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Cardiac Applications of 123I-mIBG Imaging
Amala Chirumamilla, MD, and Mark I. Travin, MD
Cardiac autonomic innervation plays a key role in maintaining hemodynamic and
electrophysiologic harmony. Cardiac sympathetic function is adversely altered in many
disease states, such as congestive heart failure, myocardial ischemia, and diabetes.123I-mIBG, a sympathetic neurotransmitter radionuclide analog, aids in the detection of
sympathetic innervation abnormalities and can be imaged with planar and single-
photon emission computed tomographic techniques. Cardiac 123I-mIBG uptake can be
assessed by the heart mediastinal ratio (H/M), tracer washout rate, and focal uptake
defects. These parameters have been widely studied and shown to correlate strongly
and independently with congestive heart failure progression, cardiac arrhythmias,
cardiac death, and all-cause mortality. There is accumulating evidence that 123I-mIBG
imaging can help to monitor a patients clinical course and response to therapy. The
ability to predict potentially lethal ventricular arrhythmias promises to help more
accurately select patients for implantable cardioverter defibrillators, limiting unneces-
sary devices and identifying additional patients at risk who do not meet current
guidelines. 123I-mIBG shows potential to help determine whether greater risk and
usually more expensive ventricular assist device therapies or cardiac transplantation
might be needed. Although more investigation in larger populations is needed to
strengthen previous findings, cardiac 123I-mIBG imaging shows promise as a new
technique for recognizing and following potentially life-threatening cardiac conditions.
Semin Nucl Med 41:374-387 2011 Elsevier Inc. All rights reserved.
Cardiac autonomic innervation plays a vital role in car-
diac function, regulating myocardial blood flow,heart rate, and contractile performance. In various cardiac
diseases, neuronal function of the heart is altered, which
often is associated with and contributing to the worsening
of the condition, thereby increasing the potential for
life-threatening cardiac arrhythmias and death to occur.
Cardiac neuronal imaging aids in understanding the pa-
thophysiology of cardiac diseases, enhances patient as-
sessment, and shows great potential for helping to guide
patient management and thereby improve outcome and
well-being. This review will provide an overview of car-
diac autonomic innervation imaging with use of the radio-
tracer 123I-mIBG and discuss in detail its potential appli-cations for patient evaluation.
Anatomy of Cardiac
Parasympathetic andSympathetic Innervation
The cardiac autonomic nervous system consists of sympa-
thetic and parasympathetic innervation. The neurotrans-
mitter of the sympathetic system is norepinephrine (NE), and
that of the parasympathetic system is acetylcholine. These
neurotransmitters work in balance together to exert stimulat-
ing or inhibitory cardiac effects via adrenergic and musca-
rinic receptors. Both are responsible for electrophysiologic
and hemodynamic adaptations of the cardiovascular system
to changing demands.
Sympathetic output is controlled by brain regulatory cen-
ters that integrate input signals from other parts of the brain
and from receptors throughout the body. Efferent signals
follow descending pathways in the spinal cord and synapse
with preganglionic fibers that leave the spinal cord at levels
T1-L3, subsequently synapsing with paravertebral stellate
ganglia, and eventually innervating the right ventricle and the
anterior and lateral left ventricle. In the heart sympathetic
nerves follow the coronary arteries in the subepicardium and
then penetrate the myocardium.1,2
Department of Nuclear Medicine and Division of Cardiology/Department of
Medicine, Montefiore Medical Center, Albert Einstein College of Medi-
cine, Bronx, NY.
Address reprint requests to Mark I. Travin, MD, Department of Nuclear
Medicine, Montefiore Medical Center, 111 East-210th Street, Bronx, NY
10467-2490. E-mail: [email protected].
374 0001-2998/11/$-see front matter 2011 Elsevier Inc. All rights reserved.doi:10.1053/j.semnuclmed.2011.04.001
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Parasympathetic fibers, scarce in comparison with sympa-thetic fibers, originate in the medulla and follow the vagusnerves. They start epicardially in the heart, cross the atrio-ventricular (AV) groove, penetrate the myocardium, and arethen located in the subendocardium. These fibers predomi-nantly innervate the atria and are scarce in the ventricle(densest in the inferior wall), in large part controlling sino-
atrial and atrioventricular nodal function.Most published literature and impending clinical applica-
bility of autonomic radionuclide imaging focuses on the sym-pathetic system, with parasympathetic imaging work limitedmostly to animals. Therefore, the ensuing discussion willfocus on the former.
Sympathetic Synapse Physiologyand Assessment with 123I-mIBGThe sympathetic mediator NE is synthesized from the aminoacid tyrosine that is stored in high concentration in synapticvesicles. As illustrated in Figure 1, in response to a stimulus,
NE-containing vesicles are released into the synaptic spaceand bind to postsynaptic1, 2, and receptors, enhancingadenyl cyclase activity through an intermediary G protein,resulting in the desired cardiac stimulatory effects.3-5 NE istaken back into the presynaptic terminal by a protein-medi-ated sodium, energy, and temperature-dependent trans-porter, known as the uptake-1 pathway, for storage or cata-bolic disposal that terminates the sympathetic response.Some synaptic NE is also taken up by non-neuronal postsyn-aptic cells, probably by sodium-independent passive diffu-sion (ie, uptake-2).6,7
Guanethidine is a false neurotransmitter analog of NE that
is also taken up by the uptake-1 pathway. Chemical modifi-cation of guanethidine produces a molecule that can be la-
beled with radioactive iodine (now most commonly 123I),becoming meta-iodobenzylguanidine (123I-mIBG). Hence, asintravenously administered 123I-mIBG diffuses into the syn-aptic space it is taken up, concentrated, and stored in thepresynaptic nerve terminal in a manner similar to that ofNE.1,4,8,9 In contrast to NE 123I-mIBG is not catabolized bymonoamine oxidase or catechol-O-methyltransferase. As a
result, 123I-mIBG is retained and localized in myocardial sym-pathetic nerve endings at a sufficient concentration to beimaged with a conventional gamma camera.7,10-12
When first developed in the late 1970s, mIBG was labeledwith 131I and used for the detection of various tumors. Be-cause 131I gives off relatively high-energy (365 keV) emis-sions, emits -particles, and has a relatively long half-life ofapproximately 8.02 days, alternative 123I labeling has beendeveloped and is preferred. 123I emits predominantly pho-tons with energies of 159 keV and has a half-life of 13.2hours; therefore, it is easily imaged and well tolerated. 123I-mIBG has been used extensively in Europe and Japan for
cardiac imaging, but at the time of this writing is not ap-proved in the United States by the Food and Drug Adminis-tration for cardiac imaging; therefore, it is considered inves-tigational in this regard. The radiotracer is approved underthe name AdreView for imaging of neuroblastoma and pheo-chromocytoma.
Cardiac Imaging with 123I-mIBG123I-mIBG injection is performed at rest, with only minimalpreparation. Medications that could potentially interfere withcatecholamine uptake, such as antidepressants, antipsychot-
ics, and some calcium channel blockers, should be held for24 hours before tracer injection and imaging. To block thy-
Figure 1 Schematic representation of sympathetic neuronal synapse. AC, adenyl cyclase; AMP, adenosine monophos-phate; cAMP, cyclic adenosine monophosphate; G, G proteins. Reprinted with permission from Travin et al.3
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roid uptake of free radioactive iodide, some recommend ad-ministering either 500 mg of oral potassium perchlorate or200 mg of potassium iodide in a 10% solution, although withnewer labeling procedures and given that 123I emissions arelow-energy gammas from a tracer with a short half-life, manyinvestigators believe that such pretreatment is unnecessary.
The appropriate dosage of 123I-mIBG has not been defini-
tively established. In several published studies investigatorshave used a dose of 3-5 mCi (111-185 MBq) during a 1-min-ute period, and this is generally satisfactory for planar imageanalysis. However, because it is often difficult to obtain sat-isfactory single-photon emission computerized tomographic(SPECT) images with this dose, particularly in patients withsevere cardiac dysfunction, a dose of up to 10 mCi (370 MBq)may be appropriate and is under investigation.4,13
Parameters for planar and SPECT acquisition of123I-mIBGare also not formally established, but common methods inuse are described in various published reviews.14,15 Planarimages are obtained in the anterior view for 10 minutes by
the use of an energy window of 159 keV 20%. SPECTimages are obtained via a standard 180 circular acquisitionfrom 45 RAO (right anterior oblique) to 45 LPO (left pos-terior oblique) by the use of 60 stops (30 stops per head ifperformed with a dual-headed camera) at 30 seconds perstop. Although low-energy collimators have been customar-ily used for 123I-mIBG acquisition, other greater-energy pho-tons emissions from 123I (eg, 529 keV) penetrate the septa,degrading image quality. Work is under way with a measuredpoint spread function to perform 3-dimensional deconvolu-tion of the septalpenetration to compensate for this effect andimprove image accuracy, particularly for quantitative param-
eters.16
Planar and SPECT images are routinely obtained at ap-proximately 15 minutes after 123I-mIBG administration(early), and again 3-5 hours later (delayed). Although someresearchers think that only the delayed image should be usedfor interpretation and analysis because it represents actualneuronal uptake (as opposed to interstitial uptake in the earlyimages), studies (mostly from Japan) from other authors havereported that tracer washout between early and delayed im-ages provides important additional information.17-21
Image Interpretation
Global cardiac uptake of123I-mIBG can be assessed from theplanar images. The customarily used quantitative indexes arethe heart/mediastinal ratio (H/M) and the myocardial wash-out rate (WR).22-24 The H/M is derived by drawing regions ofinterest (ROI) over the heart and over the upper mediastinumin an anterior planar image, and the mean counts per pixel inthe heart are divided by the mean counts per pixel in themediastinum. The exact method used by various investiga-tors has varied, with some using a limited ROI in a myocar-dial wall, others drawing an ROI around the entire heart, andstill others drawing the ROI around the entire heart but ex-cluding the cavity. Normal values for H/M range from 1.9 to
2.8, with a mean of approximately 2.2 0.3.25 The H/M ratioreflects receptor density and likely portrays the integrity of
presynaptic nerve terminals and uptake-1 function. A highratio indicates predominant localization of the tracer in themyocardium that is expected for normal hearts, whereas adecreased ratio indicates less myocardial uptake, with morein extracardiac structures, and signifies reduced cardiac ad-renergic receptor density.15 The late H/M ratio combines in-formation on neuronal function from uptake to releasethrough the storage vesicles at the nerve terminals.13 Exam-ples of patients with normal and abnormal H/M ratio are
shown in Figure 2.26
A low-energy, high-resolution collimator is customarilyused for 123I, but there are confounding factors. As previouslymentioned, low-abundance, high-energy photons emitted bythis radioisotope can penetrate collimator septa and are de-tected by the camera crystal. As the low-energy, high-resolu-tion collimator blocks 159 keV photo-peak photons, the pro-portion of greater energy photons increases, therebydegrading image quality and decreasing quantitative accu-racy. To improve quantification, Chen et al16 have developedprotocols using iterative reconstruction with a deconvolutionof septal penetration technique, showing that quantificationof 123I SPECT imaging can be achieved this way, but with
different normal values obtained for H/M. It is unclear howthis technique would be used when 123I-mIBG becomes avail-able for clinical cardiac use, and therefore what ultimatelywould be considered a normal H/M.
Techniques are being explored to standardize and improvethe reproducibility of the H/M ratio. Okuda et al27 reportedon a semiautomatic measurement of the H/M ratio that uses asoftware algorithm to automatically determine the mediasti-nal ROI on the basis of tracer uptake in the heart, lung, liver,and thyroid (after a cardiac circular ROI is manually set). Intheir study of 37 patients, the testretest intraclass correla-tion coefficient (ICC) from their method showed excellent
reproducibility for early (ICC 0.99) and delayed (ICC 0.99) imaging.
Figure 2 Examples of planar cardiac 123I-mIBG images. The exampleon the left shows normal cardiac 123I-mIBG uptake with a H/M ratio
of 2.24 and a normal tracer washout (WO) from initial to delayedimages of 10.64%. The example on the right shows an abnormal
H/M ratio of 1.29 in images with an abnormal tracer washout of23.35%. Reprinted with permission from Yong and Travin.26 (Color
version of figure is available online.)
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Myocardial 123I-mIBG washout has been shown to be animportant measure of cardiac sympathetic innervation. Theinitial and delayed planar images are used for this calculation.The WR is thought to reflect turnover of catecholamines thatrelates to the degree of sympathetic drive. Increased sympa-thetic activity, reflecting worsening heart failure, is associatedwith diminished myocardial 123I-mIBG retention on delayed
images and thus a greater myocardial 123I-mIBG washout. Anormal washout value in control subjects is reported to be8.5%-9.6%.22,28Although there are various methods of wash-out determination reported in the literature, recent European
Association of Nuclear Medicine guidelines indicate the fol-lowing29:
WRBKGcorrected{HeMe} {(HlMl) 1.21*}
HeMe) 100
Where * indicates 123I decay corrected for 3 hours and 45minutes, e early images, l late images, BKG back-ground, H heart counts per pixel, Mmediastinal countsper pixel, and WR washout rate.
Limitations of planar imaging include superposition of dif-ferent thoracic structures that exhibit 123I-mIBG uptake(lungs and liver), as well as overlap of different myocardialsegments. In some instances, SPECT images can overcomethese limitations. SPECT imaging also allows better assess-ment of the quantitative extent of cardiac neuronal abnor-malities and the presence of regional denervation. As withperfusion imaging, SPECT 123I-mIBG image findings can bedescribed qualitatively or semiquantitatively with a summedscore.30,31 Regional distribution of 123I-mIBG can be com-pared with regional distribution of a standard perfusion
tracer, such as 99mTc-sestamibi or 99mTc-tetrofosmin, inwhich the 2 sets of images may yield a matched or mis-matched pattern in the presence and extent of denervationversus perfusion abnormality(s). A mismatched pattern indi-cates that denervation is more extensive than the correspond-ing perfusion abnormality, signifying a region of denervatedbut perfused viable myocardium.15 Such regions may exhibitdenervation supersensitivity and predispose to potentiallylethal arrhythmias.32,33
Nevertheless, if global myocardial uptake of 123I-mIBG isseverely reduced, it can be difficult to acquire tomographicslices of the heart of sufficient quality for interpretation.34 In
addition, tracer uptake in extracardiac structures can inter-fere with assessment of nearby myocardial walls. Standardperfusion SPECT artifacts, such as attenuation and scatter,also impair tomographic 123I-mIBG images. Finally, unlikefor perfusion images, there are variety of normal patterns ofneuronal tracer uptake that can vary with age and gender, tobe discussed in the next section.
Normal123I-mIBG Uptake and theChallenge of Study Interpretation
123I-mIBG uptake in healthy patients can be heterogeneous.Somsen et al28 observed a large interindividual variation of
myocardial segmental uptake, often significantly lower in theinferior than in the lateral region of the left ventricle. Theseauthors suggested that the observed regional differencescould be partly explained by tissue attenuation (althoughexpected gender differences were not demonstrated in thisstudy) and spatial variation in sympathetic nerve activity.Other investigators reported that these heterogeneities are
more pronounced in older subjects and in men.21 Estorchand colleagues35 found that in athletes who have sinus bra-dycardia, 123I-mIBG uptake is lower in the inferior wall, sug-gesting that such regional variation may be the result of in-creased vagal tone in the inferior wall. Heterogeneity ofautonomic tracer uptake in healthy patients was exploredfurther by Bulow et al,36 who compared 123I-mIBG imageswith images by using the autonomic positron emission tomo-graphic (PET) tracers 11C-hydroxyephedrine (HED) and 11C-epinephrine. Although 11C-HED was regionally homoge-nous, 11C-epinephrine showed mild homogeneity withmildly reduced uptake of inferior wall, and 123I-mIBG
showed marked heterogeneity with significantly lower up-take in inferior wall. These findings suggest that normalvariations are likely the result of both technical and physio-logical factors. Whatever the origin, these normal variationsneed to be taken into account when interpreting tomo-graphic 123I-mIBG images.
Congestive Heart Failure
The increased prevalence of coronary artery disease, the ag-ing of the population, and improvements in coronary arterydisease and hypertension treatment are contributing to in-
creasing numbers of patients with congestive heart failure(CHF), of which there currently are approximately 5 millionpatients in United States, with 550,000 new cases diagnosedannually. The resulting 1 million hospitalizations also sub-stantially increase medical costs.37 Better ways of evaluatingand managing these patients is required, and because neuro-hormonal changes play a key role in the pathophysiology ofCHF, autonomic radionuclide imaging can make an impor-tant contribution.
After an initiating event that reduces cardiac pump func-tion, the process leading to clinical CHF may ensue. Many ofthe adverse sequelae from CHF result from alterations in thenormal neurohormonal balance that include activation of the
renin-angiotensin-aldosterone system and compensatory ac-tivation of the sympathetic nervous system.38 Initially, cate-cholamine stimulation helps to compensate for decreasedmyocardial function, but long-term catecholamine excess hasdetrimental effects on myocardial structure and function. De-spite elevated circulating levels of catecholamines, NE storesin the myocardium become depleted, possibly as a protectivemechanism. In one report, explanted hearts of patients withpretransplantation New York Heart Association (NYHA)functional class IV CHF demonstrated a 50% reduction in-adrenergic receptor density.39 In addition, laboratory stud-ies demonstrate a decrease in NE transporter activity.40
This reduction in myocardial NE and subsequent impairedautonomic function can be detected by imaging with 123I-
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mIBG. There is an initial increase of NE release into the syn-aptic cleft, promoting an increase in the NE transporter 1(uptake-1, NET-1) process. Eventually, the NET-1 system isoverwhelmed, with a reduction in NET-1 carrier density,leading to increased spillover of NE into plasma, likely ac-counting for the increased WR found on 123I-mIBG imagingin patients with CHF. With progression of cardiac dysfunc-
tion, there is diminished presynaptic function from loss ofneurons and down-regulation of NET-1, likely accountingfor decreased global radiotracer uptake (lower H/M) in stagesof advanced disease.41
Merlet et al42 were among the first to show that 123I-mIBGimaging can provide important prognostic information inCHF patients. In a prospective study of 90 patients withmoderate-to-severe CHF and left ventricular ejection fraction(LVEF)45%, an H/M 1.2 identified patients at high riskfor cardiovascular death, with the 123I-mIBG results being amore powerful predictor than LVEF. A subsequent study byNakata and colleagues43 of 400 patients a showed progressive
worsening of survival as the H/M decreased and that H/M wasa more powerful predictor of cardiac death than NYHA class,age, previous myocardial infarction (MI), and LVEF. In amulticenter center study involving 6 European Centers, Ag-ostini and colleagues44 reviewed the records of 290 patientswith CHF and quantitatively reanalyzed their 123I-mIBG stud-ies. Logistic regression showed that the only significant pre-dictors of major adverse cardiac events (cardiac death, trans-plant, and potentially fatal arrhythmias) over 24 months wereLVEF and H/M. Particularly striking was the ability of H/M torisk stratify patients who had LVEF 35%, with event ratesranging from5% for those who had H/M 2.18, to50%
for those who had H/R
1.45.The largest study to date is the AdreView myocardial Im-aging for Risk Evaluation in Heart Failure (ADMIRE-HF), aprospective international multicenter trial of 961 subjectswith NYHA functional class II-III CHF and LVEF35% whounderwent planar and SPECT 123I-mIBG imaging and werefollowed for a mean of 17 months.45,46 In ADMIRE-HF car-diac events occurred in 237 patients (approximately 25%),with approximately 70% of the first events being CHF pro-gression, approximately 20% being a potentially lethal ar-rhythmic event (sustained ventricular tachycardia30 s, re-suscitated cardiac arrest, and appropriate implantablecardioverter defibrillator [ICD] discharge), and approxi-
mately 10% being cardiac death, with 22% of the patientswith events experiencing multiple events. A significantlylower risk (15%) of the composite end point was observed inpatients with late H/M 1.60 compared with those withH/M 1.60 (38%; hazard ratio 0.40; P 0.001) with ahighly significant hazard ratio for each individual compo-nents of the composite primary end point, ie, CHF progres-sion 0.49 (P 0.002), life-threatening arrhythmias 0.37(P 0.02), and cardiac death 0.14 (P 0.006). Figure 3illustrates the individual event rates in relation to the H/M.46
Notably, the 2-year all-cause mortality was5 fold greater(16.1% vs 3.0%) in patients with H/M 1.60 compared with
those having an H/M 1.60, respectively. Multivariate andinteraction analysis provided relevant information about the
incremental prognostic value of123I-mIBG beyond and above
traditional risk markers. In particular, in the ADMIRE-HF
population, in a subanalysis multivariable Cox proportional
hazard analysis identified 4 independent predictors of a car-
diac event: NYHA functional class, plasma levels of B-type
natriuretic peptide (BNP), LVEF, and late H/M. Importantly
in higher-risk patients with lower ejection fraction (EF)
(29%) and greater BNP levels (140 ng/L), H/M provided
further risk stratification.
Furthermore, the interaction analysis was also applied to
investigate the incremental prognostic power of 123I-mIBG
image findings when EF and BNP were already known, and
again significantly lower event and cardiac death rates were
observed in patients with H/M 1.60, indicating an incre-
mental prognostic power of 123I-mIBG imaging beyond that
provided by traditional CHF functional and neurohormonal
markers.47 Figure 4 illustrates the interaction of H/M and
LVEF in relation to cardiac death. Approximately 20% of
patients in ADMIRE-HF had a H/M 1.60. There was only 2
cardiac deaths in these patients (1 with arrhythmia with H/M
1.60, and 1 from progressive CHF), both in patients with
LVEF 20%-29%. There were no cardiac deaths in the other
LVEF subgroups, including those with an LVEF 20%.
Similarly, among patients with BNP100 ng/dL, for those
with H/M 1.6, there was not a single cardiac death (both
deaths were for patients with BNP 100 ng/dL). Thus,
among patients with advanced CHF and high clinical risk
based on clinical and standard laboratory/LV functional pa-
rameters, 123I-mIBG imaging allows identification of a patient
subgroup that is at extremely low risk at least during an
approximately 2-year follow-up, an observation that if sub-
stantiated further could lead to changes in management.The etiology of CHF may differ and often is classified as
ischemic or nonischemic. Despite the pathophysiology and
initial insult differing, investigatory studies suggest that re-
gardless of the initial cause of heart failure, as the condition
progresses there is a common state in which characteristic
cardiac autonomic abnormalities are seen, with 123I-mIBG
imaging remaining a strong correlate of prognosis. Waka-
bayashi and colleagues48 showed that for both groups, late
H/M was the most powerful independent predictor of sudden
cardiac death (SCD), although there were different H/M
threshold values for ischemic (1.50) compared with nonisch-
emic (2.02) cardiomyopathies. For patients with an LVEF40% and a late H/M less than the identified threshold, the
cardiac death rate was greater for the ischemic group than for
the nonischemic group (18.2%/year vs 11.9%/year, respec-
tively).
Cardiac 123I-mIBGas a Guide to CHF therapy
Mortality for CHF patients remains 8%-10% per year despite
optimal pharmacologic therapy.49 Given the ability of 123I-
mIBG imaging to risk stratify patients with CHF, many re-searchers are investigating the potential of this technique to
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monitor the effectiveness of pharmacologic and other thera-pies, and to guide their use.
Studies have consistently shown that cardiac 123I-mIBGimages improve after therapy with -blockers.50-55 For exam-ple, Gerson et al,53 in a study of 22 patients with idiopathicCHF, showed that the H/M improved significantly after pa-tients were administered carvedilol, especially in those pa-
tients with an H/M ratio 1.40 (1.26 0.12 to 1.39 0.20,P 0.004). Toyama et al,56 in a study of 24 subjects withdilated cardiomyopathy, showed favorable changes of symp-toms, functional class, cardiac function, and H/M in thosetreated with metoprolol. Kasama et al57 reported on the ther-apeutic effect of carvedilol on 123I-mIBG parameters and LVremodeling in 30 patients with dilated cardiomyopathy. Af-ter patients were treated for 6 months with carvedilol, notonly was there an increase in H/M (P 0.001) and a decreasein WR (P 0.001) but also a significant decrease in LVvolumes (P 0.001) and an improvement in LVEF (P 0.003).
Although changes in autonomic function in response to-blockers are not entirely surprising, various other medica-
tions, such as angiotensin-converting enzyme inhibitors(ACE-I), angiotensin receptor blockers, and spironolactone,which all affect the renin-angiotensin system, also improvecardiac 123I-mIBG uptake.58-60 Takeishi and colleagues61
showed an increase in H/M and a decrease in tracer washoutin 19 NYHA class II-III patients treated with enalapril.Kasama and colleagues62 showed that adding the angiotensin
receptor blocker valsartan to an ACE-I improved 123I-mIBGparameters that was accompanied by an increase in LVEF andan improvement in NYHA functional class. Kasama, et al alsoassessed the influence of aldosterone treatment on cardiacsympathetic nerve activity. After 6 months of adding spirono-lactone to an ACE-I and a loop diuretic, they found that thelate H/M and the LVEF significantly increased and the latetotal defect score as well as 123I-mIBG WR significantly de-creased, with a parallel reduction of the left ventricular end-diastolic volume.63,64
Amiodarone, an antiarrhythmic medication that wouldnot be expected to directly influence cardiac sympathetic
function, has also been shown to improve 123I-mIBG param-eters in patients who have advanced CHF.65-67 This improve-
Figure 3 Cumulative event curves comparing subjects with H/M 1.60 versus 1.60. (A) Composite primary end
point; (B) heart failure progression; (C) arrhythmic event; (D) cardiac death; (E) all-cause mortality. Reprinted withpermission from Jacobson et al.46 (Color version of figure is available online.)
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ment in sympathetic innervation may related to amiodaronesother effects, including an antifibrillatory effect, the ability toprolong the action potential through alterations in potassiumtransport, a coronary vasodilatory effect, and a noncompeti-tive inhibition of-adrenergic receptors that can influencethyroid hormone metabolism and may have cardioprotectiveeffects.68A prospective study comparing amiodarone versus-blockers in the treatment of patients with idiopathic car-diomyopathy reported similar improvement in cardiacsymptoms, function, and sympathetic nerve activity withboth drugs.69
Changes in cardiac innervations have been also reported inpatients undergoing device therapy. As illustrated in Figure
5, Drakos et al70 found that for 12 patients, after 3 months ofleft ventricular assist device (LVAD) therapy, there was anincrease in early H/M (1.35 0.9 to 1.44 0.11, P 0.028), in late H/M (1.25 0.18 to 1.43 0.13, P 0.01),and a decrease in WR (51.0 23.2% to 30.6 8.7%, P 0.015), which significantly correlated with BNP and pulmo-
nary systolic blood pressure changes. Further investigationmay allow clinicians to use 123I-mIBG imaging to decide whenLVAD therapy could potentially be discontinued, or alterna-
tively when lack of response or cardiac deterioration maypush one towards cardiac transplantation.
Finally, the effects of cardiac resynchronization therapy(CRT) on myocardial innervation have also been investi-gated. Erol-Yilmaz et al71 evaluated cardiac sympathetic ac-
tivity in 13 HF patients before and after 6 months of CRT andfound that significant improvements in NYHA class, QRS
width, and echocardiographic parameters were associatedwith an increase in late 123I-mIBG H/M, as well as with areduction in WR. Similarly, Gould et al72 assessed cardiac
innervation by 123I-mIBG in 10 patients with CHF undergo-ing CRT, and found that theactivation of biventricular pacing
was associated with an increased early and late H/M. Finally,Burri et al73 reported a lower 123I-mIBG WR after CRT im-plantation in 13 CHF patients who responded clinically com-
pared with 3 nonresponders (P 0.002), with a moderate
although significant correlation (r 0.52) between LVEFincrease and WR decrease.
It is important to consider how the aforementioned find-ings could specifically direct therapy in patients with CHF.
Although some have investigated whether 123I-mIBG imagingcould help decide who might benefit from a particular med-ical therapy,55 results have not been sufficiently conclusive.
Given the high benefit to risk/cost ratio of conventional med-ical therapies, a cardiac 123I-mIBG study is unlikely to pre-clude their use.74 123I-mIBG imaging might instead be more
useful in determining whether a patients medical therapy isworking satisfactorily and could therefore help determine
whether greater-risk and usually more expensive device ther-apies or cardiac transplantation might be needed.42 A studyby Matsui et al75 of patients with severe cardiomyopathyshowed that worsening 123I-mIBG images 6 months after op-
timal medical therapy is, with BNP, an independent predictorof cardiac death. Worsening findings on serial 123I-mIBG
Figure 4 Relationship of LVEF and H/M groups to 2-year cardiacmortality (%).47
Figure 5 Effect of LVAD on cardiac 123I-mIBG uptake. After 3 months of device support, there is an increase in the H/M.Reprinted with permission from Drakos et al.70
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studies may indicate that additional or alternate therapies,such as devices or cardiac transplantation, need to be under-taken to improve outcome.
Arrhythmias
Sudden cardiac death remains one of the leading causes of
death in the United States. The presence of myocardial scarand/or unrevascularized myocardium at risk from ischemiaprovides an important substrate for the occurrence of poten-tially fatal ventricular arrhythmias.76 The presence of clinicalheart failure further increases the risk of ventricular arrhyth-mia. The sympathetic nervous system provides an importanttrigger for major arrhythmic events, both through globaloveractivity and from regional heterogeneity of sympatheticactivity. A mismatch of myocardial perfusion and innervationmay pose a particularly high risk.77,78
An LVEF30%-35% identifies a population of patients atincreased risk for sudden cardiac death. Once identified, an
ICD is effective in reducing the occurrence of sudden cardiacdeath, an American Heart Association/American College ofCardiology class I indication with level A evidence.79 How-ever, in a substantial proportion of patients who receive anICD on the basis of reduced LVEF, the device never deliverstherapy. Furthermore, most patients who die suddenly donot qualify for ICD placement under current LVEF-basedcriteria in the guidelines.
Appropriate ICD firing only occurs in only 5% of patients(per year) who receive the device.80 The number of patientsneeded to treat with ICD implantation to abort a life-threat-ening arrhythmia is high, ie, 18 in the Multicenter Automated
Defibrillator Implantation TrialII81
and 15 in the SuddenCardiac Death in Heart Failure Trial.80 In addition, there is a4% postprocedural complication rate,82 and there are knownlong-term risks, such as infection, device malfunction, leadissues, and a high rate of inappropriate shocks that canworsen quality of life. Thus, something other than LVEF isrequired to better select patients who are likely to benefitfrom an ICD.83
Given that the autonomic systemplays a key role in cardiacarrhythmias, 123I-mIBG imaging has the potential to moreaccurately select patients for ICD implantation, both limitingunnecessary implantations and identifying additional pa-tients at risk of SCD not meeting current guideline criteria. To
meet this ambitious goal, 123I-mIBG imaging should providevery sensitive and specific parameters to cost-effectively pre-dict the occurrence of fatal cardiac arrhythmias beyond thatprovided by current criteria.
Several clinical studies have indicated that 123I-mIBG im-aging can predict potentially lethal ventricular arrhythmias inpatients with CHF and thereby help guide the use of ICD.
Arora et al84 performed a pilot study on 17 patients withadvanced CHF and an ICD. They deliberately selected a bal-anced group of patients with and without previous ICD dis-charges. A decreased late H/M (threshold 1.54) was associ-ated with increased incidence of an ICD discharge, with a
positive predictive value of 71%, while an increased late H/Mhad a negative predictive value of 83%. When autonomic
imaging was combined with heart rate variability (HRV) anal-ysis, none of 3 patients who had both a high H/M and a moreabnormal HRV had an ICD discharge, whereas all 4 patientswho had a low H/M and less abnormal HRV did, shown inFigure 6. All patients in this study also had tomographic123I-mIBG and perfusion (99mTc-sestamibi) imaging. Patientswho had ICD discharges had more extensive 123I-mIBG/per-fusion (99mTc-sestamibi) mismatches on SPECT imaging.Those with autonomic perfusion mismatches were morelikely to have appropriate ICD discharges than those without,illustrated by the case examples seen in Figure 7.
In a subsequent study, Nagahara et al85 prospectively fol-
lowed 54 patients with an ICD, and found that late H/Mcorrelated significantly and independently with appropriateICD discharges and SCD. When combined with plasma BNPconcentration or LVEF, there was additional predictivepower from the imaging study.
Washout rate being another marker for autonomic dys-function, Kioka et al investigated the use of 123I-mIBG imag-ing to predict SCD in 97 patients with chronic heart failure.86
For those with an abnormal WR (defined as 27%), suddendeath was significantly more frequent than in the cohort witha normal WR. Moreover, multivariate analysis showed that
WR was the only independent predictor of SCD.In ADMIRE-HF, combined arrhythmic events (ie, self-
limited ventricular tachycardia, resuscitated cardiac arrest,appropriate ICD discharges) were more common in subjectswith H/M 1.60 (10.4%) than in those with H/M 1.6(3.5% P 0.01).46 In a subanalysis of ADMIRE-HF of pa-tients without an ICD, Senior et al87 reported no fatal arrhyth-mic events in patients with H/M 1.60 over 2 years, asshown in Figure 8. (There was one event in a patient withH/M 1.6.)
123I-mIBG imaging using SPECT tomographic images hasalso been reported to be helpful in recognizing increasedarrhythmogenicity. Bax et al, in a prospective study of pa-tients with prior MI, showed that the only difference in mul-
tivariate analysis between positive and negative inducible VT(ventricular tachycardia) in an electrophysiologic study was
Figure 6 Relationship of a combination of 123I-mIBG image results(H/M) and HRV variables (5-minute low frequency) to the occur-
rence of an ICD discharge. Modified with permission from Aroraet al.84
Cardiac applications of 123I-mIBG imaging 381
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the 4-hour 123I-mIBG SPECT results, with a defect score37having a sensitivity of 77% and specificity of 75% for predict-ing electrophysiologic results.31 In a more recent study fromthe same group, Boogers et al performed 123I-mIBG SPECTimaging in 116 patients with CHF (mean LVEF 28%)before ICD implantation, finding that over a mean of 23months (up to 3 years), the late image tomographic defect
score was an independent predictor of appropriate ICD ther-apy and cardiac death, with a score 26 associated with a13-fold greater risk.30
Yukinaka et al78 studied 123I-mIBG uptake in 50 patientswith previous MI, and related the results to the presence oflate ventricular potentials, which are frequently used to pre-dict life-threatening arrhythmias. Patients with late ventricu-lar potentials had significantly greater 123I-mIBG defect scoresand also had significantly greater mismatch scores betweenthe 123I-mIBG and perfusion defect scores (mismatch refers to
larger 123I-mIBG defects compared with perfusion defects,
suggesting viable but denervated myocardium). No signifi-
cant difference was observed in perfusion defect score be-
tween these 2 groups, suggesting that infarct size alone did
not correlate with late ventricular potentials. By 24-hour
Holter electrocardiographic monitoring, patients with late
ventricular potentials were more likely to have severe ven-
tricular arrhythmias.Various electrocardiographic parameters have been shown
to predict lethal arrhythmias and therefore proposed as cri-
teria to better help decide who would benefit from an ICD.
However, Tamaki et al compared these parameters with 123I-
mIBG image findings in 106 patients with LVEF 40%,
followed for a mean of 65 months.88 Patients who had SCD
had a statistically significant lower H/M and greater WR, and
by multivariate analysis only WR and LVEF were indepen-
dent predictors of SCD, whereas HRV, QT dispersion, and
signal-averaged ECG showed no significant relationship to
SCD.
Notably, WR showed greater specificity and predictive ac-curacy than LVEF and maintained its predictive capacity
when the subgroup of patients with LVEF 35% were con-
sidered, suggesting a role for 123I-mIBG imaging to identify
ICD candidates not included in current guidelines. These
findings are of particular interest considering that a larger
absolute number of SCDs occur in this group with greater
LVEF that includes many patients who might otherwise sur-
vive well for an extended period if not for the sudden death.
A prognostic role for 123I-mIBG imaging with greater
LVEFs has also been suggested Katoh et al who, in a study of
SwF 117 patients with preserved EF (50%), found a lower
H/M and greater WR in NYHA class III patients versus thosewith NYHA class I-II, and an independent association be-
Figure 7 123I-mIBG (neuronal) and 99mTc-sestamibi (perfusion) SPECT images in patients with ICDs. The images on the
left are from a patient without an ICD shock and show both homogeneous neuronal and perfusion tracer uptake. The
images on the right are from a patient who had received numerous appropriate ICD shocks and show neuronal/perfusion mismatching defects involving the inferior, inferolateral, and apical walls; there is a matched defect in theanterior wall. HLA, horizontal long axis, MIBG, meta-iodobenzylguanidine (123I-mIBG), MIBI, 99mTc-sestamibi, SA,
short axis. Reprinted with permission from Ji and Travin.26 (Color version of figure is available online.)
Figure 8 Arrhythmic events versus H/M ratio (HMR) in 9 patientswithout an ICD.87 (Color version of figure is available online.)
382 A. Chirumamilla and M.I. Travin
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tween WR increase and adverse cardiac events, includingcardiac death and worsening CHF requiring hospitaliza-tion.89
In addition to CHF patients, neuronal tracer uptake abnor-malities are seen in some of the more specifically character-ized primary arrhythmic disorders. Mitrani et al90 investi-gated 123I-mIBG imaging in patients presenting with
ventricular tachycardia in the absence of coronary artery dis-ease. A total of 67% patients with ventricular tachycardia hadregional cardiac sympathetic denervation compared with 8%in control patients (P 0.002). In patients with Brugadasyndrome that manifests as severe ventricular arrhythmiasand sometimes SCD, neuronal tracer uptake abnormalitieshave been shown (using the PET tracer 11C-HED) to be lo-calized to the inferior and inferoseptal walls.91 These findingsin patients with primary arrhythmic abnormalities furthersupport a potential key role of cardiac imaging with 123I-mIBG in identifying patients at risk of SCD who would mostbenefit from an ICD.
Ischemic Heart Disease
Ischemic heart disease can also be assessed with 123I-mIBG.Ischemia alters the autonomic nervous system as sympatheticnerve fibers are more susceptible to oxygen deprivation thancardiac myocytes.92 MI causes sympathetic denervation notonly in the infarcted area, but also in the peri-infarct re-gion.32,93-95 In addition, signs of injury to sympathetic inner-vation often persist after recovery of the myocytes, with thepresence of such mismatch areas shown to predispose toarrhythmias.96,97
Sympathetic denervation has also been shown to occur inpatients with stable angina in the absence of MI, with inner-vation defects present on 123I-mIBG imaging often in the ab-sence of perfusion defects. Tomoda and colleagues98 showedthat 24 12 days after an ischemic attack, only 4 of 8 pa-tients who had nonQ-wave MI had a Tl-201 perfusion de-fect, whereas all 8 had a 123I-mIBG defect; of 12 patients whohad unstable angina, none had a Tl-201 defect, whereas 7 of12 had a 123I-mIBG defect.
123I-mIBG may be useful to detect subclinical coronaryartery disease. Simula et al99 studied 30 asymptomatic volun-teers with a strong family history of disease who underwentquantitative coronary angiography, stress 99mTc-sestamibi,
and rest 123I-mIBG studies. Although all subjects had normalsestamibi studies, 3 had stenoses30%, and 6 had stenoses50% or greater. Left anterior descending artery stenosis se-verity (range 0%-54%) correlated directly with delayed 123I-mIBG uptake and inversely with 123I-mIBG washout, partic-ularly in the anteroseptal region, which is consistent with anenhanced sympathetic response in the early stages of coro-nary disease. The authors postulated that subclinical endo-thelial dysfunction in these patients caused episodes of vaso-constriction, resulting in activation of local neurohormonalsequences of events that affected local sympathetic output.
123I-mIBG imaging can also shed light on the effect of sym-
pathetic alteration on LV remodeling after MI. Sakata et al100investigated 50 patients after first MI. Although for all pa-
tients the infarct-related coronary artery was patent after rep-erfusion therapy, the presence of a high 123I-mIBG severityscore 4 days after the infarct correlated with LV end-systolicvolume dilation.
Diabetes Mellitus
Autonomic neuropathy is a common complication of diabe-tes mellitus (DM), occurring in 20%-35% of patients at pre-sentation, and it is associated with a worsened progno-sis.101,102Although diabetic autonomic neuropathy has beencustomarily diagnosed with bedside maneuvers and ECGtechniques (eg, valsalva, heart rate and blood pressure re-sponse to postural changes, HRV), radiotracer imaging showspromise in more easily detecting autonomic dysfunction, of-ten before clinical manifestations appear.15 Langer and col-leagues103 performed 123I-mIBG/99mTc-sestamibi dual isotopetomographic imaging in 65 asymptomatic patients who hadtype II DM and found greatly diminished tracer in all seg-
ments, as well as areas of 123I-mIBG/99mTc-sestamibi mis-match, including in some patients who did not have clinicalevidence of autonomic problems. Similarly, Hattori and col-leagues25 found 123I-mIBG SPECT defects in most (60%) of31 patients who had type II DM, again, including patientswho did not have clinical evidence of neuropathy, appearinginitially in the inferior wall and then gradually spreading toadjacent segments in patients who did have evidence of neu-ropathies, with the latter also showing a lower H/M on de-layed planar images. The promise of using autonomic imag-ing to identify greater-risk patients who had DM wassupported in a study by Nagamachi et al,104 who performed
123I-mIBG imaging on 144 type II DM patients without evi-dence of organic heart disease, and followed them for a meanof 7.2 years. By the use of multivariate analysis, they foundthat a combination of decreased delayed-image H/M and anabnormality on HRV predicted cardiac events (hospitaliza-tion for cardiac events, such as arrhythmias, CHF, and MI),whereas abnormal delayed H/M alone was an independentpredictor of all-cause mortality. Further work is needed todetermine how valuable and practical neuronal imagingcould be in people who have diabetes, especially those whodo not have manifestations of end organ damage. In somecases, neuronal imaging may identify patients who have sub-
clinical ischemic coronary disease and need aggressive man-agement, and may find patients who have autonomic hetero-geneities predisposing to lethal arrhythmias.
PosttransplantNeuronal Imaging
Reinnervation in patients after cardiac transplantation is clin-ically important, resulting in improved exertional heart rateresponse, contractile function, and increased peak oxygenuptake.105 123I-mIBG can be helpful for assessing posttrans-plantation cardiac reinnervation, especially to detect the time
required for cardiac reinnervation and the distribution of thesympathetic system. The absence of satisfactory reinnerva-
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tion may indicate posttransplantation problems. In a studywith 123I-mIBG by Estorch et al of 31 patients 6 months to 12years after transplantation, the H/M correlated positivelywith time after transplantation (r 0.607, P 0.001), indi-cating progressive reinnervation.106 Myocardial 123I-mIBGuptake was anterolateral in 16 patients, anterior in 3, andanterolateral and septal in 3. Myocardial 123I-mIBG uptake
was absent in 9 patients. Vasculopathy developed in 8 pa-tients, and 5 of them (63%) had decreased myocardial 123I-mIBG uptake.
Chemotherapyand Cardiac mIGB
Given the enhanced sensitivity of sympathetic nerves to myo-cardial insults, radionuclide autonomic imaging has been in-vestigated as a potential method of assessing cardiac damagefrom chemotherapeutic agents. In studies with rats, Waka-
sugi and colleagues showed that the administration of doxo-rubicin resulted in a decreased uptake of 125I-mIBG that pre-ceded a decrease in LVEF.107 In humans, Olmos andcolleagues reported a decreased cardiac uptake of 123I-mIBGas the cumulative dose of doxorubicin increased, followed bysubsequent deterioration in LVEF.108 Carri and colleaguesshowed that at a cumulative doxorubicin dose of 240-300mg/m2, there was a correlation of cardiac 123I-mIBG abnor-malities with cardiac uptake of 111In-antimyosin antibody,although in this study there was no clear association betweendecreased 123I-mIBG uptake and severe LV functional impair-ment.109 The potential role of 123I-mIBG imaging for follow-ing patients with chemotherapy therefore shows promise,
but still needs to be investigated further, particularly deter-mining how it would add in a significant way to currentlyused monitoring techniques.
Parasympathetic Activity
There is a complex, often antagonistic, interaction betweenthe parasympathetic nervous system and the sympatheticnervous system, mediated partially by the second messengerscamp and cyclic adenosine monophosphate. Cardiovasculareffects of parasympathetic activation include heart rate re-duction (indirectly by inhibition of the sympathetic nervous
system and directly by hyperpolarization of sinus node cells)and vasorelaxation (through nitric oxide synthesis) or vaso-constriction (direct activation of smooth muscle).110 Abnor-malities of parasympathetic activity can induce and maintainatrial fibrillation, whereas ablation can induce parasympa-thetic denervation and improve clinical outcome.111,112 Un-fortunately, radiotracer imaging of the cardiac parasympa-thetic innervation is difficult for various reasons, includingthe low density of cholinergic neurons in the heart and rapiddegradation of acetylcholine making tracer design difficult.
Among tracers under investigation are 18F-FEOBV (a vesa-micol derivative), 11C-MQNB (a postsynaptic muscarine re-
ceptor antagonist), and 2-deoxy-2-[18F] fluoro-d-glucose-A85380 (visualizes nicotinic acetylcholine receptors).113
Future Directions
Prospective studies are required in larger study population toconfirm 123I-mIBG efficiency to detect potential arrhythmo-genic patients and therefore guide ICD therapy and also helpmonitor pharmacotherapy. Better imaging techniques needto be developed to improve image quality and increase repro-
ducibility. Better sympathetic tracers that use PET isotopestracers are under investigation, such as 11C-HED, but cur-rently require that there be an on-site cyclotron to generatethe isotope. An F-18 tracer, LMI 1195, which would notrequire an on-site cyclotron, is under experimental investi-gation in rabbits, with only very preliminary work done inhumans.114,115
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