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  • 1 Cardiology Division, University Hospital of Pisa, Italy
  • | 2 Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy
  • | 3 Fondazione Toscana Gabriele Monasterio, Pisa, Italy
Open access

Abstract

123I-metaiodobenzylguanidine (MIBG) is a radiolabeled norepinephrine analog that can be used to investigate myocardial sympathetic innervation. 123I MIBG scintigraphy has been investigated with interest in many disease settings. In patients with systolic heart failure (HF), 123I MIBG scintigraphy can capture functional impairment and rarefaction of sympathetic terminals (which manifest as reduced early and late heart-to-mediastinum [H/M] ratio on planar scintigraphy), and increased sympathetic outflow (which can be visualized as high washout rate). These findings have been consistently associated with a worse outcome: most notably, a phase 3 trial found that patients with a late H/M 1.60 have a higher incidence of all-cause and cardiovascular mortality and life-threatening arrhythmias over a follow-up of less than 2 years. Despite these promising findings, 123I MIBG scintigraphy has not yet been recommended by major HF guidelines as a tool for additive risk stratification, and has then never entered the stage of widespread adoption into current clinical practice. 123I MIBG scintigraphy has been evaluated also in patients with myocardial infarction, genetic disorders characterized by an increased susceptibility to ventricular arrhythmias, and several other conditions characterized by impaired sympathetic myocardial innervation. In the present chapter we will summarize the state-of-the-art on cardiac 123I MIBG scintigraphy, the current unresolved issues, and the possible directions of future research.

Abstract

123I-metaiodobenzylguanidine (MIBG) is a radiolabeled norepinephrine analog that can be used to investigate myocardial sympathetic innervation. 123I MIBG scintigraphy has been investigated with interest in many disease settings. In patients with systolic heart failure (HF), 123I MIBG scintigraphy can capture functional impairment and rarefaction of sympathetic terminals (which manifest as reduced early and late heart-to-mediastinum [H/M] ratio on planar scintigraphy), and increased sympathetic outflow (which can be visualized as high washout rate). These findings have been consistently associated with a worse outcome: most notably, a phase 3 trial found that patients with a late H/M 1.60 have a higher incidence of all-cause and cardiovascular mortality and life-threatening arrhythmias over a follow-up of less than 2 years. Despite these promising findings, 123I MIBG scintigraphy has not yet been recommended by major HF guidelines as a tool for additive risk stratification, and has then never entered the stage of widespread adoption into current clinical practice. 123I MIBG scintigraphy has been evaluated also in patients with myocardial infarction, genetic disorders characterized by an increased susceptibility to ventricular arrhythmias, and several other conditions characterized by impaired sympathetic myocardial innervation. In the present chapter we will summarize the state-of-the-art on cardiac 123I MIBG scintigraphy, the current unresolved issues, and the possible directions of future research.

MIBG imaging: general concepts

A brief history of MIBG

Cardiovascular function continuously adapts to changing demands by means of the autonomic nervous system, which includes the sympathetic and parasympathetic arms, which exert stimulating or inhibitory effects on target tissues. The effects of the sympathetic nervous system are primarily mediated by the release of the neurotransmitter norepinephrine (NE) from presynaptic nerve terminals, and its binding to adrenergic receptors [1]. Around 80–90% of NE released by sympathetic nerve terminals is re-uptaken into presynaptic nerve terminals through the uptake-1 mechanism, i.e. the NE transporter (NET) [2]. Once inside the nerve terminal, NE is transported into vesicles through vesicular monoamine transporter 2 or is metabolized by monoamine oxidase. The remainder of NE is either be cleared into the circulation or on the postsynaptic side via uptake-2, which transports NE into extraneuronal tissues, such as the heart, where it is metabolized by catecholamine-O-methyl-transferase [3].

In the 1960s, guanethidine was developed as an antihypertensive drug. Guanethidine is transported across the sympathetic nerve membrane by NET and is stored, unmetabolized, in transmitter vesicles, where (at therapeutic concentrations) replaces NE and then inhibits noradrenergic transmission [4]. Combination of a benzyl group and the guanidine group of guanethidine produced metaiodobenzylguanidine (MIBG), which showed a similar affinity and capacity to NE for NET, and is similarly stored into vesicles [5]. Iodination of MIBG with a radioactive isotope enables successful imaging of sympathetic terminals and other neuroectodermally derived cells. The first clinical application of the radiolabeled MIBG with 131I was the visualization of the adrenal medulla and different neural crest-derived tumors such as pheochromocytomas and neuroblastomas [5]. The intense myocardial uptake observed in these studies led to speculate that radiolabeled MIBG with 131I could be used for myocardial imaging. However, due to the suboptimal imaging characteristics of MIBG and a less favorable radiation burden, radiolabeling of MIBG with 123I was preferred for diagnostic purposes. In 1981 Kline et al. used MIBG scintigraphy to image myocardial innervation in 5 healthy subjects, and concluded that MIBG had the potential to provide semiquantitative information on myocardial catecholamine content [6].

Basic information for clinicians

Usually, MIBG is administered intravenously after blockade of thyroid uptake of free 123I through either 500 mg potassium perchlorate or 200 mg potassium iodide (10% solution), although this could be omitted considering that 123I is a gamma emitter with a short half-life [7]. A standard dose is 185 MBq for cardiac imaging, corresponding to an effective dose of 2.4 mSv in adults [8]. The administered dose of MIBG can be down to 55–111 MBq when using the new gamma cameras.

MIBG is internalized by presynaptic nerve endings of postganglionic neuronal cells through NET. A 15% energy window is usually used, centered on the 159-keV 123I photopeak. Anterior planar images are obtained 15 minutes (early) and 4 hours (late) after injection and stored in 128*128 or 256*256 matrixes with standard single photon emission computed tomography (SPECT) camera. Because MIBG is primarily secreted via the kidneys, patients are encouraged to void frequently to facilitate rapid excretion of the tracer [7]. Importantly, differences in the rate of renal excretion did not contribute to variability in mediastinal and myocardial counts between early and late planar MIBG images [9].

The commonly evaluated parameters on MIBG scintigraphy are the heart-to-mediastinum (H/M) ratio and washout ratio (WR). On anterior planar images, regions of interest (ROIs) are drawn over the heart (H) and the mediastinum (M). The average counts in each ROI are obtained, and the H/M ratio is calculated. The WR is calculated as the difference between the early and late H/M, as a percentage of the early H/M, or by computing the actual myocardial counts during the early and late phases:
{(earlyHearlyM)(lateHlateM)(earlyHearlyM)}100

This calculation must be corrected for decay to the moment of early acquisition.

The early H/M probably reflects the integrity of presynaptic nerve terminals and NET function. The late H/M combines information on neuronal function from uptake to release through the storage vesicle at the nerve terminals. The WR is an index of the degree of sympathetic drive. Therefore, increased sympathetic activity is associated with high WR and low myocardial MIBG delayed uptake. Reference values have been identified in the Japanese Society of Nuclear Medicine normal database: early H/M, average 3.1, range 2.2–4.0; late H/M, average 3.3, range 2.2–4.4; WR, average 13, range 0–34% [10]. Early and late H/M decrease with age even in normal subjects, while WR is not affected by age [11].

The use of cardiac SPECT may provide information on regional MIBG distribution. SPECT images can be acquired after planar images with early and delayed acquisition. A tomographic reconstruction is performed, and correction for scatter or tissue attenuation may be applied. MIBG distribution in the SPECT study is similar to that of perfusion imaging tracers, but the inferior accumulation is relatively lower in an MIBG study, particularly for aged individuals [12]. Myocardial regions displaying no uptake of MIBG can still be viable, as demonstrated by perfusion imaging with a tracer such as 99mTc-tetrofosmin.

Several drugs are known, or may be expected, to interfere with organ MIBG uptake. In a review of the literature on drug interactions with MIBG uptake, the only medications for which level of evidence was judged high were labetalol and reserpine. Level of evidence was judged medium for tricyclic antidepressants, calcium channel blockers, and antiarrhythmics (specifically amiodarone). Evidence was judged sufficient to recommend withholding labetalol and the tricyclic antidepressants prior to cardiac MIBG imaging, and to suggest consideration of withdrawal of sympathomimetic amines and serotonin-norepinephrine reuptake inhibitors [13]. On the contrary, cardiac MIBG imaging can be performed in patients on beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) [14]. Withdrawal of beta-blockers (with the possible exception of labetalol), ACEi/ARB, or other HF medications is then not required [7]. Conversely, food containing vanillin and catecholamine-like compounds (such as chocolate) should be avoided as they may interfere with MIBG uptake [7].

Potential clinical applications of myocardial innervation imaging

Heart failure

Despite considerable advances in drug and device treatment, heart failure (HF) still represents a significant cause of morbidity and mortality, and its epidemiological burden is bound to increase in the next years. HF is by far the condition most intensely studied through MIBG imaging, given the crucial pathogenetic role of sympathetic overactivity in HF with reduced ejection fraction (HFrEF). As of September 2020, a search for “MIBG” and “heart failure” on Pubmed yields 556 papers, with a progressive increase in publications since the ‘80s. Many of these papers focused on the role of MIBG imaging for risk stratification, and on patients with HFrEF, considering heterogeneous endpoints, but usually cardiac death or major cardiac events.

Myocardial denervation has been consistently associated with a worse prognosis in patients with HF. For example, the mean H/M ratio in patients who died was typically 0.2–0.3 lower than in those who survived. Meta-analyses of published studies reported pooled hazard ratios of late H/M for cardiac death of 1.82 (95% confidence interval [CI] 0.80–4.12; P = 0.15) and 1.98 for cardiac events (1.57–2.50; P < 0.001) [15], and that a low H/M (with threshold ranging from 1.5 to 1.89) denoted a 5-fold higher risk of cardiac death (odds ratio [OR] 5.2, 95% CI 3.1–5.7) [16]. Furthermore, MIBG uptake was an independent and stronger predictor of mortality than late H/M [17], and a high washout rate (WR) (from 38 to 53%) was also associated with lethal events with a pooled odds ratio of 2.8 (95% CI 1.6–5.0) [16]. The H/M or WR emerged as independent predictors of adverse events from LVEF, New York Heart Association (NYHA) class, and natriuretic peptides (NPs) [18].

The results of the largest prospective trial examining the prognostic significance of MIBG imaging in HF were published in 2010. The AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) study enrolled 961 patients with stable HF, LVEF ≤35%, NYHA class II–III symptoms, and on guideline-recommended medical therapy [19]. Patients with a ventricular pacemaker that routinely functioned or had received defibrillation (either external or via an ICD), anti-tachycardia pacing, or cardioversion for ventricular arrhythmias were excluded [20]. Patients had a mean LVEF of 27%, and 66% of them were adjudicated as having ischemic HF. Over a mean follow-up of 17 months, 237 subjects (25%) experienced events (cardiac death, life-threatening arrhythmias or NYHA class progression), of which only 25 occurred in the 201 subjects with a late H/M ≥1.60 (chosen as the lower limit of normal). Two-year event rate was 15% in patients with H/M ≥1.60 and 37% in those with H/M <1.60. The H/M, LVEF, B-type NP (BNP), and NYHA class were independent predictors of outcome [19]. Post-hoc analyses of ADMIRE-HF and its extension study (ADMIRE-HFX) showed that the H/M retains its prognostic validity regardless of the intensity of treatment (based upon range of dosage) using ACEi/ARBs, beta-blockers, and MRAs) [21], and that the H/M independently predicts all-cause mortality over a median of 24 months [22]. Furthermore, adding the H/M to a well-established Seattle HF Model (SHFM) resulted in improved risk stratification, particularly in the highest-risk SHFM subset [23].

Future studies could usefully investigate the prognostic performance of MIBG imaging in patients with HFrEF receiving sacubitril/valsartan and/or sodium glucose cotransporter 2 inhibitors [SGLT2i], the added value of SPECT to planar scintigraphy and MIBG imaging over techniques such as cardiac magnetic resonance, and the possible role of MIBG imaging for the selection of candidates to cardiac resynchronization therapy (CRT), left ventricular assist device (LVAD), or heart transplantation) [23].

The degree of cardiac sympathetic stimulation, as evaluated through the WR, yielded additive prognostic significance for fast ventricular arrhythmias to other measures of autonomic dysfunction (MIBG findings, heart rate variability [HRV] on 24-h ECG Holter monitoring and baroreflex sensitivity) over a mean of 32 months [24]. Moreover, the presence and extent of an innervation/perfusion mismatch, i.e. denervated but still viable areas, has been consistently associated with increased arrhythmogenicity. For example, in a cohort of 17 patients with implantable cardiac defibrillators (ICDs), the combined assessment of innervation/perfusion mismatch and HRV allowed correct identification of patients at high and low risk for potentially fatal arrhythmias [25]. The added value of a dual isotope SPECT protocol (to assess innervation and perfusion) over a simple innervation imaging was questioned by a study on 116 HF patients referred to defibrillator implantation for primary or secondary prevention, the extent of late MIBG SPECT defects predicted appropriate ICD discharges and cardiac death over 23 ± 15 months, independent from an innervation/perfusion mismatch score [26]. Conversely, perfusion SPECT might hold additive prognostic significance to a global assessment of myocardial innervation by planar MIBG scintigraphy. In a cohort of 60 ICD patients followed for a mean of 29 months, patients with impaired MIBG uptake (H/M <1.9) and 99mTc-tetrofosmin defect score >12 had a significantly greater event rate (94%) than the group with impaired MIBG uptake and preserved 99mTc-tetrofosmin uptake [45%; P < 0.05] and the group with preserved uptake of both agents (18%) [27]. We are not aware of studies evaluating whether MIBG imaging can inform the decision as to whether an ICD should be implanted in borderline cases (for example, in patients with non-ischemic etiology and LVEF approaching the 35% threshold), or can help predict response to CRT.

The increased circulating NE levels commonly seen in patients with HF and the poor prognosis of individuals with particularly high NE levels are associated with a decreased responsiveness of the heart to adrenergic stimulation and downregulation of cardiac beta-receptors. The prognostic benefit of beta-blockers in HFrEF can be partially attributed to an improvement in cardiac sympathetic function. Imaging of myocardial sympathetic innervation provides a means to judge the recovery of this regulatory system in HF patients receiving standard-of-care medical therapy [28], CRT or LVAD [29].

Beneficial effects on cardiac sympathetic innervation have been reported after the start of HF treatment [30, 31], in agreement with the prognostic benefit from these medications in HFrEF. Conversely, patients whose cardiac sympathetic innervation does not recover or even worsens on HF therapy have a worse prognosis, as indicated in a cohort of 74 patients with LVEF <45%. During follow-up, there were 12 deaths and 11 other adverse outcomes. Although there was no difference in the mean H/M at baseline between subjects who did and did not survive, 92% of those who died showed a decrease in H/M between the two MIBG studies. The change in MIBG uptake was a better predictor of adverse long-term outcome than baseline NE or BNP or their changes over 6 months [32].

Open questions:

  1. can MIBG be routinely used to select best candidates for ICD?

  2. which is the impact of the novel therapeutic options for HFrEF on MIBG findings (most notably SGLT2i)?

  3. can MIBG imaging help identify patients with a poor response to the standard combination of ACEi/ARB, beta-blocker, and MRA, and who could then benefit most from the switch to sacubitril/valsartan or other therapies?

  4. can serial MIBG examinations better characterize the response to CRT, beyond QRS duration and changes in LV volumes and function?

  5. can MIBG imaging identify patients with HFpEF and deranged sympathetic cardiac innervation, who could have a prognostic benefit from a therapy with beta-blockers?

Ischemic heart disease

Chronic coronary syndrome

Several studies on chronic coronary syndrome (CCS) have focused on the specific disease entity known as vasospastic angina, where coronary vasospasm causes a transient ischemia in the corresponding vascular territory, leading to MIBG defects that persist even when perfusion is restored. Conflicting results have been reported on WR values, as a lower WR was associated with diagnosis of vasospastic angina [33], but a higher WR with an increased risk of recurrent events [34]. Additionally, areas of defective MIBG uptake were found in patients with silent myocardial ischemia [35].

Myocardial infarction

Following the acute phase of myocardial infarction (MI), patients can undergo MIBG imaging to assess the consequences of the ischemic insult on sympathetic nerve terminals. Small-caliber, unmyelinated fibers are more susceptible to ischemia than cardiomyocytes, resulting in fiber dysfunction (stunning) or death [36]. The area of defective MIBG uptake is larger than the perfusion defect, and the innervation defects persist after revascularization [37]. The resulting innervation/perfusion mismatch may predispose to ventricular arrhythmias [38], as demonstrated by the fact that the degree of perfusion/innervation mismatch is significantly correlated with the site of earliest activation in ventricular tachycardias (VT) [39].

A recovery from stunning and/or some degrees of reinnervation are believed to occur given that a normal MIBG uptake was found 14 weeks after MI in dogs [40], and MIBG uptake in the peri-infarcted area increased over 12 months in humans [41]. Patients with a recent MI (<14 days) also demonstrated a faster myocardial MIBG washout than normal subjects, in the whole heart as well as in the remote myocardium, denoting an increased sympathetic stimulation that might contribute to post-MI remodeling [42].

Ischemic heart failure

Many studies on the prognostic value of MIBG imaging in HF included a significant number of patients with ischemic etiology [19], while patients with ischemic HF have been less often specifically evaluated. Cardiac sympathetic nerve activity became progressively more altered in parallel with HF severity regardless of the underlying etiology [43], and late H/M was the strongest independent predictor of cardiac death in patients with LVEF <40% and either ischemic or non-ischemic etiology, with a lower best cut-off in those with ischemic HF (1.50 vs. 2.02) [44]. In a study on 50 patients with a history of MI and LVEF ≤40% referred to electrophysiological (EP) testing because of syncope or non-sustained VT, late H/M did not differ significantly between patients with inducible sustained ventricular tachyarrhythmias, while a 4-h regional defect score ≥37 yielded a sensitivity of 77% and specificity of 75% for predicting a positive EP results [45]. The notion that larger regional defects are associated with an increased risk of arrhythmias was supported by a study on patients evaluated before ICD implantation for primary (89%) or secondary prevention (11%) [26]. The late MIBG defect score was an independent predictor of both appropriate ICD discharge and cardiac death over 23 ± 15 months. Furthermore, patients with a large late MIBG SPECT defect (summed score >26) showed significantly more appropriate ICD therapy (52 vs. 5%, P < 0.01) and appropriate ICD therapy or cardiac death (57 vs. 10%, P < 0.01) than patients with a small defect (summed score ≤26) at 3-year follow-up. An innervation/perfusion mismatch score was a univariate, but not an independent predictor of both endpoints [26]. In a very recent study on patients with ischemic HF (mean follow-up of 18 months), those receiving an ICD for secondary SCD prevention had significantly larger perfusion and innervation defects, while the imaging results could not predict patients with appropriate ICD therapy among patients with ICD implants for primary prevention [46]. Finally, innervation and perfusion defects were evaluated also as predictors of response to catheter ablation of ventricular arrhythmias in patients with prior MI and low LVEF. Perfusion/innervation mismatch in a specific LV zone was an independent predictor of local abnormal ventricular activity on electroanatomic mapping, and a significant reduction in the perfusion/innervation mismatch score after ablation predicted a reduction of the arrhythmic burden [47].

Take-home message:

  1. A quite limited number of studies have evaluated MIBG imaging in patients with ischemic heart disease (from CCS to ischemic HF), and the evidence is quite fragmentary.

  2. Myocardial ischemia causes enduring innervation defects, areas of innervation/perfusion mismatch are pro-arrhythmogenic in the post-MI setting,

  3. Larger regional defects of MIBG uptake predict cardiac death and appropriate ICD discharge in ischemic HF.

Ventricular arrhythmias and prediction of sudden cardiac death in genetic disorders

The evaluation of the integrity of cardiac sympathetic innervation by MIBG scintigraphy has been long proposed as a valuable method to stratify the risk of ventricular arrhythmias (VA) and sudden cardiac death (SCD) in patients with structural heart diseases with a genetic etiology, or arrhythmogenic disorders not associated with functional and anatomic changes detectable by conventional techniques.

Idiopathic dilated cardiomyopathy

In patients with idiopathic dilated cardiomyopathy (DCM), MIBG washout was correlated with baseline LV function, and the late H/M with contractile reserve on atrial pacing [48] or contractility during dobutamine stress testing [49]. Furthermore, the late H/M emerged as the most powerful independent predictor of cardiac death in patients with DCM [44]. In another small study, a mismatch between regional innervation and perfusion was associated with a higher risk of VT [50]. These findings have not been replicated, despite their potential relevance to select patients for defibrillator implantation or to guide ablation procedures.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder, and an important cause of SCD. Preliminary results indicated an important role of cardiac sympathetic nervous innervation in LV function at baseline (HCM patients with systolic dysfunction had a significantly lower early MIBG uptake than controls with a WR decrease from normal to abnormal EF) and during exercise, even if it remains to be established if MIBG scintigraphy can predict the deterioration of cardiac function or other outcomes, most notably SCD.

Takotsubo cardiomyopathy

Takotsubo cardiomyopathy (TTC) is a condition where the heart takes on the appearance of a Japanese octopus fishing pot, and symptoms and signs of MI coexist with no demonstrable coronary artery stenosis or spasm. LV function can be remarkably depressed, but usually recovers within a few weeks. A sudden surge in sympathetic activity is considering as a crucial determinant of disease in TTC. A demonstration of adrenergic hyperactivity in TTC came from a study where 123I-mIBG planar scintigraphy was performed during the subacute phase (median of 8 days after coronary angiography). Patients (n = 32) displayed a lower late H/M and increased WR than control subjects with acute coronary syndrome. Decreased cardiac MIBG uptake was attributed to inhibited MIBG reuptake by high epinephrine levels in the synaptic cleft and/or NET downregulation. Adrenergic overactivity resolved over time, as demonstrated by late H/M and WR values after a median of 109 days [51].

The relationship among sympathetic innervation, myocardial perfusion and glucose metabolism in TTC was evaluated by MIBG gated SPECT, 99mTc-tetrofosmin or 201Tl gated SPECT and 18F-FDG gated positron emission tomography (PET), respectively [52]. Dysfunctional LV segments were found to have a normal perfusion but reduced innervation and glucose metabolism. These last alterations recovered slowly than LV motion [52]. The role of MIBG imaging for patient characterization and risk prediction after the acute phase remains to be characterized, while there is probably no room for improvement of the diagnostic workup [53].

Anthracycline cardiotoxicity

Among antineoplastic regimens, anthracyclines carry a particularly high risk of cardiotoxicity [54]. Anthracyclines cause abnormalities in myocardial adrenergic function that precede LVEF decline and overt HF. In animal studies, MIBG uptake in myocardial adrenergic neurons was reduced in a dose-dependent way [55], and MIBG imaging proved superior to echocardiography, plasma NE and cardiomyocyte staining in the early detection of doxorubicin-induced cardiotoxicity [56]. A dose-dependent decrease in MIBG uptake prior to LVEF deterioration was confirmed in humans. In patients with previous exposure to anthracycline-containing chemotherapy regimens, late H/M displayed an inverse correlation with global longitudinal strain [57], but damage to adrenergic myocardial neurons seemed to persist even in patients recovering from LV dysfunction [58]. At present, the most promising application of MIBG imaging in this setting is early diagnosis of anthracycline cardiotoxicity, but further comparisons with alternative approaches such as speckle tracking echocardiography or high-sensitivity troponins are warranted.

Heart transplantation

During heart transplantation, postganglionic sympathetic nerve fibers of the donor heart are surgically interrupted, resulting in complete denervation [59]. The denervated heart early after transplantation is a useful model to test the specificity of neuronal imaging agents, as no cardiac uptake should be detected in this condition [60]. Sympathetic reinnervation after transplantation was first reported in animal models [61], and then in human patients evaluated with MIBG SPECT as well as with PET tracers [62, 63]. For example, 48% of 23 patients evaluated 1–2 years after transplantation showed a cardiac uptake [60], and reinnervation starts from basal segments, anterior and septal walls [62, 63]. Areas of reinnervated myocardium have improved blood flow regulation, energy substrate use, cardiac performance, and exercise capacity [64], but the relationship between reinnervation and patient survival is uncertain [65].

Cardiac amyloidosis

Systemic amyloidoses are characterized by the extracellular accumulation of misfolded proteins into the beta-sheet configuration, leading to tissue damage. The two most common forms are amyloid light-chain (AL) and transthyretin amyloidosis (ATTR), the latter due to the deposition of either normal (wild-type ATTR, ATTRwt) or mutated TTR molecules (variant ATTR, ATTRv) [66–68]. The heart is the organ most commonly affected in ATTRwt and one of the main sites of light-chain deposition; furthermore, different mutations in the TTR gene have been associated with a prevalent involvement of the heart or the peripheral nervous system. Manifestations of cardiac amyloidosis (CA) include left ventricular pseudohypertrophy and conduction disturbances. Clinical evidence of autonomic dysfunction is quite common in ATTRv and AL amyloidosis, but not in ATTRwt. Sudden cardiac death has a high incidence and may result from tachyarrhythmias, but more often from electromechanical dissociation or arrhythmias not amenable to defibrillator therapy [66–68].

MIBG scintigraphy may allow to assess myocardial innervation in CA [69]. Carriers of TTR gene mutations (n = 31) displayed a reduced late H/M (<1.85) in 48% of cases, half of whom had a normal diphosphonate scan, and all the subjects with a normal H/M had a normal 99mTc-DPD scan. In the whole cohort (carriers or patients with overt ATTRv, n = 75), DPD scan was negative in all patients with normal MIBG scan except for 2 patients [70]. Therefore, sympathetic denervation may be an early marker of cardiac disease in ATTRv, and could be considered as a screening tool for cardiac involvement in TTR gene carriers.

A combined assessment of innervation, amyloid burden (with 99mTc-hydroxymethylene diphosphonate – 99mTc-HMDP), and perfusion (99mTc-tetrofosmin) with a Cadmium Zinc Telluride (CZT) camera was performed only in patients with ATTRwt, in a small study (n = 15), reporting a cardiac sympathetic denervation more evident in the inferior and septal regions. Although the same regions displayed a severe amyloid burden, the accumulation of amyloid fibers was more intense and extended to all other LV regions. Similarly, myocardial hypoperfusion was less intense than amyloid deposition, with a similar spatial distribution than denervation [71]. These results are in agreement with the notion that myocardial sympathetic denervation is not a prominent feature of ATTRwt and develops in a much later stage than amyloid deposition, contrary to ATTRv.

In summary, very fragmentary data are available on MIBG imaging in CA, with some evidence of a role for early diagnosis in ATTRv. SPECT imaging deserves consideration in future studies, exploring for example the patterns of myocardial denervation, their relationship with outcome, and the changes in response to novel therapies such as tafamidis.

Atrial fibrillation

Abnormal activity of the intrinsic cardiac autonomic nervous system seems to play an important role in the initiation and maintenance of atrial fibrillation (AF). For example, in patients with first occurrence of paroxysmal AF, a reduced late H/M predicted the development of permanent AF during a 4-year mean follow-up [72], and a high WR (calculated in a stable sinus rhythm condition 5 days after pulmonary vein isolation (PVI) independently predicted AF relapses during a mean of 14 months in patients with paroxysmal or permanent AF [73]. Furthermore, the presence of regional innervation defects after PVI on MIBG SPECT images was associated with an increased risk of AF relapses over a 6-month follow-up (40% vs. 17% of patients) [74].

The cardiac autonomic system includes thousands of neurons located in ganglionated plexuses (GPs) in the epicardial fat pads that project axons to widespread regions of the heart. Four of the 7 main GPs are located around the pulmonary veins, and the results of PVI by radiofrequency pulses may depend on effective destruction of these GPs. The standard approach to localize the GPs is to apply high-frequency stimulation to the presumed GP areas to elicit atrioventricular blocks, but this method has low specificity and sensitivity, is invasive and time-consuming [75]. MIBG imaging has been recently used to localize GPs. Stirrup et al. defined a high-resolution CZT SPECT/computed tomography (CT) protocol to identify GPs, which measure 5–10 mm, with good accuracy and reproducibility when compared to high-frequency stimulation (HFS) [76]. Left atrial innervation imaging by SPECT might replace or integrate invasive HFS in the identification of GPs, thus refining the planning of the ablation procedure. Moreover, MIBG SPECT represents an innovative tool to assess the extent of left atrium denervation and the dynamics of reinnervation after PVI, which might help predict AF recurrences [77].

Diabetes mellitus

Diabetes mellitus (DM) is the most common endocrine disease and one of the main determinants of morbidity and mortality worldwide. Long-term complications of DM include macrovascular disease, manifesting as coronary or peripheral artery disease, and microvascular damage to the retina, kidneys, and nerves. Diabetic neuropathies are a heterogeneous group of diabetic complications that affect different parts of the peripheral nervous system. Cardiac autonomic neuropathy (CAN) results from damage to the autonomic fibers innervating the heart and blood vessels, which impairs heart rate (HR) control and vascular dynamics. Clinical manifestations include resting tachycardia, inadequate increases in cardiac output during exercise, orthostatic hypotension, and asymptomatic ischemia or infarction. In a retrospective cohort of 144 patients with type 2 DM, reduced late H/M (<1.7) independently predicted all-cause mortality over 7.2 ± 3.2 years, and the combination of reduced late H/M and low HRV independently predicted cardiac events (arrhythmias, HF or MI), as well as all-cause mortality [78]. Therefore, the H/M, either alone or integrated with other measures of CAN, holds prognostic significance in patients with DM. We are not aware of studies investigating the prognostic value of MIBG SPECT, and no conclusive demonstration has been provided that a more intensive glycemic control can improve cardiac MIBG uptake.

Parkinson’s disease and related disorders

Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and pure autonomic failure are referred to as “Lewy body diseases (LBD)” because they share the presence of Lewy bodies (cytoplasmic inclusions containing alpha-synuclein protein aggregates) in neurons. The main clinical application of cardiac MIBG scintigraphy in patients with PD is currently the differential diagnosis between PD and other parkinsonisms with high sensitivity and specificity [79].

Future perspectives

The main applications of MIBG and SPECT for cardiac sympathetic imaging are recapitulated in the Summary Table. One of the possible causes why MIBG cardiac imaging has not been widely adopted in clinical practice, even for the characterization of patients with HF, is the fact that acquisition protocols remain quite heterogeneous in terms of tracer doses, timing of acquisition, ROI drawing, and use of LE instead of ME collimators, despite a proposal for standardization [7]. Lack of standardization is likely a major source of heterogeneity among study results, and may help explain why this technique has not gained widespread adoption in clinical practice, and has not entered even HF guidelines in spite of the evidence that MIBG holds prognostic significance in this condition. The only exception is a guideline by the Japanese Circulation Society Joint Working Group, which includes a class I recommendation for MIBG imaging for the assessment of severity and prognosis of HF [80]. A standardized approach to MIBG acquisition, possibly stimulated by novel and updated recommendations, can then be envisaged. The strengths of MIBG imaging, i.e. the fact that early and late acquisitions are relatively rapid, radiation exposure is limited (with an effective dose of less than 1 mSv when using CZT cameras), results are not influenced by most therapies, contraindications are limited to known hypersensitivity to MIBG or MIBG sulphate, and adverse effects are very rare [7], should be emphasized. Furthermore, the role of regional characterization through MIBG SPECT deserves further consideration as a tool to capture early stages of myocardial denervation, possibly missed by planar scintigraphy, or to identify regions of innervation/perfusion mismatch when combined with perfusion SPECT. The latest developments in SPECT imaging, namely the CZT technique and digital detector-based SPECT/CT, can also obviate the need for ME collimators. PET imaging of cardiac sympathetic innervation has many advantages over MIBG SPECT, including a greater spatiotemporal resolution and well-validated attenuation correction, the availability of many tracers that allow to explore both pre- and post-synaptic terminals, and the possibility of quantitative tracer uptake [1]. On the other hand, the need for an on-site cyclotron for all 11C-labelled tracers will greatly limit the applicability of PET in current clinical practice, and prompts a search for the settings where it can be replaced by MIBG SPECT.

Summary Table.

123I-MIBG imaging and cardiac disease: evidence from clinical studies

Diagnosis (early diagnosis or differential diagnosisRisk stratificationPatient management (planning or monitoring of drug/device therapy, follow-up)
Planar scintigraphySPECTPlanar scintigraphySPECTPlanar scintigraphySPECT
Heart failure++++++
Ischemic heart disease
Chronic coronary syndrome++
Myocardial infarction++
Ischemic heart failure++
Ventricular arrhythmias and prediction of sudden cardiac death in genetic disorders
Idiopathic DCM++
HCM
Takotsubo cardiomyopathy
Anthracycline cardiotoxicity+
Heart transplantation
Cardiac amyloidosis+
Atrial fibrillation+
Diabetes mellitus+
Parkinson's disease and related disorders+

+++, evidence from multiple clinical studies; ++, evidence from a small number of studies; +, evidence from one or very few studies; , no clear evidence from published studies.

Conflicts of interest

None.

Permissions

Not required.

Abbreviations and acronyms

ACEi/ARB

angiotensin-converting enzyme inhibitors or angiotensin receptor blockers

ADMIRE-HF

AdreView Myocardial Imaging for Risk Evaluation in Heart Failure

ADMIRE-HFX

extension study of ADMIRE-HF

AF

atrial fibrillation

AL

amyloid light-chain

ATTR

amyloid transthyretin (ATTRv, variant form; ATTRwt, wild-type form)

BNP

B-type natriuretic peptide

CA

cardiac amyloidosis

CAN

cardiac autonomic neuropathy

CCS

chronic coronary syndrome

CI

confidence interval

CRT

cardiac resynchronization therapy

CT

computed tomography

CZT

Cadmium Zinc Telluride

DCM

dilated cardiomyopathy

DLB

dementia with Lewy bodies

DM

diabetes mellitus

EP

electrophysiological

GP

ganglionated plexus

H/M

heart-to-mediastinum

HCM

hypertrophic cardiomyopathy

HF

heart failure

HFrEF

heart failure with reduced ejection fraction

HFS

high-frequency stimulation

HR(V)

heart rate (variability)

ICD

implantable cardioverter defibrillator

LBD

Lewy body diseases

LV

left ventricle/left ventricular

LVAD

left ventricular assist device

LVEF

left ventricular ejection fraction

MACE

major adverse cardiac events

MI

myocardial infarction

MIBG

metaiodobenzylguanidine

MRA

mineralocorticoid receptor antagonist

NE

norepinephrine

NET

norepinephrine transporter

NP

natriuretic peptide

NYHA

New York Heart Association

OR

odds ratio

PD

Parkinson’s disease

PV

pulmonary vein

PVI

pulmonary vein isolation

ROI

region of interest

RV

right ventricle/right ventricular

SCD

sudden cardiac death

SGLT2i

sodium glucose cotransporter 2 inhibitors

SHFM

Seattle Heart Failure Model

SPECT

single photon emission computed tomography

TTC

Takotsubo cardiomyopathy

VT

ventricular tachycardia

WR

washout rate

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    Pandit-Taskar N, Modak S: Norepinephrine transporter as a target for imaging and therapy. J Nucl Med Off Publ Soc Nucl Med 2017; 58: 39s53s.

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Chair of the Editorial Board:
Béla MERKELY (Semmelweis University, Budapest, Hungary)

Editor-in-Chief:
Pál MAUROVICH-HORVAT (Semmelweis University, Budapest, Hungary)

Executive Editor:
Charles S. WHITE (University of Maryland, USA)

Deputy Editors:
Gianluca PONTONE (Department of Cardiovascular Imaging, Centro Cardiologico Monzino IRCCS, Milan, Italy)
Michelle WILLIAMS (University of Edinburgh, UK)

Senior Associate Editors:
Viktor BÉRCZI (Semmelweis University, Budapest, Hungary)
Tamás Zsigmond KINCSES (University of Szeged, Hungary)
Hildo LAMB (Leiden University, The Netherlands)
Denisa MURARU (Istituto Auxologico Italiano, IRCCS, Milan, Italy)
Ronak RAJANI (Guy’s and St Thomas’ NHS Foundation Trust, London, UK)

Associate Editors:
Andrea BAGGIANO (Department of Cardiovascular Imaging, Centro Cardiologico Monzino IRCCS, Milan, Italy)
Fabian BAMBERG (Department of Radiology, University Hospital Freiburg, Germany)
Péter BARSI (Semmelweis University, Budapest, Hungary)
Theodora BENEDEK (University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania)
Ronny BÜCHEL (University Hospital Zürich, Switzerland)
Filippo CADEMARTIRI (SDN IRCCS, Naples, Italy) Matteo CAMELI (University of Siena, Italy)
Csilla CELENG (University of Utrecht, The Netherlands)
Edit DÓSA (Semmelweis University, Budapest, Hungary)
Marco FRANCONE (La Sapienza University of Rome, Italy)
Viktor GÁL (OrthoPred Ltd., Győr, Hungary)
Alessia GIMELLI (Fondazione Toscana Gabriele Monasterio, Pisa, Italy)
Tamás GYÖRKE (Semmelweis Unversity, Budapest)
Fabian HYAFIL (European Hospital Georges Pompidou, Paris, France)
György JERMENDY (Bajcsy-Zsilinszky Hospital, Budapest, Hungary)
Pál KAPOSI (Semmelweis University, Budapest, Hungary)
Mihaly KÁROLYI (University of Zürich, Switzerland)
Márton KOLOSSVÁRY (Semmelweis University, Budapest, Hungary)
Lajos KOZÁK (Semmelweis University, Budapest, Hungary)
Mariusz KRUK (Institute of Cardiology, Warsaw, Poland)
Zsuzsa LÉNARD (Semmelweis University, Budapest, Hungary)
Erica MAFFEI (ASUR Marche, Urbino, Marche, Italy)
Robert MANKA (University Hospital, Zürich, Switzerland)
Saima MUSHTAQ (Cardiology Center Monzino (IRCCS), Milan, Italy)
Gábor RUDAS (Semmelweis University, Budapest, Hungary)
Balázs RUZSICS (Royal Liverpool and Broadgreen University Hospital, UK)
Christopher L SCHLETT (Unievrsity Hospital Freiburg, Germany)
Bálint SZILVESZTER (Semmelweis University, Budapest, Hungary)
Richard TAKX (University Medical Centre, Utrecht, The Netherlands)
Ádám TÁRNOKI (National Institute of Oncology, Budapest, Hungary)
Dávid TÁRNOKI (National Institute of Oncology, Budapest, Hungary)
Jiayin ZHANG (Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China)
Hajnalka VÁGÓ (Semmelweis University, Budapest, Hungary)

International Editorial Board:

Gergely ÁGOSTON (University of Szeged, Hungary)
Anna BARITUSSIO (University of Padova, Italy)
Bostjan BERLOT (University Medical Centre, Ljubljana, Slovenia)
Edoardo CONTE (Centro Cardiologico Monzino IRCCS, Milan)
Réka FALUDI (University of Szeged, Hungary)
Andrea Igoren GUARICCI (University of Bari, Italy)
Marco GUGLIELMO (Department of Cardiovascular Imaging, Centro Cardiologico Monzino IRCCS, Milan, Italy)
Kristóf HISRCHBERG (University of Heidelberg, Germany)
Dénes HORVÁTHY (Semmelweis University, Budapest, Hungary)
Julia KARADY (Harvard Unversity, MA, USA)
Attila KOVÁCS (Semmelweis University, Budapest, Hungary)
Riccardo LIGA (Cardiothoracic and Vascular Department, Università di Pisa, Pisa, Italy)
Máté MAGYAR (Semmelweis University, Budapest, Hungary)
Giuseppe MUSCOGIURI (Centro Cardiologico Monzino IRCCS, Milan, Italy)
Anikó I NAGY (Semmelweis University, Budapest, Hungary)
Liliána SZABÓ (Semmelweis University, Budapest, Hungary)
Özge TOK (Memorial Bahcelievler Hospital, Istanbul, Turkey)
Márton TOKODI (Semmelweis University, Budapest, Hungary)

Managing Editor:
Anikó HEGEDÜS (Semmelweis University, Budapest, Hungary)

Pál Maurovich-Horvat, MD, PhD, MPH, Editor-in-Chief

Semmelweis University, Medical Imaging Centre
2 Korányi Sándor utca, Budapest, H-1083, Hungary
Tel: +36-20-663-2485
E-mail: maurovich-horvat.pal@med.semmelweis-univ.hu

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2020  
CrossRef Documents 7
CrossRef Cites 0
CrossRef H-index 1
Days from submission to acceptance 17
Days from acceptance to publication 70
Acceptance Rate 43%

Imaging
Publication Model Gold Open Access
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Imaging
Language English
Size A4
Year of
Foundation
2020 (2009)
Publication
Programme
2020 Volume 12
Volumes
per Year
1
Issues
per Year
2
Founder Akadémiai Kiadó
Founder's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2732-0960 (Online)

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