Idiopathic Ventricular Tachycardia and Fibrillation.Inpatients presenting with idiopathic ventricular tachycardiaand fibrillation, no structural or functional abnormalities ofthe myocardium can be shown by conventional imaging andclinical testing. Early diagnosis and treatment are of clinicalimportance because ventricular fibrillation is the most com-mon arrhythmia at the time of sudden death (41). Typicalarrhythmias in these patients can be provoked by physical ormental stress or by catecholamine application. Schafers

et al. (42), using 123I-MIBG, 11C-hydroxyephedrine, and11C-CGP, showed that in patients with idiopathic right ven-tricular outflow tract tachycardia, both the presynaptic myo-cardial catecholamine reuptake and the postsynaptic myo-cardialb-adrenoceptor density were reduced despite normalblood catecholamine levels (Fig. 7). The maximal bindingcapacity of theb-adrenoceptor antagonist was reduced inpatients with right ventricular outflow tract tachycardia, incomparison with healthy volunteers (6.86 1.2 vs. 10.262.9 pmol/g) (43). These scintigraphic findings represent theonly demonstrable myocardial abnormality in patients withidiopathic tachycardia and fibrillation and suggest that myo-cardialb-adrenoceptor downregulation in these patients oc-curs subsequent to increased local synaptic catecholaminelevels caused by impaired catecholamine reuptake (43).

Secondary CardioneuropathiesDilated Cardiomyopathies.After the onset of myocardial

failure, enhanced sympathetic nervous system activity playsan important role in supporting the cardiovascular systemby increasing heart rate, contractility, and venous return.Blood pressure to preserve organ perfusion is supported bysystemic arterial constriction, but on the other hand, in-creased sympathetic activity has deleterious effects on thecardiovascular system (7,9). Vascular constriction and in-creased salt and water retention by the kidneys increase theenergy requirement of the myocardial wall. Altered sympa-thetic cardiac adrenergic function may also cause arrhyth-mias, desensitization of postsynapticb-adrenoceptors, andactivation of other neurohumoral systems, such as the re-nin–angiotensin system, which may themselves exert ad-verse effects and contribute to progression of myocardialdysfunction. In addition, prolonged exposure to norepineph-rine may contribute to disease progression by acting directlyon the myocardium to modify cellular phenotype and resultin myocyte death (44,45).

In patients with dilated cardiomyopathies, because of theincreased concentration of circulating catecholamines re-

FIGURE 6. SPECT images of MIBG distribution in patientpresenting with partial reinnervation after heart transplantation.MIBG activity (arrows) is seen in anterobasal segments of myo-cardium. HLA 5 horizontal long axis; HSA 5 horizontal shortaxis; VLA 5 vertical long axis.

FIGURE 7. SPECT images of resting perfusion (201Tl) andsympathetic presynaptic innervation (123I-MIBG) of left ventric-ular myocardium in patient with idiopathic ventricular tachycar-dia. Typically, regional innervation in segments of inferior wall isblunted, whereas same segments show no perfusion abnormality.


sulting from heart failure, the myocardial responsiveness tob-adrenoceptor agonists is blunted. Frequently, alterationsof cardiac sympathetic innervation contribute to fatal out-comes in patients with heart failure. Merlet et al. (46–48),studying patients with functional classes II–IV and,40%left ventricular function, and using transplantation and car-diac or noncardiac death as endpoints, showed that the onlyindependent predictors of mortality were low MIBG uptakeand left ventricular ejection fraction. In addition, MIBGuptake and circulating norepinephrine concentration werethe only predictors for life duration when using multivariatelife table analysis. Therefore, impaired cardiac adrenergicinnervation as assessed by MIBG imaging seems to bestrongly related to mortality in patients with heart failure(Figs. 8 and 9). Along the same line, Maunoury et al. (49)found that cardiac adrenergic neuronal function was im-paired in children with idiopathic dilated cardiomyopathy,although that particular study did not have sufficient fol-low-up for assessment of prognosis. Patients with conges-tive cardiomyopathy typically have accelerated washoutrates (.25% from 15 to 85 min), in comparison withhealthy volunteers (,10%). Momose et al. (50) assessed theprognostic value of washout rate in heart failure patients andfound that it was the most powerful independent predictorof prognosis and that a threshold of 52% clearly separatednegative outcome from survival. Cohen-Solal et al. (51)showed that MIBG parameters correlated with other predic-tors of prognosis such as peak volume of oxygen use.Cardiac MIBG SPECT has also been used to assess changesin cardiac sympathetic neuronal uptake function caused bypharmacologic intervention (52). Somsen et al. (33) showedthat enalapril improved cardiac sympathetic uptake functionbut did not affect plasma noradrenaline levels in a group ofpatients with heart failure, supporting the concept that a

restoration of cardiac neuronal uptake of noradrenaline is abenefit of enalapril treatment in these patients. Suwa et al.(53) prospectively evaluated whether MIBG myocardialimaging was useful in predicting responses toa-blockertherapy in patients with dilated cardiomyopathy. Heart-to-mediastinum ratios on early and delayed images were eval-uated, as well as the percentage washout rate. The heart-to-mediastinum ratio on delayed images was a good predictorof the response toa-blocker therapy, with a threshold of 1.7identifying responders to bisoprolol with a sensitivity of91% and a specificity of 92%. These results indicate that theresponse toa-blocker therapy may be monitored with se-quential quantitative MIBG studies (Fig. 10).

The concept that prolonged sympathetic hyperactivity isdetrimental in chronic heart failure has been supported by

FIGURE 8. SPECT MIBG study of patient with dilated cardio-myopathy. Short-axis tomograms and reconstructed polarmaps show decreased and heterogeneous myocardial MIBGactivity.

FIGURE 9. Planar MIBG images of patient with dilated car-diomyopathy and almost absent cardiac MIBG uptake. Thispattern of denervation is associated with very poor outcome,and heart transplantation has to be considered.

FIGURE 10. Sequential MIBG polar maps of patient who re-sponded to a-blocker therapy. Studies were obtained beforeand at follow-up intervals after a-blocker administration. MIBGdistribution improves over time, and washout rate is progres-sively less. Left ventricular ejection fraction (LVEF) improvesfrom 28% to 65%.


trials that showed beneficial effects from angiotensin-con-verting enzyme inhibitors andb-adrenoceptor antagonists.Therefore, reduction of sympathetic nervous activity is con-sidered an important target for drug treatment of heartfailure. Several mechanisms may contribute to reducedb-adrenoceptor responsiveness in heart failure, such asdownregulation ofb-adrenoceptors, uncoupling of subtypesof b-adrenoceptors, upregulation ofb-adrenoceptor kinase,increased activity of G protein, decreased activity of adeny-lyl cyclase, and increased nitric oxide. Myocardial remod-eling involves hypertrophy and apoptosis of myocytes, re-gression to a fetal phenotype, and changes in the nature ofthe extracellular matrix. Noradrenaline seems to contributeto many of these changes by direct stimulation of adreno-ceptors on cardiac myocytes and fibroblasts. The hypertro-phic effect of noradrenaline is associated with the reexpres-sion of fetal genes and the downregulation of several adultgenes. Cardiac neurotransmission imaging can play a role infuture trials to assess new forms of medical therapy forimproving outcomes in heart failure.

The death of cardiac myocytes by apoptosis may contrib-ute to pathologic remodeling. Apoptosis is a highly regu-lated sequence of molecular and biochemical events guidedby a genetic program. Although apoptosis was thought notto occur in terminally differentiated cardiac myocytes, Na-rula et al. (54) showed that apoptosis was present in themyocardium of patients with end-stage dilated cardiomyop-athy, leading to the concept that continuing loss of viablemyocytes contributes to progressive myocardial failure.Several studies have suggested that the toxic effect ofb-ad-renoceptor stimulation is mediated in part by apoptosis. Incultured myocytes, exposure to noradrenaline for 24 h stim-ulates the frequency of apoptosis, which is inhibited bypropranolol. In comparison, little is known about the effectsof noradrenaline on the extracellular matrix, although nor-adrenaline stimulates the expression of transforming growthfactors that regulate extracellular matrix proteins. Cardiacneurotransmission imaging can help to improve understand-ing of the mechanisms responsible for increased sympa-thetic activity in heart failure, and knowledge of how sym-pathetic overactivity exerts its deleterious actions will resultin better therapy and outcome for patients with heart failure,which is still a major cause of disability and mortality andrepresents a major health problem despite therapeutic ad-vances.

Coronary Artery Disease.Sympathetic nervous tissuemay be more sensitive to the effects of ischemia than ismyocardial tissue. Uptake of123I-MIBG has been shown tobe significantly reduced in areas of myocardial infarctionand of acute and chronic ischemia (55–57). A decrease inMIBG uptake in ischemic tissue represents loss of integrityin postganglionic, presynaptic neurons. Ischemia likely in-duces damage to sympathetic neurons, which may take along time to regenerate, and repetitive episodes of ischemialikely result in a relatively permanent loss of MIBG uptake

(Fig. 11). Early after infarction, sympathetic denervation inadjacent noninfarcted regions is frequently observed (56).Studies have shown that a transmural infarction producesacute sympathetic denervation in noninfarcted sites apical tothe necrotic regions as measured by norepinephrine contentand response to stellate stimulation. Nontransmural infarc-tion may also lead to regional ischemic damage of sympa-thetic nerves but may spare subepicardial nerve trunks thatcourse the region of infarction to provide a source of inner-vation to distal areas of the myocardium.

Minardo et al. (58) used123I-MIBG to show that the areaof denervation extended beyond the region of infarction.McGhie et al. (56), evaluating patients with MIBG scintig-raphy on day 10 after acute myocardial infarction, foundthat the area of reduced uptake was more extensive than thearea of the thallium perfusion defect. These regions may beassociated with spontaneous ventricular tachyarrhythmiasafter myocardial infarction (59). Sympathetic stimulation isknown to lower the threshold of ventricular tachycardia andfibrillation during acute myocardial ischemia. Adrenergicdenervation of viable myocardium results in denervationsupersensitivity, with an exaggerated response of myocar-dium to sympathetic stimulation. Denervation supersensi-tivity is related to vulnerability to ventricular arrhythmias.Regional sympathetic denervation is possibly one of themechanisms that renders patients with coronary artery dis-ease susceptible to ventricular arrhythmias during myocar-dial ischemia. Reinnervation late after myocardial infarctionin periinfarct regions has also been shown by reappearance

FIGURE 11. Myocardial exercise/rest perfusion studies (99mTc-tetrofosmin) and sympathetic innervation studies (123I-MIBG) per-formed before and 6 mo after exercise rehabilitation in patientwith coronary artery disease. Before rehabilitation, myocardialperfusion study shows anterior and apical ischemia. MIBGstudy shows decreased uptake in same territories. After reha-bilitation, marked improvement in myocardial perfusion is seen,whereas sympathetic innervation study is similar to study beforeexercise rehabilitation, suggesting persistent neuronal damageafter repetitive myocardial ischemia. HSA 5 horizontal shortaxis; VLA 5 vertical long axis; HLA 5 horizontal long axis.


of MIBG uptake by 14 wk after infarction (60,61). Rein-nervation may be, in part, responsible for the return offunction during this period. However, reinnervation may beincomplete as late as 3 mo after acute infarction. Harti-kainen et al. (60) examined MIBG uptake at 3 and 13 moafter a first infarction and found no difference in MIBGactivity over time within the infarcted zone but an increasein activity in the periinfarcted region without a change inperfusion.

The eventual concordance between the extent of MIBGdefect at rest and perfusion defect at exercise in patientswith coronary artery disease suggests that mild degrees ofischemia may be injurious to the integrity of myocardialsympathetic neurons (62–65). Correlation between theMIBG defect and the area at risk and the presence of anginafurther supports the concept of neuronal damage in theischemic territory. Although association between MIBGdefects and clinical angina can be explained as a conse-quence of ischemia, it is intriguing that the perception ofpain occurs from the area that lacks sympathetic innerva-tion. Because MIBG defects in the ischemic territory are notabsolute, partial neuronal innervation may allow perceptionof chest pain. The MIBG studies in cardiac allograft recip-ients also support the finding of both susceptibility ofsympathetic neurons to ischemia and adequacy of partialinnervation for nociception. Reinnervation in transplantrecipients is almost never complete; still, these patients canperceive pain. On the other hand, in all patients who sustainearly episodes of allograft vasculopathy, reinnervation doesnot develop even up to 12 y after heart transplantation. Thisfinding also supports the concept of extreme sensitivity ofsympathetic innervation to ischemic stress—even greaterthan the sensitivity of the myocyte (65–68).

Hypertrophic Cardiomyopathy.Hypertrophic cardiomy-opathy is genetically determined; however, autonomic dys-function seems to play a role in the phenotypic expression.Several clinical features of hypertrophic cardiomyopathysuggest increased sympathetic outflow. The incidence ofchest pain and myocardial hypercontractility, the propensityto ventricular arrhythmias and sudden death, and the bene-ficial effect of a-blockers suggest increased delivery ofnorepinephrine to myocardial adrenoceptors. Cardiac pre-synaptic catecholamine reuptake is impaired in hypertrophiccardiomyopathy, in association with reduced postsynapticb-adrenoceptor density, suggesting an increased neurotrans-mitter concentration in the synaptic cleft. This increase canbe shown by quantitative PET studies using11C-hy-droxyephedrine and11C-CGP (69,70). An increased wash-out rate (.25%) between initial and delayed images hasalso been described in hypertrophic cardiomyopathy, sec-ondary to activation of the sympathetic nervous system. Theautonomic dysfunction in these patients is probably relatedto disease progression and, ultimately, heart failure (71,72).In patients studied with13N-ammonia and18F-fluorodopa-mine, the18F:13N ratio is lower in hypertrophied than innonhypertrophied regions (72), indicating decreased neuro-

nal uptake of catecholamines in hypertrophied myocardiumof patients with hypertrophic cardiomyopathy.

Arrhythmogenic Right Ventricular Cardiomyopathy.Fi-brolipomatous degeneration of the right ventricular myocar-dium is the main structural abnormality in arrhythmogenicright ventricular cardiomyopathy. In these patients, the ev-idence of ventricular tachyarrhythmias and cardiac arrestthat can be provoked during exercise or stress, and thesensitivity to catecholamines, strongly suggest that thesympathetic nervous system is involved in arrhythmo-genesis (73,74). Studies with MIBG-SPECT and11C-hy-droxyephedrine PET have shown that although the leftventricle is not involved in the disease, there is evidence ofglobal and regional denervation in presynaptic catechol-amine reuptake and storage of the left ventricle, as well asa reduction in the postsynapticb-adrenoceptor density as-sessed by11C-CGP PET (75,76). Bmax values for CGP of5.96 1.3 pmol/g of tissue have been shown in patients witharrhythmogenic cardiomyopathy versus 10.26 2.9 pmol/gtissue in healthy volunteers (77). These findings suggestreduced activity of the noradrenaline transporter (uptake-1)with subsequentb-adrenoceptor downregulation and have apotential impact on diagnostic evaluation and therapeuticmanagement of patients with arrhythmogenic right ventric-ular cardiomyopathy.

Diabetes Mellitus.The sympathetic nervous system ap-pears to be activated during the early stages of diabetes,with elevated plasma catecholamine levels. This prolongedexposure to catecholamines leads to downregulation of ad-renergic receptors and to alterations in adrenergic nervefibers in the myocardium. Hyperglycemia and insulin defi-ciency may also contribute to the abnormalities in cardiacinnervation in diabetes. Kim et al. (78) showed decreased123I-MIBG uptake associated with autonomic dysfunction indiabetic patients and a correlation between decreased car-diac MIBG uptake and increased mortality. MIBG scintig-raphy seems more sensitive than autonomic nervous func-tion tests for the detection of autonomic neuropathy indiabetes, particularly in early stages of the disease. Scog-namiglio et al. (79) showed that impairment of cardiacsympathetic innervation, as revealed by MIBG studies, cor-relates with an abnormal response to exercise in diabeticpatients and may contribute to left ventricular dysfunctionbefore the appearance of irreversible damage and overtheart failure. Hattori et al. (80) reported that diabetic pa-tients with scintigraphic evidence of severe myocardial de-nervation present with hyperreaction to dobutamine stress.This finding may, in part, explain the high incidence ofsudden death in patients with advanced diabetes mellitus.

Hypertension.Scintigraphy of cardiac sympathetic inner-vation may play a role in the assessment of arterial andpulmonary hypertension. Morimoto et al. (81) investigatedthe relationship between hypertensive cardiac hypertrophyand cardiac nervous function before and after hypertensivetherapy in patients with untreated essential arterial hyper-tension. A regional and global improvement in cardiac


sympathetic nervous function, as seen on123I-MIBG stud-ies, appeared to be related to regression of hypertensivecardiac hypertrophy. Furthermore, in patients with pulmo-nary hypertension, the uptake ratio of MIBG between theinterventricular septum and the left ventricular myocardiumcorrelated with right ventricular overload (82,83). There-fore, scintigraphic assessment of the adrenergic nervoussystem may, conceivably, play a role in the multidisci-plinary assessment and management of hypertension.

Drug-Induced Cardiotoxicity.MIBG studies have alsobeen used to assess impairment of adrenergic innervationfrom anthracycline cardiotoxicity. Decreased myocardialMIBG uptake has been observed after administration ofdoxorubicin hydrochloride, with limited morphologic dam-age (84). In these studies, decreased myocardial MIBGuptake preceded deterioration of ejection fraction. MIBGuptake revealed a dose-dependent decline that could becaused by excessive compensatory hyperadrenergic wash-out from the myocardium or by direct adrenergic neurondamage. Hyperadrenergism seems unlikely because myo-cardial norepinephrine does not decline as plasma norepi-nephrine levels rise with increasing dose, suggesting a spe-cific adrenergic neuron toxicity rather than a nonspecificresponse to an impairment in ventricular function. Valde´sOlmos et al. (85) reported decreased myocardial MIBGuptake in patients with severely decreased ejection fractionafter doxorubicin administration. A correlation with param-eters derived from radionuclide angiocardiography sug-gested a global process of myocardial adrenergic derange-ment.

A decrease in myocardial MIBG uptake has also beenreported regardless of the patient’s functional status, sug-gesting a specific effect. Progressive myocyte necrosis dur-ing doxorubicin cardiotoxicity can be associated with car-diac neuroadrenergic tissue necrosis. In fact, the clinicalcourse of doxorubicin cardiotoxicity suggests altered neu-roendocrine physiology. This suggestion is supported by theobservation of decreased adrenergic responsiveness andmyocardial catecholamine stores with increased plasma cat-echolamines. The decrease in myocardial MIBG accumula-tion parallels the evolution of ejection fraction (86). Whenreceiving intermediate cumulative doses of 240–300 mg/m2, 25% of patients present with some decrease in MIBGuptake. At maximal cumulative doses, MIBG uptake de-creases significantly, consistent with impaired cardiac ad-renergic activity. A moderate to marked decrease in myo-cardial MIBG uptake at high cumulative doses wasobserved in all but 1 patient with a 10% decrease in ejectionfraction (86). These data suggest that the assessment ofdrug-induced sympathetic damage can be used to selectpatients at risk of severe functional impairment and whomay benefit from cardioprotective agents or changes in theschedule or administration technique of antineoplasticdrugs.

FUTURE DIRECTIONS

The neuronal function of the heart is altered in manycardiac disorders, such as congestive heart failure, ischemia,cardiac arrhythmias, and certain cardiomyopathies. Cardiacneurotransmission imaging opens many possibilities for im-proving our understanding of the pathophysiology of thediseases, improving our selection of patients for varioustreatments, and improving our assessment of the results oftherapy. As new drugs are shown effective for heart failure,the identification of markers predictive of drug efficacy forindividual patients becomes increasingly important. Clearly,neuronal receptor function can be modulated with appropri-ate treatments; therefore, cardiac neurotransmission studieshave great potential for affecting clinical decision making ifthe effectiveness of treatments can be assessed and pre-dicted using SPECT or PET (87,88).

Future directions include developing new and more phys-iologic tracers, such as the non–carrier-added123I-fluoro-iodobenzylguanidine (89), which is a more physiologic cat-echolamine analog than MIBG; implementing cardiacneurotransmission imaging in clinical practice; and focusingon the assessment and prediction of therapy. Also, devel-opment of99mTc analogs of MIBG may lead to widespreadapplication of cardiac neurotransmission imaging. In addi-tion to PET tracers, SPECT ligands have to be developed forimaging the expression of adrenergic and muscarinic recep-tors. Labeling iododexetimide with123I for SPECT imaginghas been attempted (90). Studies are needed to validatethese tracers in clinical practice. Other types of receptorsthat can be targeted, and for which preliminary attemptsindicate the feasibility of such an approach, include benzo-diazepine receptors (91), which have a role in the modula-tion of cardiac vagal tone; angiotensin receptors; and recep-tors of endothelin and adenosine. Targeting of secondmessenger molecules, generated after binding of transmit-ters to their receptors, may offer a new way of assessingcardiac neurotransmission processes. Some radiotracers forthe second messenger system are already on the horizon(92). Recent research onb-adrenoceptors has detected ge-netic variants that may have major implications in the futuredevelopment of heart failure and early associated mortality.Early assessment of cardiac sympathetic innervation andearly treatment to prevent heart failure in genetically pre-disposed individuals may be an important future applicationof cardiac neurotransmission imaging (93).

Several clinical goals need to be met to establish theclinical usefulness of cardiac neurotransmission imaging.Congestive heart failure accounts for a great burden on theMedicare budget; we need to evaluate whether MIBG im-aging is more useful than available methods for triage ofpatients to transplantation or medical therapy. We also needto define the function of cardiac neurotransmission imagingin determining the risk of sudden death in patients withviable but denervated myocardium after myocardial infarc-tion. Finally, we need to determine the role of cardiac


neurotransmission imaging in the early detection of auto-nomic neuropathy in diabetes mellitus. If the role of cardiacneurotransmission imaging in control of therapy and assess-ment of prognosis is established, the future of cardiac nu-clear medicine will be ensured and bright.

ACKNOWLEDGMENTS

Figure 1 was provided courtesy of Dr. Dominique LeGuludec; Figure 3 was provided courtesy of Dr. RenatoValdes; Figures 4, 8, and 10 were provided courtesy of Dr.Junichi Yamazaki; and Figures 5 and 7 were providedcourtesy of Dr. Michael Scha¨fers.

REFERENCES

1. James TN. Primary and secondary cardioneuropathies and their functional sig-nificance.J Am Coll Cardiol.1983;2:983–1002.

2. Myeburg RJ, Castellanos A. Cardiac arrest and sudden cardiac death. In: Braun-wald E, ed.Heart Disease. Philadelphia, PA: Saunders; 1997:742–747.

3. Randall WC, Ardell JL. Functional anatomy of the cardiac efferent innervation.In: Kulbertus HE, Franck G, eds.Neurocardiology. New York, NY: FuturaPublishing; 1988:3–24.

4. Zipes DP, Inoue H. Autonomic neural control of cardiac excitable properties. In:Kulbertus HE, Franck G, eds.Neurocardiology. New York, NY: Futura Publish-ing; 1988:787–796.

5. McDougall AJ, McLeod JG. Autonomic neuropathy. I. Clinical features, inves-tigation, pathophysiology, and treatment.J Neurol Sci.1996;137:79–88.

6. Dae MW, O’Connell J, Botvinick EH, et al. Scintigraphic assessment of regionalcardiac innervation.Circulation. 1989;79:634–644.

7. Bristow M. Mechanism of action of beta-blocking agents in heart failure.Am JCardiol. 1997;80:26L–40L.

8. Colucci W. The sympathetic nervous system in heart failure. In: Hosenpud JD,Greenberg BH, eds.Congestive Heart Failure.Philadelphia, PA: Lippincott;2000:189–197.

9. Esler MD, Jennings GL, Korner P, et al. Assessment of human sympatheticnervous system activity from measurements of norepinephrine turnover.Hyper-tension.1988;11:3–20.

10. Goldstein D, Eisenhofer G, Dunn B, et al. Positron emission tomographicimaging of cardiac sympathetic innervation using 6-18F-fluorodopamine: initialfindings in humans.J Am Coll Cardiol.1993;22:1961–1971.

11. Luxen A, Perlmutter M, Bida GT, et al. Remote, semiautomated production of6-[18F]fluoro-L-dopa for human studies with PET.Int J Rad Appl Instrum.1990;41:275–281.

12. Schwaiger M, Kalff V, Rosenpire K, et al. Noninvasive evaluation of sympatheticnervous system in human heart by positron emission tomography.Circulation.1990;82:357–464.

13. Rosenpire KC, Haka MS, Jewett DM, et al. Synthesis and preliminary evaluationof 11C-meta-hydroxyephedrine: a false neurotransmitter agent for heart neuronalimaging.J Nucl Med.1990;31:1328–1334.

14. Chakraborty PK, Gildersleeve DL, Jewett DM, et al. High yield synthesis of highspecific activity11C-epinephrine for routine PET studies in humans.Nucl MedBiol. 1993;20:939–944.

15. Munch G, Nguyen N, Nekolla S, et al. Evaluation of sympathetic nerve terminalswith 11C-epinephrine and11C-hydroxyephedrine and positron emission tomogra-phy. Circulation. 2000;101:516–523.

16. Ungerer M, Hartmann F, Karoglan M, et al. Regional in vivo and in vitrocharacterization of autonomic innervation in cardiomyopathic human heart.Cir-culation.1998;97:174–180.

17. Short JH, Darby TD. Sympathetic nervous system blocking agents: derivatives ofbenzylguanidine.J Med Chem.1967;10:833–840.

18. Wieland DM, Brown LE, Rogers WL, et al. Myocardial imaging with a radio-iodinated norepinephrine storage analog.J Nucl Med.1981;22:22–31.

19. Wieland DM, Wu JI, Brown LE, et al. Radiolabeled adrenergic neuron-blockingagents: adrenomedullary imaging with123I-iodobenzylguanidine.J Nucl Med.1980;21:349–353.

20. Sisson JC, Wieland DM, Sherman P, Mangner MC, Tobes MC, Jacques S.Metaiodobenzylguanidine as an index of adrenergic nervous system integrity andfunction.J Nucl Med.1987;28:1620–1624.

21. Sisson JC, Bolgos G, Jhonson J. Measuring acute changes in adrenergic nerveactivity of the heart in the living animal.Am Heart J.1991;121:1119–1123.

22. Knickmeier M, Matheja P, Wichter T, et al. Clinical evaluation of no-carrier-added meta-(123I)iodobenzylguanidine for myocardial scintigraphy.Eur J NuclMed.2000;3:302–307.

23. Gill JS, Hunter GJ, Gane G, Camm AJ. Heterogeneity of the human myocardialsympathetic innervation: in vivo demonstration by iodine 123-labeled metaiodo-benzylguanidine scintigraphy.Am Heart J.1993;126:390–398.

24. Delforge J, SyrotaA, Lancon JP. Cardiac beta-adrenergic receptor density mea-sured in vivo using PET, CGP 12177, and a new graphical method.J Nucl Med.1991;32:739–748.

25. Qing F, Rahman S, Hayes M, et al. Effect of long termb2-agonist dosing onhuman cardiacb-adrenoceptor expression in vivo: comparison with changes inlung and mononuclear leukocyteb-receptors.J Nucl Cardiol.1997;4:532–538.

26. Schaffers M, Schober O, Lerch H, Cardia Schaffers M, Schober O, Lerch H.Cardiac sympathetic neurotransmission scintigraphy.Eur J Nucl Med.1998;25;435–441.

27. Berridge MS, Nelson AD, Zheng L, et al. Specific beta-adrenergic receptorbinding of carazolol measured with PET.J Nucl Med.1994;35:1665–1676.

28. Visser T, vanWaarde A, van der Mark T, et al. Characterization of pulmonary andmyocardial beta-adrenoceptors with S-19-(fluorine-18)fluorocarazolol.J NuclMed.1997;38:169–174.

29. Valette H, Deleuze P, Syrota A, et al. Canine myocardial beta-adrenergic mus-carinic receptor densities after denervation: a PET study.J Nucl Med.1995;36:140–146.

30. Le Guludec D, Cohen A, Delforge J, et al. Increased myocardial muscarinicreceptor density in idiopathic dilated cardiomyopathy: an in vivo PET study.Circulation. 1997;96:3416–3422.

31. Estorch M, Carrio´ I, BernaL, et al. Myocardial iodine-labeled metaiodobenzyl-guanidine uptake relates to age.J Nucl Cardiol.1995;2:126–132.

32. Yamazaki J, Muto H, Ishiguro K, Okamoto H, Nakano H, Morishita T. Quanti-tative scintigraphic analysis of123I-MIBG by polar map in patients with dilatedcardiomyopathy.Nucl Med Commun.1997;3:219–229.

33. Somsen GA, Borm JJ, deMilliano PA, et al. Quantitation of myocardial iodine-123-MIBG uptake in SPECT studies: a new approach using the left ventricularcavity and a blood sample as a reference.Eur J Nucl Med.1995;22:1149–1154.

34. Somsen A.Cardiac Neuronal Dysfunction in Heart Failure Assessed by 123-Iodine Metaiodobenzylguanidine Scintigraphy[thesis]. Amsterdam, The Nether-lands: University of Amsterdam; 1996.

35. Goldstein DS, Holmes C, Cannon RE, et al. Sympathetic cardioneuropathy indysautonomias.N Engl J Med.1997;336;696–702.

36. De Marco T, Dae M, Yuen MS, et al. Iodine-123 MIBG scintigraphic assessmentof the transplanted human heart: evidence for late reinnervation. J Am CollCardiol. 1995;25:927–931.

37. Schwaiger M, Hutchins GB, Kalff V. Evidence for regional catecholamine uptakeand storage sites in the transplanted human heart by positron emission tomogra-phy. J Clin Invest.1991;87;1681–1690.

38. Dae M, DeMarco T, Botvinick E, et al. Scintigraphic assessment of MIBG uptakein globally denervated human and canine hearts: implications and clinical studies.J Nucl Med.1992;33:1444–1450.

39. Di Carli MF, Tobes MC, Mangner T, et al. Effects of cardiac sympatheticinnervation on coronary blood flow.N Engl J Med.1997;336:1208–1215.

40. Estorch M, Camprecio´s M, Flotats A, et al. Sympathetic reinnervation of cardiacallografts evaluated by123I-MIBG imaging. J Nucl Med.1999;40:911–916.

41. Lerch H, Wichter T, Schamberger R, et al. Sympathetic myocardial innervationin idiopathic ventricular tachycardia and fibrillation [abstract].Eur J Nucl Med.1995;22:805.

42. Schafers M, Lerch H, Wichter T, et al. Cardiac autonomic dysfunction in patientswith idiopathic ventricular tachycardia assessed by PET CGP 12177 [abstract].J Nucl Med.1997;38(suppl):171P.

43. Schafers M, Lerch H, Wichter T, et al. Cardiac sympathetic innervation inpatients with idiopathic right ventricular outflow tract tachycardia.J Am CollCardiol. 1998;32:181–186.

44. Ungerer M, Bohm M, Elce J, et al. Altered expression of beta-adrenergic receptorkinase and beta-adrenergic receptors in the failing human heart.Circulation.1993;87:454–463.

45. Henderson EB, Kahn JK, Corbet J, et al. Abnormal I-123-MIBG myocardialwash-out and distribution may reflect myocardial adrenergic derangement inpatients with congestive cardiomyopathy.Circulation. 1988;78:1192–1199.

46. Merlet P, Dubois JL, Adnot S, et al. Myocardial beta-adrenergic desensitizationand neuronal norepinephrine uptake function in idiopathic dilated cardiomyopa-thy. J Cardiovasc Pharmacol.1992;19:10–16.

47. Merlet P, Valette H, Dubois JL, et al. Prognostic value of cardiac metaiodoben-zylguanidine imaging in patients with heart failure.J Nucl Med.1992;33:471–477.


48. Merlet P, Benvenuti C, Moyse D, et al. Prognostic value of MIBG imaging inidiopathic dilated cardiomyopathy. J Nucl Med.1999;40:917–923.

49. Maunoury C, Agostini D, Acar P, et al. Impairment of cardiac neuronal functionin childhood dilated cardiomyopathy: an123I-MIBG scintigraphic study.J NuclMed.2000;41:400–404.

50. Momose M, Kobayashi H, Iguchi N, et al. The comparison of parameters ofI-123-MIBG scintigraphy for predicting prognosis in patients with dilated car-diomyopathies.Nucl Med Commun.1999;20:529–535.

51. Cohen-Solal A, Esanu Y, Logeart D, et al. Cardiac metaiodobenzylguanidineuptake in patients with moderate chronic heart failure: relationship with peakoxygen uptake and prognosis. J Am Coll Cardiol.1999;33:759–766.

52. Nakajima K, Taki J, Tonami M, et al. Decreased123I-MIBG uptake and increasedclearance in various cardiac disorders.Nucl Med Commun.1994;15:317–323.

53. Suwa M, Otake Y, Moriguchi A, et al. Iodine-123 metaiodobenzylguanidinemyocardial scintigraphy for prediction of response to beta-blocker therapy inpatients with dilated cardiomyopathy.Am Heart J.1997;133:353–358.

54. Narula J, Haider N, Virmani R, et al. Programmed myocyte death in end-stageheart failure.N Engl J Med.1996;335:1182–1189.

55. Fagret D, Wolf JE, Comet M. Myocardial uptake of meta-[123I]-iodobenzylgua-nidine ([123I]-MIBG) in patients with myocardial infarct. Eur J Nucl Med.1989;15:624–628.

56. McGhie AI, Corbett JR, Akers MS, et al. Regional cardiac adrenergic functionusing I-123 meta-iodobenzylguanidine tomographic imaging after acute myocar-dial infarction.Am J Cardiol.1991;67:236–242.

57. Nishimura T, Oka H, Sago M, et al. Serial assessment of denervated but viablemyocardium following acute myocardial infarction in dogs using iodine-123MIBG and thallium-201 chloride myocardial single photon emission tomogra-phy. Eur J Nucl Med.1992;19:25–29.

58. Minardo JD, Tuli MM, Mock BH, et al. Scintigraphic and electrophysiologicalevidence of canine myocardial sympathetic denervation and reinnervation pro-duced by myocardial infarction or phenol application.Circulation. 1988;78:1008–1019.

59. Hartikainen J, Ma¨ntysaari M, Kuikka J, La¨nsimies E, Pyo¨rala K. Extent ofcardiac autonomic denervation in relation to angina on exercise test in patientswith recent acute myocardial infarction.Am J Cardiol.1994;74:760–763.

60. Hartikainen J, Kuikka J, Mantsayaari M, et al. Sympathetic reinnervation afteracute myocardial infarction.Am J Cardiol.1996;77:5–9.

61. Hartikainen J, Mustonen J, Kuikka J, Vanninen E, Kettunen R. Cardiac sympa-thetic denervation in patients with coronary artery disease without previousmyocardial infarction.Am J Cardiol.1997;80:273–277.

62. Nakata T, Nagao K, Tsuchihashi K, Hashimoto A, Tanaka S, Iimura O. Regionalcardiac sympathetic nerve dysfunction and the diagnostic efficacy of metaiodo-benzylguanidine tomography in stable coronary artery disease.Am J Cardiol.1996;78:292–297.

63. Kramer CM, Nicol PD, Rogers WJ, et al. Reduced sympathetic innervationunderlies adjacent noninfarcted region dysfunction during left ventricular remod-elling. J Am Coll Cardiol.1997;30:1079–1085.

64. Podio V, Spinnler MT, Spandonari T, et al. Regional sympathetic denervationafter myocardial infarction: a follow-up study using [123I]MIBG. Q J Nucl Med.1995;39:40–43.

65. Matsunari I, Schricke U, Bengel FM, et al. Extent of cardiac sympatheticneuronal damage is determined by the area of ischemia in patients with acutecoronary syndromes.Circulation. 2000;22:2579–2585.

66. Dae MW, O’Connell JW, Botvinik E, et al. Acute and chronic effects of transientmyocardial ischemia on sympathetic nerve activity, density, and norepinephrinecontent.Cardiovasc Res.1995;30:270–280.

67. Agostini D, Lecluse E, Belin A, et al. Impact of exercise rehabilitation on cardiacneuronal function in heart failure: an iodine-123 metaiodobenzylguanidine scin-tigraphy study.Eur J Nucl Med.1998;25:235–241.

68. Estorch M, Flotats A, Serra-Grima R, et al. Influence of exercise rehabilitation onmyocardial perfusion and sympathetic heart innervation in ischemic heart dis-ease.Eur J Nucl Med.2000;3:333–339.

69. Lefroy DC, DeSilva R, Choudury L, et al. Myocardial beta-adrenoceptor densityis reduced in hypertrophic cardiomyopathy [abstract].Circulation. 1992;86:I-26.

70. Lefroy DC, deSilva R, Choudury L, et al. Diffuse reduction of myocardial

beta-adrenoceptors in hypertrophic cardiomyopathy: a study with positron emis-sion tomography.J Am Coll Cardiol.1993;22:1653–1660.

71. Schaffers M, Dutka D, Rhodes CG, et al. Myocardial pre and post-synapticautonomic dysfunction in hypertrophic cardiomyopathy.Circ Res.1998;82:56–62.

72. Li ST, Tack CJ, Fananapazir L, Goldstein DS. Myocardial perfusion and sym-pathetic innervation in patients with hypertrophic cardiomyopathy.J Am CollCardiol. 2000;7:1867–1873.

73. Choudury L, Guzzeti S, Lefroy DC, et al. Myocardial beta-adrenoceptors and leftventricular function in hypertrophic cardiomyopathy.Heart. 1996;75:50–55.

74. Lerch H, Bartenstein P, Wichter T, et al. Sympathetic innervation of the leftventricle is impaired in arrhythmogenic right ventricular disease.Eur J Nucl Med.1993;20:207–212.

75. Wichter T, Hindricks G, Lerch H, et al. Regional myocardial sympatheticdysinnervation in arrhythmogenic right ventricular cardiomyopathy: an analysisusing123I-MIBG scintigraphy.Circulation. 1994;89:667–683.

76. Wichter T, Lerch H, Schafers M, et al. Reduction of postsynaptic beta-receptordensity in arrhythmogenic right ventricular dysplasia: assessment with positronemission tomography [abstract].Circulation. 1996;94(suppl I):I-543.

77. Wichter T, Schafers M, Rhodes CG, et al. Abnormalities of cardiac sympatheticinnervation in arrhythmogenic right ventricular cardiomyopathy: quantitativeassessment of presynaptic norepinephrine reuptake and postsynaptic beta-adren-ergic receptor density with PET.Circulation. 2000;13:1552–1558.

78. Kim SJ, Lee JD, Ryu YH, et al. Evaluation of cardiac sympathetic neuronalintegrity in diabetic patients using iodine-123 MIBG.Eur J Nucl Med.1996;23:401–406.

79. Scognamiglio R, Avogaro A, Casara D, et al. Myocardial dysfunction andadrenergic cardiac innervation in patients with insulin-dependent diabetes.J AmColl Cardiol. 1998;31:404–412.

80. Hattori N, Tamaki N, Hayasi T, et al. Regional abnormality of iodine-123-MIBGin diabetic hearts.J Nucl Med.1996;37:1985–1990.

81. Morimoto S, Terada K, Keira N, et al. Investigation of the relationship betweenregression of hypertensive cardiac hypertrophy and improvement of cardiacsympathetic nervous dysfunction using iodine-123-MIBG.Eur J Nucl Med.1996;23:756–761.

82. Morimitsu T, Miyahara Y, Sinboku H, et al. Iodine-123-metaiodobenzylguani-dine myocardial imaging in patients with right ventricular pressure overload.J Nucl Med.1996;37:1343–1346.

83. Sakamaki F, Satoh T, Nagaya N, et al. Correlation between severity of pulmonaryarterial hypertension and123I-metaiodobenzylguanidine left ventricular imaging.J Nucl Med.2000;7:1127–1133.

84. Wakasugi S, Fischman AJ, Babich JW, et al. Metaiodobenzylguanidine: evalu-ation of its potential as a tracer for monitoring doxorubicin cardiomyopathy.J Nucl Med.1993;34:1282–1286.

85. Valdes Olmos RA, ten Bokkel Huinink WW, ten Hoeve RF, et al. Assessment ofanthracycline-related myocardial adrenergic derangement by123I-MIBG scintig-raphy.Eur J Cancer.1995;31A:26–31.

86. CarrioI, Estorch M, Berna´ L, et al.111In-antimyosin and123I-MIBG studies in theearly assessment of doxorubicin cardiotoxicity.J Nucl Med.1995;36:2044–2049.

87. Munch G, Ziegler S, Nguyen BS, et al. Scintigraphic evaluation of cardiacautonomic innervation.J Nucl Cardiol.1996;3:265–277.

88. Tamaki N. Imaging of cardiac neuronal and receptor function.J Nucl Cardiol.1997;4:553–554.

89. Vaidyanathan G, Zhao XG, Strickland DK, Zalutsky MR. No-carrier-addediodine-131-FIBG: evaluation of an MIBG analog.J Nucl Med.1997;38:330–334.

90. Hicks RJ, Kassiou M, Eu P, et al. Iodine 123 N-methyl-4-iodoexetimide: a newradioligand for single photon emission tomographic imaging of myocardialmuscarinic receptors.Eur J Nucl Med.1995;22:339–345.

91. Fischman A. Radionuclide imaging probes for expressed proteins.J Nucl Car-diol. 1999;6:438–448.

92. Takahashi T, Ido T, Ootake A, et al.18F-labeled 1,2-diacylglicerols: a new tracerfor the imaging of second messenger systems.J Labeled Radiopharm.1994;35:517–519.

93. Liggett SB, Wagoner LE, Craft LL, et al. The Ile164 beta2-adrenergic receptorpolymorphism adversely affects the outcome of congestive heart failure.J ClinInvest.1998;102:1534–1539.


Documents

CONTINUING EDUCATION Cardiac Neurotransmission Imaging*jnm.snmjournals.org/content/42/7/1062.full.pdf · Cardiac Neurotransmission Imaging* Ignasi Carrio´ Department of Nuclear Medicine,

CONTINUING EDUCATION Cardiac Neurotransmission Imagingjnm.snmjournals.org/content/42/7/1062.full.pdf · Cardiac Neurotransmission Imaging Ignasi Carrio´ Department of Nuclear Medicine,