Introduction

Autonomic neuronal innervation plays a critical role in cardiac function. The heart is richly innervated with sympathetic and parasympathetic fibers that work in conjunction with circulating catecholamine mediators, such as norepinephrine (NE), to precisely regulate cardiac output at rest and during periods of increased cardiovascular demand. An impairment of cardiac autonomic function, usually the result of cardiac disease, both reflects the severity of the condition and contributes to the pathophysiologic impairment that can worsen patient outcome. As cardiac autonomic function involves molecular processes, imaging with radionuclide tracers is an ideal method of assessment.

Cardiac autonomic function is controlled by various centers in the brain that respond to incoming signals from peripheral receptors. Sympathetic efferent signals following descending pathways from the brain through the spinal cord, synapsing with pre-ganglionic fibers that leave the spinal cord at levels T1-L3, subsequently synapsing with post-ganglionic fibers that innervate both ventricles. Sympathetic nerves follow the coronary arteries in the subepicardium before penetrating the myocardium. The principle chemical mediator of sympathetic function is norepinephrine.1,2

Parasympathetic fibers are scarce in comparison with sympathetic. They originate in the medulla and follow the vagus nerves. In the heart they start epicardially, cross the AV groove and then penetrate the myocardium, located thereafter in the subendocardium. Parasympathetic fibers innervate the atria but are scare in the ventricle (mostly the inferior wall), and also modulate SA and AV nodal function. The major chemical mediator of parasympathetic function is acetylcholine.

Most published literature and current clinical applicability of autonomic radionuclide imaging is of the sympathetic system, with parasympathetic imaging studies limited mostly to animals. Therefore, the following discussion will deal predominantly with cardiac sympathetic imaging.

Radionuclide Tracers

Cardiac sympathetic innervation imaging currently focuses on the synaptic junction, illustrated in Figure 1.3 Most radiotracers that have been developed image pre-synaptic anatomy and function, but newer tracers that bind to post-synaptic α and β receptors are also being designed and investigated.

Figure 1
figure 1

Schematic representation of sympathetic neuronal synapse. AC, adenyl cyclase; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; G, G proteins; NE, norepinephrine. Reprinted from Cardiology Clinics: Nuclear Cardiology—From Perfusion to Tissue Biology, Vol. 27, Travin MI, Cardiac neuronal imaging at the edge of clinical application, p. 312, Copyright 2009, with permission from Elsevier3

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Norepinephrine (NE) is produced in the presynaptic sympathetic nerve terminal through multiple biochemical processes starting with tyrosine, and ultimately stored at high concentrations in presynaptic vesicles. In response to a stimulus, the NE-containing vesicles are released into the synaptic space and bind to postsynaptic receptors, resulting in various cardiac stimulatory effects.4,5

Termination of the sympathetic response occurs through a transporter protein-mediated, sodium-, energy-, and temperature-dependent process, known as ‘‘uptake-1,’’ for storage and/or catabolic disposal. Some synaptic NE is also taken up by non-neuronal postsynaptic cells, probably by sodium-independent passive diffusion (i.e., the ‘‘uptake-2’’ system).6,7

Most neuronal imaging has been with radiolabeled analogs of norepinephrine. Guanethidine is a false neurotransmitter analog of NE that is taken up via the uptake-1 pathway. Chemical modification of guanethidine produces a molecule, metaiodobenzylguanidine (mIBG) that can be labeled with radioactive iodine and therefore imaged. While early in its development mIBG was labeled with 131I, the high energy emissions of this isotope and its relatively long half life of 8 days led to the development of the now preferred 123I-mIBG. 123I emits predominantly gamma photons with energies of 159 keV, and has a half-life of 13.2 hours, therefore well tolerated and easily imaged with a SPECT (single photon emission computed tomography) camera. Unlike NE, 123I-mIBG is not catabolized by monoamine oxidase (MAO) or catechol-o-methyltransferase, allowing it to localize in myocardial sympathetic nerve endings to a higher cytoplasmic concentration than NE.8-10 123I-mIBG has for many years been used for cardiac imaging in Europe and Japan, but in the US is at the time of this writing under FDA review for this purpose.

There are also various PET (positron emission tomography) analogs of norepinephrine under investigation.6 Compared with 123I-mIBG, current PET tracers are more similar to NE in composition, thereby having distinct biologic advantages, and they also have better physical properties for imaging. The most commonly investigated neuronal PET tracer is 11C-meta-hydroxyephedrine (HED) that has higher uptake-1 selectivity than 123I-mIBG, resulting in better differentiation between innervated and denervated myocardium, recently found to be of particular advantage in evaluating neuronal heterogeneity in hibernating myocardium.11 In normal patients, 11C-HED also appears to have more homogeneous uptake than 123I-mIBG. Other less well-studied 11C neuronal tracers include 11C-epinephrine and 11C-phenylephrine. The latter is rapidly metabolized by MAO and therefore could potentially play a role in assessment of vesicular storage function. More recently an 18F labeled tracer has been developed and is under investigation.12,13

Imaging Methods and Interpretation

Intravenous injection of 123I-mIBG is performed at rest, and needs only minimal preparation. Medications that might interfere with catecholamine uptake, such as various antidepressants, antipsychotics, and some calcium channel blockers, should be held for 24 hours before tracer injection and imaging. There are differences of opinion regarding the need for administration of thyroid-blocking agents before 123I-mIBG administration. Historically such blockade has been undertaken to shield the thyroid from exposure to unbound impurities such as 124I and 125I, but with modern production methods the amount of impurities and unbound 123I is minimal.

Tracer dosage has not been formally established. A dose of 3 to 5 mCi (111-185 MBq) over a 1-minute period has been customarily used, and is generally satisfactory for planar image analysis. Nevertheless, as it is often difficult to obtain satisfactory SPECT images in patients who have severe cardiac dysfunction, a dose of up to 10 mCi (370 MBq) may be appropriate and is under consideration.4

Planar and SPECT images are routinely obtained approximately 15 minutes following tracer administration (early), and again 3 to 5 hours later (delayed). Although some believe that only the delayed image should be used for interpretation and analysis as it represents actual neuronal uptake (as opposed to interstitial uptake for the early images), tracer washout between early and delayed planar images may provide important additional information.14,15

Parameters for planar and SPECT acquisition of 123I-mIBG are not formally established, but current methods are described in various published reviews.1,16 Planar images are obtained in the anterior view for 10 minutes using an energy window of 159 keV ± 20%. SPECT images are obtained using the same energy window by way of a 180° circular acquisition from 45° right anterior oblique to 45° left posterior oblique, using a total of 60 stops (30 stops per head if done with a dual-headed camera) at 30 seconds per stop. Although low-energy collimators have customarily been used for 123I-mIBG acquisition, multiple low-abundance higher-energy photon emissions (including one at 529 keV) are emitted by 123I and more freely penetrate the septa, degrading image quality. Work is under way using a measured point spread function to perform three-dimensional deconvolution of the septal penetration to compensate for this effect and improve image accuracy, particularly for quantitative parameters that have different values when these corrections are applied.17

Interpretation of cardiac 123I-mIBG images currently consists of assessment of global tracer uptake on planar images, tracer washout between early and delayed planar images, and regional uptake on tomographic images. The standard measure of global 123I-mIBG uptake is the heart mediastinal ratio (HMR), derived through assessment of per pixel activity in a region of interest over the heart in reference to a background area in the upper mediastinum. The HMR has been derived in various ways in the literature and has not yet been standardized, although interestingly all methods appear to give similar results in any given patient study.8,15,18,19 A recently reported normal value for HMR is 2.2 ± 0.3, with a ratio of <1.6 (2 standard deviations below the mean) considered to be abnormal and correlate with increased patient risk.20

123I-mIBG washout (compensated for radioactive decay) may reflect turnover of catecholamines attributable to the sympathetic drive, and measures the ability of myocardium to retain mIBG. A normal value has been reported to be 10% ± 9%, with sicker patients having higher values.15,21 Washout may correlate with increased sympathetic tone, but the complexity of this relationship has not been fully elucidated. Figure 2 shows examples of normal and abnormal planar cardiac 123I-mIBG images.

Figure 2
figure 2

Examples of planar cardiac 123I-mIBG images. The example on the left shows normal cardiac 123I-mIBG uptake with a heart mediastinal (H/M) ratio of 2.24 and a normal tracer washout (WO) from initial to delayed images of 10.64%. The example on the right shows abnormal a heart mediastinal ratio of 1.29 in images with an abnormal tracer washout of 23.35%

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Assessing regional uptake of 123I-mIBG on tomographic images is less well studied and established. The potential clinical utility is based on the concept that regional abnormalities may create areas of electrical instability predisposing to dangerous ventricular arrhythmias, particularly if these territories are perfused and have viable myocytes, i.e., a neuronal/perfusion mismatch that may produce denervation supersensitivity.22-24 Difficulties with tomographic imaging include poor image quality in patients with markedly decreased cardiac uptake, overlying non-cardiac activity (lung and liver) interfering with image reconstruction, and a frequently reported heterogeneity of regional 123I-mIBG uptake in normal patients that may vary with age and gender.21,25,26 There are reports of less normal variation when PET tracers such as 11C-HED are used that may be related both to differences in soft tissue attenuation and in tracer properties and kinetics.27

Neuronal Imaging in Congestive Heart Failure

Congestive heart failure (CHF) is a worsening epidemic in developed countries due in large part to a progressively aging population and to better survival from acute cardiac events that leave patients with damaged hearts. In the United States close to 5 million people have CHF, with 550,000 new cases each year. Mortality can reach 50% annually, with CHF being a major underlying or contributing cause of death in close to 300,000 people per year. CHF is an expensive condition with more Medicare dollars spent on it than on any other condition, promising to go even higher with the increasing use of devices.28,29

Despite dramatic improvements in diagnosis and treatment of CHF, there remain major knowledge gaps in the prediction of treatment response and disease progression, making imperative the need for better understanding of the biomolecular pathophysiology and its translation into clinical outcomes.30 As CHF is in large part a condition involving disruption of the neurohormonal state, cardiac neuronal innervation is thought to play a crucial role. An increased sympathetic response is initially favorable by serving as compensation for decreased cardiac output, but as CHF progresses this response leads to deleterious neurohormonal and myocardial structural changes that worsen the condition and increase the likelihood of arrhythmias and cardiac death. Numerous studies have shown that assessment of the cardiac autonomic state with radiotracers such as 123I-mIBG can evaluate the cardiac condition beyond that available from conventional markers, can help track the effects of therapeutic interventions, and could potentially help guide therapy in a cost-effective manner. Among 123I-mIBG image changes observed in CHF is increased washout, perhaps the result of competition for the uptake-1 process by increased circulating NE, and decreased HMR as CHF becomes more advanced with loss of sympathetic neurons and/or impaired uptake-1 function.31

Studies have consistently shown that a decreased 123I-mIBG HMR predicts a poor prognosis in patients with advanced CHF.32-34 Among the first to demonstrate this was Merlet et al in a study of 90 patients with severe CHF and mean left ventricular ejection fraction (LVEF) of 22%. Patients with HMR < 1.2 had a 12-month survival of 40% compared with 100% for patients with a higher ratio. Multivariate analysis showed that HMR was a better predictor of outcome than LVEF and heart size.35 Nakata et al showed that prognosis progressively worsened in CHF patients as the HMR got lower,36 and Wakabayashi et al demonstrated that HMR predicted outcome for CHF of both ischemic and non-ischemic origin.37

Similarly, increased 123I-mIBG washout worsens prognosis in patients with CHF. Ogita et al showed that in patients with CHF and LVEF < 40%, over a 4-year period those with tracer washout ≥27% had a 35% cardiac death rate compared with 0 deaths in patients with normal washout.15 There was also a greater than threefold increase in hospital admissions for CHF in the high washout group. A later study from the same group reported that increased washout predicts sudden cardiac death.38

More recently, larger, carefully designed multicenter studies have been undertaken to examine the potential role of 123I-mIBG imaging in CHF. Agostini and colleagues reported on 290 CHF involving six sites in Europe, finding that by logistic regression the only significant predictors of major cardiac events—cardiac death, need for transplant, and potentially fatal arrhythmias—over 2 years was LVEF and HMR.39 Particularly striking was the ability of HMR to risk stratify patients who had LVEF ≤ 35%, with event rates ranging from less than 5% for those who had HMR ≥ 2.18, to more than 50% for those who had HMR ≤ 1.45. At the same time, patients with a higher LVEF of 35-49% who had HMR ≤ 1.45 had an event rate >10%.

Most recently the ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure, AdreView = 123I-mIBG) study was undertaken in 96 sites in the US, Canada, and Europe, in which 961 patients with NYHA (New York Heart Association) Class II-III CHF and LVEF ≤ 35% underwent rest and delayed 123I-mIBG imaging.20 The primary goal was to relate an HMR < 1.6 on the 4-hour delayed planar image with the occurrence of progression of CHF (worsening NYHA Class), a potentially life threatening arrhythmia, and/or cardiac death over a 2-year follow-up. As shown in Figure 3, the HMR well separated patients with and without cardiac events. However, approximately 2/3 of these events were CHF progression. When data analysis focused on the 201 (21%) of patients with HMR ≥ 1.6, there were only two cardiac deaths, indicating that in such patients with advanced CHF a normal HMR predicted a <1% yearly risk of cardiac death.40 A subsequent multivariate analysis substudy showed that HMR was a predictor of both cardiac and all-cause death independent of other clinical and image variables, including age, LVEF, and BNP (brain natriuretic peptide).41

Figure 3
figure 3

Cumulative 2-year event rates comparing subjects with HMR < 1.6 vs ≥1.6. Composite end point includes heart failure progression, arrhythmic events, and cardiac mortality. *P < .0001 compared with HMR < 1.6; **P < .001 compared with HMR < 1.6. HMR, Heart mediastinal ratio40

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Potential Role of 123I-mIBG in Guiding Therapy for CHF

While the use of cardiac adrenergic imaging to risk stratify patients may have value in itself, the potential to more effectively guide specific therapies would provide greater clinical utility. There are numerous reports demonstrating that 123I-mIBG imaging effectively monitors the effects of conventional CHF medical therapies. As one might expect, 123I-mIBG images frequently improve after institution of β-blocker therapy, associated in some studies with decreased ventricular volumes, improved LVEF, and symptom relief.18,42-45 Nevertheless, various other medications that do not directly influence cardiac sympathetic function, i.e., ACE (angiotensin converting enzyme) inhibitors, ARB (angiotensin receptor blocking) agents, spironolactone, and amiodarone also lead to improvements in 123I-mIBG image findings.46-50 It is important to consider how the above findings could specifically direct therapy. Use of 123I-mIBG to decide who might benefit from a particular medical therapy such as β-blockers has shown insufficient separation,51,52 and given the high benefit to risk/cost ratio of conventional medical therapies, a cardiac 123I-mIBG study is unlikely to preclude their use.53 123I-mIBG imaging might instead be more useful as an indicator of whether or not a patient’s medical therapy is working satisfactorily, and could therefore help determine whether higher risk and usually more expensive device therapies or cardiac transplantation are needed.32 A study by Matsui et al of patients with severe cardiomyopathy showed that a worsening HMR after 6 months of optimal medical therapy had, with BNP, the highest, independent predictive value for cardiac death.54 It is possible that in patients with worsening HMR on serial studies, institution of additional or alternate therapies, such as devices, need to be undertaken to improve outcome. A recent study by Drakos et al of patients on LVAD (left ventricular assist device) therapy found that clinical improvement paralleled improvement in 123I-mIBG image parameters.55 Alternatively, a recent study showed that a decreased HMR was associated with poor response to cardiac resynchronization therapy.56

123I-mIBG Imaging and Ventricular Arrhythmias

A major cause of death in patients with advanced heart failure is ventricular arrhythmia-induced sudden cardiac death (SCD).57 While in some cases the terminal arrhythmia is the natural result of end-stage irreversible pump dysfunction, in other cases a patient may otherwise be doing relatively well only to be struck down by SCD. For the latter reason, based on trials such as SCD-HEFT, it is a Class IA indication that patients with LVEF ≤ 35% receive a prophylactic implantable cardioverter defibrillator (ICD) for primary prevention.58,59 Nevertheless, most patients who receive an ICD based on these criteria do not use their device,60-62 with it widely acknowledged that LVEF is an imperfect measure of the risk of arrhythmic death.63-65 Given the potentially adverse clinical consequences of ICD implantation, including operative complications, device malfunction, pain, psychiatric problems associated with shocks, and life style restrictions, as well as a cost of about $28,000 for the device, a better approach for deciding who should get an ICD is needed.66

Although mechanisms of cardiac arrhythmias are complex and multifactorial, the cardiac autonomic nervous system is a crucial component,5,67 suggesting a potential role of 123I-mIBG imaging to help better identify at risk patients who would benefit from an ICD. Early dog studies showed that artificial creation of focal areas of cardiac denervation resulted in regional 123I-mIBG defects associated with production of supersensitive action potential refractory periods.24 Other work has shown an association between focal 123I-mIBG defects and ventricular arrhythmias on Holter monitoring.68,69

As performing clinical research studies on SCD is difficult, particularly given that ascertaining a definitive arrhythmic cause of death is often not possible, a suitable group to investigate would be patients who already have an ICD. Although occurrence of an ICD shock in these patients does not necessarily mean that they would have experienced SCD if not for the device, it may be one suitable method to use at this time. With this approach, Arora and colleagues performed a pilot study on 17 patients with advanced CHF who already had an ICD, deliberately selecting a balanced group of patients with and without prior ICD discharges.70 A reduced late HMR (threshold 1.54) was associated with increased likelihood of an ICD discharge, with a positive predictive value of 71% and a negative predictive value of 17%. Combining autonomic imaging with heart rate variability (HRV) analysis, none of three patients who had both a high HMR and a more abnormal HRV had an ICD discharge, whereas all four patients who had a low HMR and less abnormal HRV did. In addition, patients who had ICD discharges had more extensive 123I-mIBG/perfusion (99mTc-sestamibi) mismatches on SPECT imaging. All patients in this study also had tomographic 123I-mIBG and perfusion (99mTc-sestamibi) imaging. Those with autonomic perfusion mismatches were more likely to have appropriate ICD discharges than those without, with case examples seen in Figure 4.

Figure 4
figure 4

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 the anterior wall. HLA, horizontal long axis; ICD, implantable cardioverter defibrillator; MIBG, metaiodobenzylguanidine (123I-mIBG); MIBI, 99mTc-sestamibi; SA, short axis

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A subsequent study by Nagahara and colleagues showed that SCD or an appropriate ICD discharge strongly correlated with late HMR independent of numerous other variables, including LVEF.71 Combining HMR with LVEF or BNP gave additional predictive power. Finally, Kioka and colleagues reported an association of high 123I-mIBG washout and SCD.38

In ADMIRE-HF combined “arrhythmic” events (self-limited ventricular tachycardia, resuscitated cardiac arrest, appropriate ICD discharges) were more common in subjects with HMR < 1.60 (10.4%) than in those with HMR ≥ 1.6 (3.5% P < 0.01).40 As illustrated in Figure 5 from a subanalysis by Senior et al, the highest arrhythmic rate was in patients with an intermediate decrease in HMR, while patients with an extremely low HMR were less often had an arrhythmic event, but rather were more likely to die from pump failure.72 Also of interest in this subanalysis, of patients without an ICD who had HMR ≥ 1.6, there was only one arrhythmic death. In another recent study, Boogers et al performed 123I-mIBG SPECT imaging in patients prior to ICD implantation, finding that over a mean 23-month follow-up (up to 3 years), the late tomographic defect score was an independent predictor of appropriate ICD therapy and cardiac death.73

Figure 5
figure 5

Arrhythmic events vs heart mediastinal ratio72

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In summary, recent large studies consistently show that cardiac neuronal imaging provides better predictive potential for SCD in CHF patients than currently accepted standards of LVEF and NYHA class, and in at least one study better than various ECG criteria.74 Of course, further validation is merited before wider acceptance and consideration of 123I-mIBG imaging in CHF and arrhythmia consensus guidelines. A high negative predictive value is crucial. At the same time, cardiac neuronal imaging could potentially identify those patients with CHF in the “lower risk” subgroups (e.g., LVEF ≥ 35%) who are in fact at significant risk of SCD that may indicate an ICD.

Primary Arrhythmic Disease

In addition to having potential clinical utility in CHF-associated ventricular arrhythmias, imaging with 123I-mIBG or similar tracers has shown cardiac abnormalities in patients with primary arrhythmic conditions. Mitrani and colleagues saw regional sympathetic denervation in 55% of patients who presented with VT but had structurally normal hearts compared with none in controls.75 Gill and colleagues found asymmetrical uptake of 123I-mIBG in about half of the patients they studied who had VT and ‘‘clinically normal’’ hearts, particularly obvious in patients who had exercise-induced VT.76

Neuronal tracer uptake abnormalities are also seen in some of the more specifically characterized primary arrhythmic disorders. Schäfers and colleagues found abnormal 11C-HED uptake distribution in patients with idiopathic right ventricular outflow tract tachycardia, as well as decreased uptake of the postsynaptic tracer 11C-CGP12177 indicating reduced density of postsynaptic β-adrenoceptor density.77 Neuronal tracer uptake in Brugada syndrome is especially interesting in that 123I-mIBG defects seem localized to the inferior and inferoseptal walls, suggesting that a local dominance of parasympathetic tone in these regions may be related to a propensity for arrhythmogenesis.78

Cardiac Transplantation

During cardiac transplantation, postganglionic sympathetic fibers of the donor heart are interrupted, resulting in complete sympathetic denervation of the transplanted heart. The new heart thus has an impaired response to the demands of exercise. Over time, though, at least some sympathetic reinnervation occurs.79-81 Bengel and colleagues used 11C-HED imaging to demonstrate progressive post-transplant cardiac reinnervation, with a follow-up study showing a correlation with an enhanced contractile response to exercise and improved exercise times.82,83 On the other hand, the absence of reinnervation could indicate complications and co-morbidities such as a coronary vasculopathy.

123I-mIBG Imaging in Ischemic Heart Disease

Sympathetic nerve trunks course along the coronary arterial pathways before penetrating the myocardium. Myocardial ischemia/infarction disrupts sympathetic transmission, in which case myocardium distal to and beyond the site of injury but not otherwise involved in the ischemic process may be affected. In addition cardiac sympathetic nervous tissue is more sensitive to ischemia than myocytes, and takes longer to recover. The result can be perfused and viable, but denervated myocardium, with such areas exhibiting denervation supersensitivity that predisposes to arrhythmias. Simões et al found that the presence of post MI 123I-mIBG/201Tl imaging mismatches correlated with electrophysiological abnormalities of prolonged QTc intervals and delayed depolarization on signal averaged ECG, both considered to predispose to lethal arrhythmias, although there were insufficient cardiac events to assess prognostic implications.22 Sasano et al, using a pig model to create LAD infarcts, found that the creation of perfusion/innervation mismatches increased inducibility of sustained VT.23 In accordance with the above discussion of CHF, 123I-mIBG and other methods of neuronal imaging could also potentially guide post-MI ICD patient selection.

Another potential use of 123I-mIBG imaging in ischemic heart disease takes advantage of the persistence of neuronal injury after resolution of the ischemic insult, i.e., ischemic memory. Watanabe and colleagues performed rest 123I-mIBG studies on patients within 2 weeks of documented vasospastic angina on cardiac catheterization, and found that tracer defects were seen in 100% of the 123I-mIBG images despite no Tl-201 perfusion abnormalities appreciated, versus in only 86% of 123I-BMIPP (β-Methyl-p-[123I]-iodophenyl-pentadecanoic acid) images.84 Similarly, in a study by Tomoda et al, 24 ± 12 days after an ischemic attack, only 4 of 8 patients with non-Q-wave MI had a Tl-201 perfusion defect whereas all 8 had an 123I-mIBG defect. In the same study, none of 12 patients with unstable angina had a Tl-201 defect, 7 of 12 had an 123I-mIBG defect.85

123I-mIBG Imaging and Diabetes Mellitus

Diabetes is a systemic, multi-organ disease, with morbidity and mortality increased by the presence of autonomic neuropathy. While various noninvasive tests help to detect the presence of diabetic-induced neuropathy, they predominantly assess parasympathetic function. Cardiac imaging assessment of sympathetic function may provide a unique approach to assess neuropathy. Stevens and colleagues found abnormalities of 11C-HED retention in 40% of autonomic neuropathy-free diabetic patients, first appearing in the inferior wall and then spreading to other parts of the heart. In patients who had severe neuropathies, increased absolute tracer retention (hyperinnervation) was seen in proximal myocardial segments in combination with more decreased retention (denervation) in distal segments, an innervation pattern that could result in electrical instability and predispose to life-threatening arrhythmias.86

The promise of using autonomic imaging to identify higher risk patients with DM was supported in a study by Nagamachi of type II patients who had no evidence of organic heart disease, followed a mean of 7.2 years. By multivariate analysis, a combination of decreased HMR on a delayed 123I-mIBG image and an abnormality on HRV predicted cardiac events, whereas abnormal delayed HMR alone was an independent predictor of all-cause mortality.87

Further work is needed to determine the value and practicality of neuronal imaging in diabetics, especially those without evidence of end organ damage. Neuronal imaging may identify patients who have subclinical ischemic coronary disease and need more aggressive management, and may find patients with autonomic heterogeneities predisposing to lethal arrhythmias.

123I-mIBG Imaging and Chemotherapy

Given the enhanced sensitivity of sympathetic nerves to myocardial insults, neuronal imaging has been investigated as a potential method of assessing cardiac damage from chemotherapy. In rat studies, Wakasugi and colleagues showed that doxorubicin administration resulted in a decrease in cardiac uptake of 125I-mIBG, preceding a decrease in LVEF.88 In humans, Olmos and colleagues reported decreased cardiac uptake of 123I-mIBG as the cumulative dose of doxorubicin increased, followed by subsequent deterioration in LVEF.89 Carrió and colleagues showed that at a cumulative doxorubicin dose of 240-300 mg · m2 there was a correlation of cardiac 123I-mIBG abnormalities with cardiac uptake of 111In antimyosin antibody, but there was no clear association between decreased 123I-mIBG uptake and severe LV functional impairment.90 The potential role of 123I-mIBG imaging in patients with chemotherapy shows promise, but still needs further investigation, particularly determining how it would add to currently used monitoring techniques.

Postsynaptic Sympathetic Imaging

Cardiac postsynaptic receptors transmit sympathetic signal to the myocardial tissue, regulating chronotropic, dromotropic, and inotropic cardiac effects, and are good targets for imaging. At this time only a few radiotracers have been synthesized for it, the main problem being the difficulty of finding a compound that is easily made and has sufficient specificity.91 Some clinical work has been done with 11CCGP12177, a nonselective, hydrophilic β-receptor binding agent that produces good-quality cardiac PET images. Caldwell and colleagues studied 13 patients with ischemic CHF and 25 age-matched healthy controls using 11C-HED for presynaptic imaging and 11C-CGP12177 to assess postsynaptic β-adrenergic receptor (BAR) density.92 Although patients with CHF had a decrease in 11C-HED and in BAR density compared with controls, the decrease in HED uptake was significantly greater, resulting in marked presynaptic/postsynaptic mismatch, especially in the inferior and lateral walls. Of four patients who had an adverse event over 18 months, three had a mean mismatch score greater than six standard deviations above the mean of healthy subjects.

Imaging of the Cardiac Parasympathetic System

Abnormalities of parasympathetic activity also contribute to cardiac pathophysiology. Parasympathetic innervation and activation can induce and maintain atrial fibrillation, whereas ablation can induce parasympathetic denervation and improve clinical outcome.93,94 Due to the lack of sufficient experience and data, imaging of cardiac parasympathetic system has been limited. There is a low density of cholinergic neurons in the heart, as well as difficulty in tracer design because of rapid degradation of acetylcholine by esterase and a high specificity of the presynaptic receptor system for acetylcholine. Vesamicol is the base structure for tracer design. 18F-FEOBV and has been investigated in rats, but it has a low myocardial specificity. 11C-MQNB is a postsynaptic muscarinic receptor agonist, with some work done in humans. 18F-D-Glucose-A85380 visualizes nicotinic acetylcholine receptors and has been used in humans with neurodegenerative disorders.91

Conclusions

Disruption of the cardiac neuronal system may occur as a result of cardiac disease and/or itself may be the cause of cardiac problems. Cardiac neuronal abnormalities occur in a variety of cardiac disease states and patients with cardiac neuronal abnormalities are at increased risk, including a higher potential for sudden, arrhythmic death. Thus, the ability to image cardiac neuronal system with radiotracers should be a powerful tool to assess and risk-stratify patients, and to guide the therapeutic approach in terms of pharmacologic therapy, implantation of mechanical devices, and determining the need for further intervention such as cardiac transplantation. Given that radiotracer imaging allows visualization and quantitative measurements of the underlying molecular aspects of cardiac disease, it should provide a perspective that other cardiac tests cannot.