The use of Cardiac ¹²³I-mIBG Scintigraphy in Clinical Practice: The Necessity to Standardize!

Abstract

Cardiac adrenergic imaging has a great potential in a wide variety of clinical applications. Cardiac ¹²³I-meta-iodobenzylguanidine (¹²³I-mIBG) scintigraphy has a key role to assess chronic heart failure (CHF) by risk stratifying patients for cardiac events. The mIBG is a norepinephrine (NE) analogue that can evaluate cardiac sympathetic activity by assessing the down expression of β-adrenergic receptor (β-AR) in CHF. Furthermore, ¹²³I-mIBG scintigraphy in combination with other parameters of left ventricular function can be used to identify the best responder for implantable cardiac devices, as well as to assess oncological cardiotoxicity. Despite its usefulness, ¹²³I-mIBG scintigraphy is not widely performed because of the lack of standardization between different institutions. Thus, standardization and validation may contribute to its acceptance in clinical setting.

Keywords
Heart Failure; Myocardium/diagnostic imaging; Radionuclide Imaging; 3-Iodobenzylguanidine; Sympathetic Nervous System

Resumo

A avaliação da atividade adrenérgica cardíaca através de exames de imagem apresenta grande potencial em uma ampla variedade de aplicações clínicas. A cintilografia miocárdica com ¹²³I-mIBG desempenha papel importante na avaliação de insuficiência cardíaca crônica (ICC) ao estratificar o risco de pacientes para eventos cardíacos. A mIBG, um análogo da norepinefrina (NE), pode ser utilizada para avaliar a atividade simpática cardíaca ao se analisar a diminuição da expressão do adrenorreceptor (AR) β na ICC. Além disso, a cintilografia miocárdica com ¹²³I-mIBG em combinação com outros parâmetros de função ventricular esquerda pode ser usada para identificar o melhor respondedor a dispositivos cardíacos implantáveis, assim como avaliar cardiotoxicidade oncológica. Ainda que útil, a cintilografia miocárdica com ¹²³I-mIBG não é amplamente realizada devido à falta de padronização entre as diferentes instituições. Portanto, sua padronização e validação podem contribuir para sua aceitação na prática clínica.

Palavras-chave
Insuficiência Cardíaca; Miocárdio/diagnóstico por imagem; Cintilografia; 3-Iodobenzilguanidina; Sistema Nervoso Simpático

Introduction

The cardiac sympathetic system is an important neurohormonal compensation mechanism in the pathogenesis of chronic heart failure (CHF). Patients with CHF have increased cardiac sympathetic activity with increased exocytosis of norepinephrine (NE) from the presynaptic vesicles and impaired NE re-uptake via the norepinephrine transporter (NET) in the sympathetic terminal nerve axons. This results in increased NE levels in the synaptic cleft. Initially, β-adrenergic receptor (AR) stimulation by increased synaptic NE levels helps to compensate for impaired myocardial function. However, long-term NE excess has detrimental effects on myocardial structure and gives rise to a down regulation and availability of postsynaptic β-AR. This leads to left ventricular remodeling and is associated with increased mortality and morbidity in CHF.

Cardiac sympathetic activity can non-invasively be visualized by nuclear medicine techniques. The most clinically used tracer is the radiolabeled NE analogue ¹²³I-meta-iodobenzylguanidine ¹²³I-mIBG). From the planar ¹²³I-mIBG images, semi-quantitative measurements of myocardial ¹²³I-mIBG uptake can be derived: early heart-to-mediastinum (H/M) ratio (HMR), derived 15 min post injection (p.i.) of ¹²³I-mIBG; late HMR, derived 4 h p.i. of ¹²³I-mIBG; and ¹²³I-mIBG washout, calculated as the difference between early and late HMR and expressed as a percentage of the early HMR. While HMR reflects the ¹²³I-mIBG uptake in nerve terminals, washout rate indicates their integrity - neuronal retention.¹

Although arrhythmia, lethal cardiac events and prognosis are multifactorial and have several determinants, cardiac ¹²³I-mIBG scintigraphy alone and more likely in combination with other determinants may be able to better select CHF patients at increased risk for events. Indeed, a large number of studies on the prognostic value of ¹²³I-mIBG-assessed cardiac sympathetic activity in CHF have been published. In addition, cardiac ¹²³I-mIBG scintigraphy can be used in other pathophysiological conditions, for example to assess chemotherapy-induced cardiotoxicity. However, the lack of standardization between different institutions have hampered wide scale clinical implementation.

The purpose of this paper is to discuss how to further standardization of cardiac ¹²³I-mIBG scintigraphy and to discuss the use of cardiac ¹²³I-mIBG in different patient populations.

Physiology of cardiac sympathetic innervation and ¹²³I-mIBG uptake

The cardiac sympathetic nervous system is a complex agonist-receptor system with NE as neurotransmitter. Both β- and α-ARs belong to the G-protein family and have a transmembrane location. There are four types of β-AR that form the postsynaptic portion of sympathetic neurotransmission, the most abundant β-AR being β₁, β₂ and β₃. β₁- and β₂-ARs determine positive inotropic response. Two types of α-ARs have been identified (i.e. α₁ and α₂), each with three known subtypes.^2,3 The postsynaptic α₁-ARs are important to modulate cardiac inotropy and arterial vasoconstriction. The α_2A- and α_2C-ARs subtypes have a postsynaptic localization and regulate myocardial catecholamine release. The presynaptic α_2B-ARs seem to be associated with the pathogenesis of salt-induced hypertension. In addition, there are muscarine, angiotensin, adenosine, and cardiac opioid receptors.

Norepinephrine is synthesized from tyrosine and stored in high concentrations in vesicles in the presynaptic sympathetic nerve terminals. Upon stimulation, these vesicles release their content into the synaptic cleft. Most of the released NE is actively taken back up into the presynaptic sympathetic nerve terminals with a mechanism known as uptake-1 (i.e. the NET). This is a highly specific process, but with limited capacity. In addition, there is a less specific, but highly capable, postsynaptic re-uptake mechanism known as uptake-2.

Meta-iodobenzylguanidine is an analog of NE and can be radiolabeled with iodine. Radiolabeled mIBG follows the same re-uptake mechanism as NE (i.e. the NET). Once taken up in the presynaptic sympathetic nerve terminals, mIBG is not metabolized. ¹²³I-mIBG is not only used in the cardiac sympathetic nervous activity assessment. Of note, the first clinical application of radio-labeled mIBG (i.e. 131I-mIBG) was the visualization of the adrenal medulla and different neural crest-derived tumors, such as pheochromocytomas and neuroblastomas. Radiolabeling with 131I also enables radionuclide therapy for these types of neoplasms. The striking myocardial uptake, however, made Wieland et al.⁴ suggest the potential use of radio-labeled mIBG for myocardial imaging.

Patient preparation for ¹²³I-mIBG cardiac scintigraphy

In our department, patients referred for ¹²³I-mIBG myocardial scintigraphy undergo a medical interview to obtain clinical information relevant to the procedure and to guide image interpretation, and to provide the patient with relevant explanation about the test. Special care should be taken regarding pregnant or breastfeeding women. Especially in these patients, it is necessary to discuss whether the procedure will bring real benefit, if the procedure could be rescheduled for later or if there are alternatives to evaluate the clinical question. Free iodine, either ¹²³I or 131I, is excreted in breast milk. Therefore, it is recommended to interrupt breastfeeding for at least 36 hours when ¹²³I-mIBG is used, and to discontinue breastfeeding completely when 131I-mIBG is used.^5,6

Because of "free" iodine, the thyroid should be blocked with perchlorate, potassium iodide or Lugol's solution, at least 30 minutes before the administration of the ¹²³I/131I-mIBG. Dose adjustment can be made taking into consideration the weight of the patient.

¹²³I has a half-life of 13.22 hours, it decays by electron capture to ¹²³Tellurium with gamma-ray emission of primarily 159 keV, which enables its use in obtaining images with a gamma camera. In addition, ¹²³I decays with a small fraction of high energy photons. ¹²³I is produced in a cyclotron by xenon irradiation.

Some food and drugs need to be discontinued before the administration of mIBG due to known or suspected interference with mIBG uptake. It is also recommended to discontinue the use of drugs, such as tricyclic antidepressants, antipsychotics, opioids, and sympathomimetics, at least for 5 biological half-lives prior to mIBG administration.⁷ In addition, beta-blockers and angiotensin-converting-enzyme (ACE) inhibitors are also known to influence the uptake of mIBG. Sometimes the discontinuation of these medications is considered unethical, such as in psychotic and heart failure (HF) patients. Therefore, the recommendation to discontinue these medications is not always possible and the decision to discontinue the medication should always be made after carefully considerations and on an individual patient basis.

Protocol for ¹²³I-mIBG administration and planar image acquisition

We recommend administering the radiopharmaceutical via an intravenous catheter (e.g. in the antecubital vein), slowly, for about two minutes. This procedure prevents some side effects, such as dizziness, pruritus or blood pressure changes. Moreover, mIBG is considered contraindicated to patients with known hypersensitivity to iobenguane or iobenguane sulfate.¹

As previously mentioned and despite their lower abundance,¹²³I decay is accompanied with other higher-energy photons - 400 keV (2.87%) and 529 keV (1.28%). These high-energy photons may lead to the penetration of collimator septa. Therefore, some authors recommend acquiring images with a medium energy (ME) collimator for greater precision in the quantification of images.

The image acquisition protocols recommend an early acquisition 15 minutes after tracer injection and a late acquisition up to 4 hours after tracer injection. The planar images are recommended to be acquired in anterior projection for 10 minutes using a 128x128 or 256x256 matrix. Although a ME collimator seems to be preferred, these collimators are not widespread available. Because of their widespread availability, low-energy high-resolution (LEHR) collimators are very often used. Images can also be acquired using a count limit for the early acquisitions (e.g. 1 million counts), and then correct the duration of the late image acquisition for decay between the two acquisitions. It is important to exclude the liver as much as possible from the field of view, as this may deteriorate the myocardial image quality.¹

Protocol for acquisition of SPECT images and quantification

For SPECT acquisition, a system similar to the acquisition of myocardial perfusion imaging is used, with 180-degree rotation, starting in 45-degree right anterior oblique rotating in counterclockwise direction to 45-degree left posterior oblique. It is recommended to acquire 64 projections (32 for each detector), going through 180 degrees. Reconstruction may be performed using established methods, such as filtered back-projection (FBP), or iterative methods, such as ordered subsets expectation maximization (OSEM).¹

While various quantitation methods for measuring myocardial uptake have been used, the simplest and most practically used index has been HMR (Figure 1).¹ However, there are inter-institutional variations in HMR, even for normal values. Especially the choice of collimator introduces considerable variations.^8,9 Therefore, the need for standardization of ¹²³I-mIBG myocardial uptake has been recognized. However, the availability of practical clinical standardization approaches is limited. To overcome this variation and to unify HMRs from various data acquisition systems, a cross-calibration phantom was developed.^10,11 Using this cross-calibration phantom in Japan and Europe has resulted in conversion coefficients for many different gamma-camera collimator combinations.^11,12 There was a good agreement between Japanese and European LEHR, low-medium energy (LME) and medium-energy general purpose (MEGP) collimators. These findings are most likely a good basis for comparing the data from different camera collimator systems worldwide.

Figure 1
Examples of normal cardiac ¹²³I-mIBG images. Early planar image showing regions of interest (ROI) in the heart (red) and mediastinum (blue) for determination of heart-to-mediastinum ratio (A). Early SPECT images showing uniform distribution of ¹²³I-mIBG on the walls of the left ventricle (B).

Use of ¹²³I-mIBG scintigraphy in CHF

The action of NE in association with myocardial β-AR is the trigger responsible for muscle contraction, involving the sequential action of adenylate cyclase and cAMP and, subsequently, transmembrane calcium influx.¹³ In CHF, the initial beneficial adrenergic hyperstimulation has detrimental effects on the long term, and may result in cardiac remodeling.¹⁴ In addition, there is a reduction in the sensitivity and the expression of β-AR, which contributes to progressive worsening of cardiac function.¹⁵ Heart failure presents high mortality rates, and around 50% of deaths are related to sudden death.¹⁶ In 2014, only in Brazil, more than 26,000 deaths were related to HF, and approximately half of them occurred in the southeast of the country.¹⁷

Although arrhythmia, lethal cardiac events and prognosis are multifactorial and have several determinants, cardiac ¹²³I-mIBG scintigraphy alone and more likely in combination with other determinants may be able to better select CHF patients with increased risk. Indeed, a large number of studies on the prognostic value of ¹²³I-mIBG assessed cardiac sympathetic activity in CHF have been published.

In 1992, Merlet et al.¹⁸ demonstrated the prognostic value of ¹²³I-mIBG cardiac scintigraphy and its superiority over other diagnostic methods. In 90 patients with CHF (New York Heart Association - NYHA class II to IV) and left ventricular ejection fraction (LVEF) lower than 45% evaluated using radionuclide ventriculography (RV), late HMR was the best predictor of survival (p < 0.0001).¹⁸ From then on, new studies emerged confirming those results. A Japanese study evaluated 414 consecutive patients with known or suspected cardiac disease and showed that, apart from the non-heart-related deaths, a compromised sympathetic innervation evaluated by ¹²³I-mIBG scintigraphy was the best predictor of cardiac death.¹⁹

A retrospective European multicenter study used ¹²³I-mIBG scintigraphy to determine the risk of cardiac events in patients with CHF. Cardiac events were defined as cardiac death from any cause, cardiac transplantation and potentially fatal arrhythmias. It was shown that patients with events had lower HMR than those without events (average HMR of 1.51 and 1.97, respectively, p < 0.0001). Patients with a HMR lower than 1.75 had a higher risk of events with an odds ratio of 7.6 (p < 0.0001). Furthermore, 2-year event-free survival using an optimum HMR threshold of 1.75 was 62% for HMR less than 1.75, and 95% for HMR greater than or equal to 1.75 (p < 0.0001).²⁰ In a systematic review, Verberne et al. analyzed 18 studies including 1,755 patients, and observed a worse prognosis in patients with CHF and a reduced late HMR and increased cardiac washout.²¹

In 2010, the publication of ADMIRE-HF, a prospective multicenter study, confirmed the prognostic value of ¹²³I-mIBG cardiac scintigraphy in CHF. The late HMR was a prognostic predictor independent from other markers, such as brain natriuretic peptide (BNP) and LVEF. That study included 961 CHF patients with NYHA class II or III HF, LVEF ≤ 35% and optimized medical therapy. Progression of HF, potentially fatal arrhythmias and cardiac death were defined as cardiac events. The risk of event occurrence was significantly higher in patients who presented HMR < 1.6, with a 2-year event rate of 38% (p < 0.001). Moreover, the 2-year death rate, whether cardiac or all-cause, decreases linearly with increased HMR, dropping from 20% with HMR < 1.1 to 0% with HMR ≥ 1.8.²² Other studies confirmed the power of ¹²³I-mIBG scintigraphy in the evaluation of cardiac risk in patients with CHF. Currently, there is an effort to better understand the relation between ¹²³I-mIBG scintigraphy findings and the occurrence of arrhythmic events. It appears that there is no linear relation between HMR and occurrence of arrhythmia, thus suggesting that the evaluation of the risk of arrhythmic events may be focused on SPECT,^14,23 as similarly demonstrated in a PET study.²⁴

Use of ¹²³I-mIBG scintigraphy in the selection of patients for implantable cardiac devices

Another promising application of ¹²³I-mIBG myocardial scintigraphy is to better identify CHF patients who will benefit from implantable cardioverter-defibrillators (ICD) or cardiac resynchronization therapy (CRT). The implantation of these devices has contributed to significantly modify the survival of CHF patients,^25,26 and it is indicated in several guidelines.^27,28 Nevertheless, there still is a large number of patients that do not benefit from implantation (i.e. no therapeutic effects from CRT or no therapeutic discharge from ICD).^29-31 In light of the increasing incidence of HF and the concomitantly increasing costs associated with HF, a better selection of patients for these expensive devices is mandatory. In this context, ¹²³I-mIBG scintigraphy could possibly be used to better discriminate between patients who most likely will benefit from these device implantations and patients who will not.

Publications on this subject are encouraging, but with a limited number of patients evaluated. With 30 patients, Nishioka et al.³² demonstrated that HMR was an independent predictor of CRT response (p = 0.01). A HMR > 1.36 had a sensitivity of 75% and specificity of 71% for the identification of potential CRT responders. Response to CRT with functional improvement of LVEF was also found in significantly higher frequency in patients with left ventricular dyssynchrony and late HMR ≥ 1.6 in a study performed by Tanaka et al.³³ Moreover, the evolution of this group over 3 years was significantly more favorable than that of patients whose sympathetic function was more impaired. Moreover, CRT not only improves left ventricular function, but is also associated with an improved HMR.³⁴ This supports the close relation between cardiac autonomic nervous activity and left ventricular function.

Regarding ICD, the ADMIRE-HF study already showed that possible fatal arrhythmias could be predicted by a HMR < 1.6.²² A better selection of patients for ICD is above all related to prevention (i.e. primary prevention) and not those patients referred for already proven (possible) lethal arrhythmias (i.e. secondary prevention). Nagahara et al.³⁵ showed that late HMR was a predictor of the occurrence of ICD shock in patients with HF and LVEF < 50% and BNP > 187 pg/ml. When combined with high levels of BNP, HMR < 1.95 had a specificity of 94% and a positive predictive value of 82% for the appropriate use of ICD.³⁵

In addition to global cardiac sympathetic activity assessed with ¹²³I-mIBG scintigraphy, there is evidence that, in ischemic HF, regional innervation/perfusion mismatch with a larger defect size on ¹²³I-mIBG SPECT than on myocardial perfusion imaging SPECT predisposes to ventricular arrhythmias.^36-38 In a large prospective study in 116 CHF patients, eligible for ICD implantation for both primary and secondary prevention of sudden cardiac death (SCD), ¹²³I-mIBG SPECT was shown to be an independent predictor of appropriate ICD therapy and cardiac death.³⁹ The cumulative incidence of appropriate ICD therapy during 3 years of follow-up was significantly higher when a relatively large ¹²³I-mIBG SPECT defect (median summed score ≥ 26) was present. Similar results have been shown in a prospective PET study using ¹¹C-hydroxyephedrine for assessing sympathetic activity in ischemic heart disease (n=204), in which the innervation defect size predicted cause-specific mortality from SCD independently of LVEF and infarct volume.²⁴

The screening ¹²³I-mIBG scintigraphy for a better selection of ICD candidates seems to be cost-effective. Screening is associated with a reduction in ICD utilization of 21%, resulting in a number needed to screen to prevent 1 ICD implantation of 5. Screening reduced the costs per patient by US$5500 and US$13,431 (in 2013 dollars) over 2 and 10 years, respectively, in comparison with no screening, and resulted in losses of 0.001 and 0.040 life-years, respectively, over 2 and 10 years.⁴⁰ These findings are encouraging in better discriminating responders from non-responders to ICD. However, larger studies are necessary to better define the role of ¹²³I-mIBG cardiac scintigraphy in identifying responders to ICD in HF. The results of a large randomized trial (i.e. ADMIRE-ICD) are therefore awaited with great anticipation.

Use of ¹²³I-mIBG scintigraphy in the evaluation of cardiotoxicity

Anthracyclines have been used as antineoplastic agents in a wide variety of hematological and solid tumors. It is a powerful therapeutic agent, but with cardiotoxic effects.⁴¹ Cardiotoxicity may be acute or chronic, the latter could arise months or years later.⁴¹ Some risk factors are known, such as cumulative dose, female sex, age, previous irradiation, other concomitant chemotherapeutic drugs, and existing cardiac dysfunction.⁴² Mechanisms involved may include free radicals, myocyte death due to calcium overload and altered adrenergic function.⁴²

Preventive measures have been adopted in experimental studies. Some studies have demonstrated that amifostine may be useful in the bleaching of hydroxyl and superoxide radicals.⁴³ Other agents used are probucol, selenium and L-carnitine. Dexrazoxane has been very useful as a cardioprotector against the cardiotoxic effects of anthracyclines. Dexrazoxane is an iron chelator and results in the reduction of free radicals. However, its use in children has been questioned for possible interference with the antitumor effect of anthracyclines. Beta-blockers and ACE inhibitors, which are part of the arsenal in the treatment of HF, have also been employed, and have been useful to treat cardiotoxicity caused by anthracyclines. However, these drugs do not protect the myocardium from possible anthracycline cardiotoxicity. Monitoring cardiotoxicity is a challenge and involves a series of procedures such as endomyocardial biopsy that, despite providing a histopathological diagnosis, is an invasive procedure and requires evaluation by an experienced pathologist.⁴⁴

Left ventricular dysfunction is the most common manifestation found in cardiotoxicity and may contribute to an increased mortality rate. Traditional non-invasive imaging methods, such as RV and echocardiography (ECHO), can be used to show changes, even if subtle, before the heart starts to fail. RV does not only provide a LVEF but also generates other information on left ventricular function that can be very useful, such as peak filling rate. All these parameters can be used to evaluate systolic and diastolic function, respectively. Ejection fraction and peak filling rate seem to correlate with the early stages of cardiotoxicity.⁴⁵

Nousiainen et al. prospectively evaluated late impairment of cardiac function in 30 patients with non-Hodgkin lymphoma who were submitted to doxorubicin treatment in a low cumulative dose. The authors found that > 4% reduction after a 200-mg cumulative dose had a sensitivity of 90% and specificity of 72% to induce late cardiotoxicity.⁴⁶ It should be taken into account that a certain cell mass should be damaged before the LVEF begins to fail due to myocardial compensatory reserve. In this way, the evaluation of ventricular (dys)function is the most appropriate approach.

Another study by Dos Santos et al.⁴⁷ evaluated the late cardiotoxic effect of anthracyclines by assessing sympathetic activity with ¹²³I-mIBG. That study was performed in a sample of 89 young patients with mean age of 5.4 years and similar sex distribution. While patients receiving chemotherapy had a reduction in LVEF compared to controls, there was no difference in early or late HMR uptake ratios or washout rates of ¹²³I-mIBG.⁴⁷¹²³I-mIBG has good reproducibility and seems sensitive enough to detect alterations in adrenergic innervation before ventricular dysfunction occurs.

A recent study looked at the interrelation between HMR and washout rate and parameters obtained through ECHO, such as GLS and GRS (global longitudinal and radial strain), and serum markers. The authors evaluated 59 women with breast cancer, 1 year after treatment with anthracycline. The parameters found as the most robust were those obtained with ¹²³I-mIBG scintigraphy - late HMR and washout rate. Nevertheless, it is important to emphasize that there was a significant correlation between HMR and GRS.⁴⁸

In another smaller study (n=9), the use of ¹²³I-mIBG scintigraphy for the evaluation of trastuzumab-related cardiotoxicity and ventricular (dys)function was investigated. The data suggest that, in patients with a persistently decreased LVEF, ¹²³I-mIBG scintigraphy might indicate whether recovery will occur and, consequently, whether retreatment may be initiated.⁴⁹ Taking all these preliminary data into account, it seems feasible to assess cardiotoxicity with cardiac ¹²³I-mIBG scintigraphy. ¹²³I-mIBG scintigraphy in combination with parameters of left ventricular mechanical function seem to be promising for the routine clinical use in these oncology patients.

Use of ¹²³I-mIBG scintigraphy in the evaluation of ischemia and diabetes mellitus

The potential use of ¹²³I-mIBG scintigraphy has also found its place in the evaluation of ischemia and in patients with diabetes mellitus (DM). It is important to highlight the association of DM with autonomic neuropathy. The evaluation of ischemia with ¹²³I-mIBG is of interest as sympathetic innervation is more susceptible to ischemia as compared to myocytes. This difference in ischemia susceptibility may be at the base of arrhythmogenicity.⁵⁰

Simões et al. evaluated electrophysiological findings in denervated myocardium of 67 patients with acute myocardial infarction treated with early reperfusion. They correlated these electrophysiological findings with rest 201TI perfusion scintigraphy and sympathetic innervation with ¹²³I-mIBG. The data showed disagreement in size on perfusion imaging compared to ¹²³I-mIBG in 90% of the patients. In other words, ischemia-related adrenergic changes are more pronounced than perfusion defects alone. In addition, electrophysiological findings showed that these areas with perfusion innervation mismatch were correlated with prolonged repolarization.³⁶

Diabetic autonomic neuropathy is the most common and troublesome complication of DM. Although involvement of the autonomic nervous system is generally diffuse, symptoms may be confined to a single target organ or organ system. The exact mechanism has not been elucidated yet. As with other diseases, cardiac ¹²³I-mIBG scintigraphy allows for the assessment of the sympathetic activity. Numerous reports have shown that in diabetic patients, uptake abnormalities of ¹²³I-mIBG are correlated with a poor prognosis, even in the absence of clinical neuropathy.^51,52 Impaired glucose tolerance (IGT) is associated with an increased risk of type 2 DM and cardiovascular disease. However, Asgahr et al.⁵³ showed that global and regional measures of ¹²³I-mIBG uptake and washout, as well as cardiac autonomic function, did not differ between subjects with IGT and healthy controls.

Another study looked at the impact of DM on cardiac sympathetic innervation in patients with HF. Diabetic patients with HF showed lower cardiac ¹²³I-mIBG uptake than HF patients not having DM or than DM patients with a similar degree of autonomic dysfunction not having HF. HbA1c correlated with the degree of reduction in cardiac ¹²³I-mIBG uptake.⁵⁴ So it is important to realize that DM may have an impact on myocardial sympathetic activity and that these patients may be at an increased risk for events.

Conclusion

Cardiac sympathetic activity can be assessed non-invasively by cardiac ¹²³I-mIBG scintigraphy. However, the lack of standardization of acquisition and post-acquisition analysis has hampered comparison between different institutions, and therefore wide scale clinical implementation. Cross-calibration of gamma-camera collimator combinations results in a good reproducibility with a small inter- and intra-observer variation. Moreover, the standardized cardiac ¹²³I-mIBG scintigraphy outcomes seem to have good prognostic value. Therefore, major objections for clinical implementation seem to have been overcome. Furthermore, the use of standardized HMR allows for the development of universal prognostic cut-off values (high vs. low risk). These cut-off values can be calculated by re-analysis of the data of previous published multicenter studies. Finally, it should be stressed that standardization of the HMR is essential for the preparation of adequate risk models. In conclusion, improving standardization and validation of cardiac ¹²³I-mIBG scintigraphy will lead to a much more accepted application for individual HF management.

• Sources of Funding
  There were no external funding sources for this study.
• Study Association
  This study is not associated with any thesis or dissertation work.

References

• ¹
  Flotats A, Carrió I, Agostini D, Le Guludec D, Marcassa C, Schaffers M, et al; EANM Cardiovascular Committee; European Council of Nuclear Cardiology. Proposal for standardization of 123I-metaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology. Eur J Nucl Med Mol Imaging. 2010;37(9):1802-12. doi: 10.1007/s00259-010-1491-4.
  » https://doi.org/10.1007/s00259-010-1491-4
• ²
  Brede M, Wiesmann F, Jahns R, Hadamek K, Arnolt C, Neubauer S, et al. Feedback inhibition of catecholamine release by two different a2-adrenoceptor subtypes prevents progression of heart failure. Circulation. 2002;106(19):2491-6. PMID: 12417548.
• ³
  Chen GP, Tabibiazar R, Branch KR, Link JM, Caldwell JH. Cardiac receptor physiology and imaging: an update. J Nucl Cardiol. 2005;12(6):714-30. doi: 10.1016/j.nuclcard.2005.09.008.
  » https://doi.org/10.1016/j.nuclcard.2005.09.008
• ⁴
  Wieland DM, Wu JI, Brown LE, Mangner TJ, Swanson DP. Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I] iodobenzylguanidine. J Nucl Med. 1980;21(4):349-53. PMID: 7381563.
• ⁵
  Hedrick WR, Di Simone RN, Keen RL. Radiation dosimetry from breast milk excretion of radioiodine and pertechnetate. J Nucl Med. 1986;27(10):1569-71. PMID: 3020191.
• ⁶
  Hsiao E, Huynh T, Mansberg R, Bautovich G, Roach P. Diagnostic I-123 scintigraphy to assess potential breast uptake of I-131 before radioiodine therapy in a postpartum woman with thyroid cancer. Clin Nucl Med. 2004;29(8):498-501. PMID: 15249829.
• ⁷
  Travin MI. Clinical applications of myocardial innervation imaging. Cardiol Clin. 2016;34(1):133-47. doi: 10.1016/j.ccl.2015.06.003.
  » https://doi.org/10.1016/j.ccl.2015.06.003.
• ⁸
  Verberne HJ, Feenstra C, de Jong WM, Somsen GA, van Eck-Smit BL, Busemann Sokole E. Influence of collimator choice and simulated clinical conditions on 123I-MIBG heart/mediastinum ratios: a phantom study. Eur J Nucl Med Mol Imaging. 2005;32(9):1100-7. doi: 10.1007/s00259-005-1810-3.
  » https://doi.org/10.1007/s00259-005-1810-3.
• ⁹
  Verschure DO, de Wit TC, Bongers V, Hagen PJ, Sonneck-Koenne C, D'Aron J, et al. 123I-MIBG heart-to-mediastinum ratio is influenced by high-energy photon penetration of collimator septa from liver and lung activity. Nucl Med Commun. 2015;36(3):279-85. doi: 10.1097/MNM.0000000000000238.
  » https://doi.org/10.1097/MNM.0000000000000238.
• ¹⁰
  Nakajima K, Matsubara K, Ishikawa T, Motomura N, Maeda R, Akhter N, et al. Correction of iodine-123-labeled meta-iodobenzylguanidine uptake with multi-window methods for standardization of the heart-to-mediastinum ratio. J Nucl Cardiol. 2007;14(6):843-51. doi: 10.1016/j.nuclcard.2007.08.002.
  » https://doi.org/10.1016/j.nuclcard.2007.08.002.
• ¹¹
  Nakajima K, Okuda K, Yoshimura M, Matsuo S, Wakabayashi H, Imanishi Y, et al. Multicenter cross-calibration of I-123 metaiodobenzylguanidine heart-to-mediastinum ratios to overcome camera-collimator variations. J Nucl Cardiol. 2014;21(5):970-8. doi: 10.1007/s12350-014-9916-2.
  » https://doi.org/10.1007/s12350-014-9916-2.
• ¹²
  Verschure DO, Poel E, Nakajima K, Okuda K, van Eck-Smit BL, Somsen GA, et al. A European myocardial 123I-mIBG cross-calibration phantom study. J Nucl Cardiol. 2017 Jan 24. doi: 10.1007/s12350-017-0782-6. [Epub ahead of print].
  » https://doi.org/10.1007/s12350-017-0782-6
• ¹³
  Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, et al. Decreased catecholamine sensitivity and b-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307(4):205-11. doi: 10.1056/NEJM198207223070401.
  » https://doi.org/10.1056/NEJM198207223070401
• ¹⁴
  Verschure DO, Veltman CE, Manrique A, Somsen GA, Koutelou M, Katsikis A, et al. For what endpoint does myocardial 123I-MIBG scintigraphy have the greatest prognostic value in patients with chronic heart failure? Results of a pooled individual patient data meta-analysis. Eur Heart J Cardiovasc Imaging. 2014;15(9):996-1003. doi: 10.1093/ehjci/jeu044.
  » https://doi.org/10.1093/ehjci/jeu044
• ¹⁵
  Chirumamilla A, Travin MI, editors. Cardiac applications of 123 I-mIBG imaging. Semin Nucl Med.2011;41(5):374-87. doi:10.1053/j.semnuclmed.2011.04.001
  » https://doi.org/10.1053/j.semnuclmed.2011.04.001
• ¹⁶
  Hage FG, Aggarwal H, Patel K, Chen J, Jacobson AF, Heo J, et al. The relationship of left ventricular mechanical dyssynchrony and cardiac sympathetic denervation to potential sudden cardiac death events in systolic heart failure. J Nucl Cardiol. 2014;21(1):78-85. doi: 10.1007/s12350-013-9807-y.
  » https://doi.org/10.1007/s12350-013-9807-y.
• ¹⁷
  Ministério da Saúde. Datasus. Óbitos infantís-Brasil [Internet]. Brasilia; 2015. [Citado em 2016 dez.10] Disponívem em: http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sim/cnv/obt10uf.def
  » http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sim/cnv/obt10uf.def
• ¹⁸
  Merlet P, Valette H, Dubois-Randé J, Moyse D, Duboc D, Dove P, et al. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. Journal of nuclear medicine: official publication, Society of Nuclear Medicine. 1992;33(4):471-7. PMID: 1552326.
• ¹⁹
  Nakata T, Miyamoto K, Doi A, Sasao H, Wakabayashi T, Kobayashi H, et al. Cardiac death prediction and impaired cardiac sympathetic innervation assessed by MIBG in patients with failing and nonfailing hearts. Journal of Nuclear Cardiology. 1998;5(6):579-90. PMID: 9869480.
• ²⁰
  Agostini D, Verberne HJ, Burchert W, Knuuti J, Povinec P, Sambuceti G, et al. I-123-mIBG myocardial imaging for assessment of risk for a major cardiac event in heart failure patients: insights from a retrospective European multicenter study. Eur J Nucl Med Mol Imaging. 2008;35(3):535-46. doi: 10.1007/s00259-007-0639-3
  » https://doi.org/10.1007/s00259-007-0639-3
• ²¹
  Verberne HJ, Brewster LM, Somsen GA, van Eck-Smit BL. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J. 2008;29(9):1147-59. doi: 10.1093/eurheartj/ehn113.
  » https://doi.org/10.1093/eurheartj/ehn113
• ²²
  Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. J Am Coll Cardiol. 2010;55(20):2212-21. doi: 10.1016/j.jacc.2010.01.014.
  » https://doi.org/10.1016/j.jacc.2010.01.014
• ²³
  Dimitriu-Leen AC, Scholte AJ, Jacobson AF. 123I-MIBG SPECT for evaluation of patients with heart failure. J Nucl Med. 2015;56 Suppl 4:25S-30S. doi: 10.2967/jnumed.115.157503.
  » https://doi.org/10.2967/jnumed.115.157503
• ²⁴
  Fallavollita JA, Heavey BM, Luisi AJ, Michalek SM, Baldwa S, Mashtare TL, et al. Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy. J Am Coll Cardiol. 2014;63(2):141-9. doi: 10.1016/j.jacc.2013.07.096.
  » https://doi.org/10.1016/j.jacc.2013.07.096
• ²⁵
  Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346(12):877-83. doi: 10.1056/NEJMoa013474.
  » https://doi.org/10.1056/NEJMoa013474
• ²⁶
  Connolly S, Hallstrom A, Cappato R, Schron E, Kuck K-H, Zipes D, et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. Eur Heart J. 2000;21(24):2071-8. doi: 10.1053/euhj.2000.2476.
  » https://doi.org/10.1053/euhj.2000.2476
• ²⁷
  Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-200. doi: 10.1093/eurheartj/ehw128.
  » https://doi.org/10.1093/eurheartj/ehw128
• ²⁸
  Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes NM, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [corrected]. Circulation. 2012;126(14):1784-800. doi: 10.1161/CIR.0b013e3182618569
  » https://doi.org/10.1161/CIR.0b013e3182618569
• ²⁹
  Moss AJ, Greenberg H, Case RB, Zareba W, Hall WJ, Brown MW, et al; Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II) Research Group. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation. 2004;110(25):3760-5. doi: 10.1161/01.CIR.0000150390.04704.B7.
  » https://doi.org/10.1161/01.CIR.0000150390.04704.B7
• ³⁰
  Daubert JP, Zareba W, Cannom DS, McNitt S, Rosero SZ, Wang P, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. Journal of the American College of Cardiology. 2008;51(14):1357-65. doi: 10.1016/j.jacc.2007.09.073.
  » https://doi.org/10.1016/j.jacc.2007.09.073
• ³¹
  Pires LA, Abraham WT, Young JB, Johnson KM; MIRACLE and MIRACLE ICD Investigators. Clinical predictors and timing of New York Heart Association class improvement with cardiac resynchronization therapy in patients with advanced chronic heart failure: results from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) and Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE-ICD) trials. Am Heart J. 2006;151(4):837-43. doi: 10.1016/j.ahj.2005.06.024.
  » https://doi.org/10.1016/j.ahj.2005.06.024
• ³²
  Nishioka SA, Martinelli Filho M, Brandão SC, Giorgi MC, Vieira ML, Costa R, et al. Cardiac sympathetic activity pre and post resynchronization therapy evaluated by 123I-MIBG myocardial scintigraphy. J Nucl Cardiol. 2007;14(6):852-9. doi: 10.1016/j.nuclcard.2007.08.004.
  » https://doi.org/10.1016/j.nuclcard.2007.08.004.
• ³³
  Tanaka H, Tatsumi K, Fujiwara S, Tsuji T, Kaneko A, Ryo K, et al. Effect of left ventricular dyssynchrony on cardiac sympathetic activity in heart failure patients with wide QRS duration. Circ J. 2011;76(2):382-9. PMID: 22130315.
• ³⁴
  Scholtens A, Braat A, Tuinenburg A, Meine M, Verberne H. Cardiac sympathetic innervation and cardiac resynchronization therapy. Heart Fail Rev. 2014;19(5):567-73. doi: 10.1007/s10741-013-9400-0.
  » https://doi.org/10.1007/s10741-013-9400-0.
• ³⁵
  Nagahara D, Nakata T, Hashimoto A, Wakabayashi T, Kyuma M, Noda R, et al. Predicting the need for an implantable cardioverter defibrillator using cardiac metaiodobenzylguanidine activity together with plasma natriuretic peptide concentration or left ventricular function. J Nucl Med. 2008;49(2):225-33. doi: 10.2967/jnumed.107.042564.
  » https://doi.org/10.2967/jnumed.107.042564.
• ³⁶
  Simões MV, Barthel P, Matsunari I, Nekolla SG, Schömig A, Schwaiger M, et al. Presence of sympathetically denervated but viable myocardium and its electrophysiologic correlates after early revascularised, acute myocardial infarction. European heart journal. 2004;25(7):551-7. doi: 10.1016/j.ehj.2004.02.016.
  » https://doi.org/10.1016/j.ehj.2004.02.016
• ³⁷
  Sasano T, Abraham MR, Chang KC, Ashikaga H, Mills KJ, Holt DP, et al. Abnormal sympathetic innervation of viable myocardium and the substrate of ventricular tachycardia after myocardial infarction. J Am Coll Cardiol. 2008;51(23):2266-75. doi: 10.1016/j.jacc.2008.02.062.
  » https://doi.org/10.1016/j.jacc.2008.02.062
• ³⁸
  Marshall A, Cheetham A, George RS, Mason M, Kelion AD. Cardiac iodine-123 metaiodobenzylguanidine imaging predicts ventricular arrhythmia in heart failure patients receiving an implantable cardioverter-defibrillator for primary prevention. Heart. 2012;98(18):1359-65. doi: 10.1136/heartjnl-2012-302321.
  » https://doi.org/10.1136/heartjnl-2012-302321
• ³⁹
  Boogers MJ, Borleffs CJ, Henneman MM, van Bommel RJ, van Ramshorst J, Boersma E, et al. Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients. J Am Coll Cardiol. 2010;55(24):2769-77. doi: 10.1016/j.jacc.2009.12.066.
  » https://doi.org/10.1016/j.jacc.2009.12.066
• ⁴⁰
  O'Day K, Levy WC, Johnson M, Jacobson AF. Cost-Effectiveness Analysis of Iodine-123 Meta-Iodobenzylguanidine Imaging for Screening Heart Failure Patients Eligible for an Implantable Cardioverter Defibrillator in the USA. Appl Health Econ Health Policy. 2016;14(3):361-73. doi: 10.1007/s40258-016-0234-5.
  » https://doi.org/10.1007/s40258-016-0234-5
• ⁴¹
  O'Hare M, Sharma A, Murphy K, Mookadam F, Lee H. Cardio-oncology Part I: chemotherapy and cardiovascular toxicity. Expert Rev Cardiovasc Ther. 2015;13(5):511-8. doi: 10.1586/14779072.2015.1032940.
  » https://doi.org/10.1586/14779072.2015.1032940
• ⁴²
  Smith TA, Phyu SM, Akabuogu EU. Effects of administered cardioprotective drugs on treatment response of breast cancer cells. Anticancer Res. 2016;36(1):87-93. PMID: 26722031.
• ⁴³
  Herman EH, Zhang J, Chadwick DP, Ferrans VJ. Comparison of the protective effects of amifostine and dexrazoxane against the toxicity of doxorubicin in spontaneously hypertensive rats. Cancer Chemother Pharmacol. 2000;45(4):329-34. doi: 10.1007/s002800050048.
  » https://doi.org/10.1007/s002800050048
• ⁴⁴
  Tashakori Beheshti A, Mostafavi Toroghi H, Hosseini G, Zarifian A, Homaei Shandiz F, Fazlinezhad A. Carvedilol administration can prevent doxorubicin-induced cardiotoxicity: a double-blind randomized trial. Cardiology. 2016;134(1):47-53. doi: 10.1159/000442722.
  » https://doi.org/10.1159/000442722
• ⁴⁵
  Skovgaard D, Hasbak P, Kjaer A. BNP predicts chemotherapy-related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography. PLoS One. 2014;9(5):e96736. doi: 10.1371/journal.pone.0096736.
  » https://doi.org/10.1371/journal.pone.0096736.
• ⁴⁶
  Nousiainen T, Jantunen E, Vanninen E, Hartikainen J. Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients. British journal of cancer. 2002;86(11):1697-700. doi: 10.1038/sj.bjc.6600346.
  » https://doi.org/10.1038/sj.bjc.6600346.
• ⁴⁷
  Dos Santos MJ, da Rocha ET, Verberne HJ, da Silva ET, Aragon DC, Junior JS. Assessment of late anthracycline-induced cardiotoxicity by 123I-mIBG cardiac scintigraphy in patients treated during childhood and adolescence. J Nucl Cardiol. 2017;24(1):256-264. doi: 10.1007/s12350-015-0309-y.
  » https://doi.org/10.1007/s12350-015-0309-y
• ⁴⁸
  Bulten BF, Verberne HJ, Bellersen L, Oyen WJ, Sabaté-Llobera A, Mavinkurve-Groothuis AM, et al. Relationship of promising methods in the detection of anthracycline-induced cardiotoxicity in breast cancer patients. Cancer Chemother Pharmacol. 2015;76(5):957-67. doi: 10.1007/s00280-015-2874-9.
  » https://doi.org/10.1007/s00280-015-2874-9
• ⁴⁹
  Stokkel MP, Boekhout A. I-123-MIBG myocardial imaging in trastuzumab-based cardiotoxicity: the first experience. Nucl Med Commun. 2013;34(1):19-24. doi: 10.1097/MNM.0b013e32835ae523.
  » https://doi.org/10.1097/MNM.0b013e32835ae523
• ⁵⁰
  Miyazaki T, Zipes DP. Presynaptic modulation of efferent sympathetic and vagal neurotransmission in the canine heart by hypoxia, high K+, low pH, and adenosine. Possible relevance to ischemia-induced denervation. Circ Res. 1990;66(2):289-301. PMID: 2153468.
• ⁵¹
  Langer A, Freeman MR, Josse RG, Armstrong PW. Metaiodobenzylguanidine imaging in diabetes mellitus: assessment of cardiac sympathetic denervation and its relation to autonomic dysfunction and silent myocardial ischemia. J Am Coll Cardiol. 1995;25(3):610-8. doi: 10.1016/0735-1097(94)00459-4.
  » https://doi.org/10.1016/0735-1097(94)00459-4.
• ⁵²
  Hattori N, Tamaki N, Hayashi T, Masuda I, Kudoh T, Tateno M, et al. Regional abnormality of iodine-123-MIBG in diabetic hearts. J Nucl Med. 1996;37(12):1985. PMID: 8970519.
• ⁵³
  Asghar O, Arumugam P, Armstrong I, Ray S, Schmitt M, Malik R. Individuals with impaired glucose tolerance demonstrate normal cardiac sympathetic innervation using I-123 mIBG scintigraphy. J Nucl Cardiol. 2015;22(6):1262-8. doi: 10.1007/s12350-015-0070-2.
  » https://doi.org/10.1007/s12350-015-0070-2
• ⁵⁴
  Paolillo S, Rengo G, Pagano G, Pellegrino T, Savarese G, Femminella GD, et al. Impact of diabetes on cardiac sympathetic innervation in patients with heart failure. Diabetes Care. 2013;36(8):2395-401. doi: 10.2337/dc12-2147.
  » https://doi.org/10.2337/dc12-2147

Publication Dates

• Publication in this collection
  21 Sept 2017
• Date of issue
  Nov-Dec 2017

History

• Received
  20 Apr 2017
• Reviewed
  23 Apr 2017
• Accepted
  05 June 2017