Illuminating the Hidden: Standardizing Cardiac MIBG Imaging for Sympathetic Dysfunction

Abstract

The heart’s innervation relies on a delicate balance between the sympathetic and parasympathetic nervous systems, each using distinct neurotransmitters to regulate heart rate, contractility, and vascular tone. The sympathetic division primarily uses norepinephrine, whereas the parasympathetic division operates through acetylcholine. A range of diseases, through intrinsic and extrinsic mechanisms, can disrupt these neural pathways, resulting in autonomic dysfunction. This review highlights intrinsic causes such as dysautonomias, amyloidosis, diabetes mellitus, Parkinsonian syndromes, and Lewy body dementia, as well as extrinsic factors such as heart failure, myocardial ischemia, infarction, and drug-induced cardiotoxicity. This article examines the effects of various conditions on cardiac sympathetic innervation and highlights how ¹²³I-radiolabeled metaiodobenzylguanidine (MIBG), a norepinephrine analog, can target the cardiac sympathetic nervous system for early detection and disease characterization. Currently, variability in cardiac ¹²³I-MIBG imaging protocols across institutions leads to inconsistencies in image acquisition and interpretation, limiting the establishment of universal benchmarks for distinguishing normal from abnormal cardiac sympathetic innervation. To address this, we propose a simple, clinically useful, standardized protocol based on European Association of Nuclear Medicine guidelines and the AdreView Myocardial Imaging for Risk Evaluation in Heart Failure trial, incorporating both qualitative and semiquantitative methods for disease assessment and highlight cutoff values for some pathologies that can assist in visual interpretation. Standardizing these protocols will enhance the consistency, reliability, and diagnostic accuracy of ¹²³I-MIBG imaging, improving clinical decision-making and optimizing patient outcomes.

cardiac ¹²³I-MIBG
sympathetic nervous system imaging
cardiac autonomic dysfunction
dysautonomia

ANATOMY AND PHYSIOLOGY OF CARDIAC INNERVATION

The heart is innervated by the autonomic nervous system, comprising the sympathetic and parasympathetic systems, which regulate chronotropy, lusitropy, dromotropy, and inotropy (1). Sympathetic nerves release catecholamines such as norepinephrine to stimulate adrenergic receptors, increasing heart rate and contractility, whereas parasympathetic nerves release acetylcholine to stimulate muscarinic receptors, decreasing heart rate and contractility (1–5). Sympathetic signals originate in the brain, travel through the spinal cord, and exit at T1–T4, synapsing with postganglionic fibers near the vertebral column that primarily target the ventricles (Fig. 1) (1,3). Parasympathetic fibers originate in the medulla, traverse the vagus nerve, and synapse within the heart, mainly innervating the atria to regulate nodal function (Fig. 1) (1,3).

FIGURE 1.

Sympathetic (brown) and parasympathetic (blue) innervation of heart and systemic vasculature. Postganglionic sympathetic neurons are seen innervating heart and systemic vasculature.

Norepinephrine, derived from tyrosine, is synthesized and stored in presynaptic vesicles at high concentrations (Fig. 2) (3,4,6). On stimulation, it is released into the synaptic space, binding to α-1, β-1 (the primary cardiac adrenergic receptor), and β-2 receptors on cardiac myocytes, increasing heart rate and contractility (4,7). Most norepinephrine is recycled and stored via the norepinephrine uptake-1 pathway or catabolized (3). This pathway helps regulate synaptic norepinephrine levels, preventing excessive catecholamine effects on the heart (Fig. 2).

FIGURE 2.

Diagram of sympathetic neuronal synapse with cardiac myocyte, demonstrating norepinephrine (NE) synthesis, storage, release, and reuptake.

CARDIAC AUTONOMIC DYSFUNCTION

Cardiac sympathetic dysfunction can arise from intrinsic nerve abnormalities or external disease processes, leading to neurohormonal imbalances, myocyte damage, or sympathetic denervation (1,3,4,8,9). Regardless of the cause, this dysfunction results in systemic dysautonomia, manifesting as heart rate irregularities, blood pressure instability, arrhythmias, and impaired diastolic relaxation (1). We will discuss the following intrinsic and extrinsic causes of cardiac sympathetic dysfunction.

Intrinsic Mechanisms

Dysautonomias

Dysautonomia, or autonomic dysfunction, encompasses congenital and acquired disorders that disrupt autonomic functions such as blood pressure, temperature regulation, breathing, and heart rate (9–11). Its diverse symptoms complicate diagnosis and treatment. Dysautonomia exists in primary (inherited or idiopathic) and secondary forms. Primary dysautonomia has been observed in Ashkenazi Jewish and Eastern European populations (10). Secondary dysautonomia arises from systemic conditions such as amyloidosis, Parkinsonian syndromes, malignancies, and inflammatory diseases, including long coronavirus disease 2019 (10,11).

Amyloidosis

Amyloidosis involves misfolded protein aggregates infiltrating organs, including the heart, leading to a poor prognosis with risks of heart failure, arrhythmias, and restrictive cardiomyopathy (12–14). It also causes dysautonomia due to sympathetic denervation and conduction tissue infiltration. Cardiac dysautonomia is most common in hereditary transthyretin-related (ATTR) and immunoglobulin light chain amyloidosis but not in wild-type or senile ATTR (13).

Diabetes Mellitus

Diabetes mellitus is a common cause of intrinsic cardiac autonomic dysfunction, though its exact pathology remains unclear (1,3,6,15–19). It leads to autonomic denervation, primarily affecting distal axons, through mechanisms such as glycosylation and ischemia (1). Although parasympathetic involvement has been demonstrated, its impact on sympathetic signaling is complex (1).

Parkinsonian Syndromes

Parkinsonian syndromes are neurologic disorders characterized by dopaminergic neuron degeneration, including Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy, corticobasal syndrome, and dementia with Lewy bodies (DLB) (20). In addition to neuron loss, some syndromes exhibit cardiac dysautonomia and sympathetic denervation (21). MSA affects preganglionic neurons, preserving cardiac sympathetic innervation, whereas PD impacts postganglionic neurons, leading to cardiac sympathetic denervation (21–23).

Extrinsic Mechanisms

Heart Failure

Heart failure, most commonly caused by ischemia, leads to neurohormonal dysregulation, activating the renin–angiotensin and sympathetic nervous systems (1,4). This triggers oxidative stress in the brain, increasing catecholamine levels that deplete norepinephrine storage, reduce adrenergic receptor expression, and impair norepinephrine reuptake (4). The resulting sympathetic synapse dysfunction leads to excessive catecholamine levels, eventually becoming cytotoxic.

Myocardial Ischemia or Infarction

Cardiac sympathetic nerves are highly susceptible to ischemia and can undergo denervation after chronic ischemia or infarction (1,3,6,24). Denervation occurs at and around the infarct site, alongside ventricular remodeling (3). Similar to heart failure, neurohormonal changes lead to elevated catecholamine levels, depleted presynaptic norepinephrine storage, reduced norepinephrine transporter activity, and decreased postsynaptic adrenergic receptor expression, resulting in dysfunctional sympathetic synapses (3).

IMAGING WITH ¹²³I-METAIODOBENZYLGUANIDINE (MIBG)

MIBG is a guanethidine analog taken up by sympathetic adrenergic neurons and chromaffin cells (6,25). Labeled with ¹²³I, a pure γ-emitter, it can be imaged using γ-cameras. Structurally similar to norepinephrine (Fig. 3), ¹²³I-MIBG shares its release, reuptake, and storage mechanisms but has no physiologic effect on postsynaptic receptors (Fig. 4). ¹²³I-MIBG was initially developed in the early 1970s to image the adrenal medulla and later to detect pheochromocytoma, neuroendocrine tumors, neuroblastoma, and, to a lesser extent, carcinoid, medullary thyroid carcinoma, and paraganglioma (25–27). Normally, it is distributed in sympathetic-innervated areas, including the salivary glands, thyroid, heart, liver, spleen, adrenal glands, kidneys, and bladder (28). Stored in presynaptic sympathetic vesicles without being catabolized, ¹²³I-MIBG uptake in the heart should be significantly higher than in the mediastinum (Fig. 4) (29). Reduced uptake indicates sympathetic denervation or dysfunction; these conditions also accelerate its washout (Fig. 5). Thus, ¹²³I-MIBG imaging quantifies cardiac sympathetic dysfunction by measuring decreased uptake and increased washout.

FIGURE 3.

Chemical structure of norepinephrine and norepinephrine radiolabeled with ¹²³I-MIBG.

FIGURE 4.

Sympathetic postganglionic presynaptic nerve synapsing with cardiac myocyte. ¹²³I-MIBG uptake at synapse mimics norepinephrine (NE) reuptake and does not bind to adrenergic receptors on myocyte membrane nor result in downstream sympathetic effects.

FIGURE 5.

After injection of ¹²³I-MIBG (yellow), patient undergoes imaging with 3 generalized outcomes. Normal physiologic uptake signifies global radiotracer distribution throughout heart’s sympathetic regions significantly more than background mediastinal activity. Globally decreased (lighter yellow) or focally absent uptake (black) signifies conditions with abnormally reduced sympathetic innervation, such as PD or heart failure. Lastly, focally decreased uptake can be observed in conditions causing localized defects in sympathetic innervation, such as ischemic infarcts.

Cardiac ¹²³I-MIBG Scanning

Significant protocol and image analysis variation in the literature limits widespread clinical applicability of cardiac ¹²³I-MIBG imaging (30,31). Standardization of ¹²³I-MIBG imaging and analysis is required for comparison of results across different institutions, interreader reliability, ordering provider confidence in the results, and insurance reimbursement. Studies on cardiac ¹²³I-MIBG imaging demonstrate variability in the imaging technique (planar/SPECT), collimators (low-energy, high resolution/medium energy), planar image projections (anterior/left anterior oblique), image timing (varying early and delayed time points), and analytic measurements (semiquantitative SPECT values, heart-to-mediastinum ratios [HMR], and washout rates [WRs]), among other parameters (3,30,31). The most widely used protocol in the literature is similar to that proposed by the European Association of Nuclear Medicine (EANM) Cardiovascular Committee and the European Council of Nuclear Cardiology in 2010 (30). The large, multicenter, prospective AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF) trial that used cardiac ¹²³I-MIBG imaging for risk assessment in heart failure patients used a similar protocol with planar and SPECT imaging (32). Primarily using the EANM proposal and methods from the ADMIRE-HF trial, we share the imaging protocol used clinically in our institution with an attempt to offer a simplified procedure and image interpretation for ¹²³I-MIBG scans (30,32–35).

Indications and Contraindications

Cardiac ¹²³I-MIBG imaging evaluates sympathetic innervation, aiding in diagnosing and assessing cardiac dysautonomia causes such as systemic dysautonomia, amyloidosis, diabetes, Parkinsonian syndromes, heart failure, and ischemic heart disease (Table 1) (3). The scan is contraindicated in patients with known hypersensitivity to MIBG/MIBG sulfate (Table 1). Its safety in neonates under 1 mo is unestablished, and the benzyl alcohol in ¹²³I-MIBG preparations poses additional risks in neonates, including gasping syndrome, hypotension, metabolic acidosis, and kernicterus (35). Patients with severe renal impairment or those on dialysis require special consideration, as ¹²³I-MIBG is renally excreted but not cleared by dialysis (30). This can lead to prolonged radiation exposure and increased background activity, potentially impairing scan quality and diagnostic accuracy.

View this table:

TABLE 1.

¹²³I-MIBG Cardiac Scintigraphy Provider Summary and Protocol

Patient Information and Preparation

Patients may have concerns about radiation exposure and should receive written instructions covering the procedure, benefits, risks, preparation, and postscan guidelines (Table 1). Reassurance on radiation exposure to others and methods to minimize it for themselves should be provided. The following patient preparation items, detailed in Tables 1 and 2, are particularly pertinent:

View this table:

TABLE 2.

Common Drugs Affecting ¹²³I-MIBG Uptake

Certain medications interfere with ¹²³I-MIBG uptake and may need to be withheld, whereas essential cardiac medications may be continued if necessary (Table 2) (29,30,36–38).
Foods containing vanillin or catecholaminelike compounds (e.g., chocolate, blue cheese) should be avoided before the scan (39).
Pregnancy and lactation should be assessed, as ¹²³I crosses the placenta and is excreted in breast milk. Breastfeeding should be discontinued for at least 48 h, with the package insert suggesting up to 6 d to minimize risk (30,35).
To protect the thyroid, iodine or perchlorate medications should be administered before the scan (36,40,41).
Patients with a prior thyroidectomy do not need thyroid blocking.
Hydration and frequent voiding help reduce bladder radiation exposure, as ¹²³I-MIBG is excreted primarily through the kidneys and is not cleared by dialysis (30). Patients with severe renal impairment require special consideration because of prolonged radiation exposure.

Radiopharmaceutical Administration

An activity of 10 mCi (370 MBq) of ¹²³I-MIBG should be administered via standard slow intravenous injection over 1–2 min for patients 16 y or older or for patients weighing 70 kg or more if less than 16 y of age (Table 1) (30,35,37). For pediatric patients younger than 16 y and weighing less than 70 kg, the North American Consensus Guidelines’ recommended activity is 0.14 mCi/kg (5.2 MBq/kg) with a minimum recommended activity of 1 mCi (37 MBq), whereas the EANM pediatric guidelines are slightly higher (42,43). The radiopharmaceutical injection should be followed by an injection of 0.9% sodium chloride to ensure complete radiopharmaceutical delivery.

Image Acquisition

Assessment of uptake can be obtained with early (10–15 min) and delayed (3 h 50 min or 4 h) anterior planar imaging for 10 min each (Table 3) (29,30,32–34). The delayed time point not only incorporates neuronal integrity seen in the early images but also incorporates the complete neuronal functioning of norepinephrine uptake, storage in vesicles, and release and reuptake mechanism. At our institution, because of the delayed image advantages and consistent results, we only perform delayed imaging.

View this table:

TABLE 3.

¹²³I-MIBG Scintigraphy Imaging Parameters

A γ-camera with a large field of view should be used. The collimators should be low-energy, high-resolution, parallel hole collimators (Table 3). Energy windows should be centrally set at 20%, with the window centered at a 159-keV photopeak. A preferable planar image matrix of 256 × 256 is used if possible, but a 128 × 128 matrix may be used if a higher resolution is not available (29).

The patient should be in the supine position, with female patients imaged without a bra. SPECT with or without CT should be performed for adequate visual assessment and to avoid any confounding ¹²³I-MIBG activity on anterior planar images. SPECT images also eliminate the need for lateral planar images. SPECT images are performed with a patient’s arms elevated above the head.

Image Processing and Quantification

Cardiac ¹²³I-MIBG uptake is assessed using the HMR, calculated from counts per pixel in regions of interest (ROI). Although both early and delayed images can be used, delayed HMR is preferred because of reduced confounding from blood pool uptake and more consistent results. This approach aligns with the ADMIRE-HF trial, which used delayed HMR for primary analysis (32). Normal delayed uptake indicates intact postganglionic sympathetic innervation (44).

For HMR calculation, the anterior projection is used, with an ROI drawn over the heart. Some protocols contour the myocardium precisely, whereas others encompass the entire heart to reduce variability (45). This method also simplifies the process for technologists, particularly in cases in which low or absent uptake makes delineation of the ventricular wall challenging on planar images. In our practice, we typically use a circular ROI encompassing the entire heart or a freehand ROI to match its shape, calculating mean counts per pixel.

For the mediastinum, conventional 7 × 7 pixel ROI placement on a 128 × 128 matrix can be cumbersome because of patient variability and software limitations (35,37). Instead, we use a longitudinal rectangular ROI in the midline mediastinum at least 4 pixels below the clavicular heads, avoiding the thyroid, muscles, lungs, or abnormal MIBG activity (Fig. 6). This ensures placement in the area with the lowest background counts, from which the mean mediastinal counts per pixel are calculated. The HMR is then determined by dividing mean myocardial counts by mean mediastinal counts, providing a key semiquantitative measure of myocardial sympathetic innervation: $\text{[math]}$

FIGURE 6.

Example of ¹²³I-MIBG ROIs drawn for HMR calculation. Horizontal black line indicates location of clavicular heads, below which there is freehand rectangle for mediastinal background ROI (our technologists freehand draw these rectangles). Yellow circle encloses myocardial uptake.

Myocardial WR reflects nerve integrity and sympathetic drive, mainly representing the norepinephrine uptake-1 mechanism (44). Cardiac disorders increase sympathetic activity and decrease norepinephrine reuptake, causing higher ¹²³I-MIBG washout and decreased delayed cardiac uptake. The WR is calculated as the percentage decrease in myocardial radiotracer from early to delayed images, normalized to mediastinal activity (Fig. 7): $\text{[math]}$

FIGURE 7.

Example of early (15 min) (A) and delayed (4 h) (B) images for ¹²³I-MIBG scan demonstrating abnormal increased WR of 42.45%.

SPECT Reconstruction

SPECT or SPECT/CT imaging improves contrast resolution and should be performed to better visualize uptake in the myocardium (3,31,46). Additionally, SPECT imaging can provide segmental analysis of ¹²³I-MIBG uptake throughout the left ventricle. Segmental analyses in the literature use a semiquantitative technique on 5–20 segments, commonly scoring 0–3 or 0–4 for each segment (0 represents normal uptake and 3 or 4 represent absent uptake) (47,48). These scores can be summed for the left ventricle and correlated with disease pathology. For example, a summed score of 26 or greater on delayed SPECT imaging was shown to predict implantable cardioverter–defibrillator therapy appropriateness and cardiac death among heart failure patients (3). Further work on SPECT-delayed summed-score cutoffs needs to be conducted for a variety of cardiac pathologies to determine the optimal prognostic scores.

For SPECT imaging, we use a dual head camera, 128 × 128 matrix with a 360° orbit and 180° acquisition starting at 45° right anterior oblique and proceeds counterclockwise to 45° left posterior oblique. We use 120 steps (60 steps per detector) and 30 s per step. No gating is performed.

INTERPRETATION

¹²³I-MIBG interpretation includes qualitative, semiquantitative, and quantitative methods. Planar imaging uses qualitative and quantitative analysis, whereas SPECT imaging uses semiquantitative techniques. Early (15 min) and delayed (4 h) imaging should be evaluated qualitatively for myocardial uptake relative to the mediastinum and quantitatively for the HMR and WR. Normal delayed HMR ranges from 1.9 to 3.0, whereas WR varies between 21% and 37%, though values depend on physiologic and technical factors (31,49,50). Age, sex, cardiac function, and activity level impact physiologic variability, with HMR decreasing and WR increasing with age (3). Technical factors include ROI placement, administered activity, ¹²³I-MIBG–specific activity, and image acquisition settings (e.g., collimation, acquisition time) (3,5,31,51).

SPECT imaging uses a summed segmental approach, similar to perfusion imaging, but regional uptake differences create interpretation challenges, especially in older patients and men (3,31,48,52). Athletes may show lower inferior wall uptake due to increased vagal tone (53). Additionally, attenuation artifacts and absent myocardial uptake can affect SPECT accuracy (5,31).

Despite these variations, ¹²³I-MIBG remains a valuable tool for assessing sympathetic denervation and cardiac dysautonomia across multiple pathologies (3,5,31,54). Our institution has established HMR and WR thresholds based on data from the largest studies in the literature (Table 4) (32,46,48,55–60).

View this table:

TABLE 4.

Large Clinical Trials and Cohort Studies Using ¹²³I-MIBG for Heart Failure Prognostication and PD or DLB Diagnosis

CHARACTERIZING CARDIAC AUTONOMIC DYSFUNCTION WITH ¹²³I-MIBG

Disruption of cardiac neural networks through intrinsic and extrinsic mechanisms results in autonomy dysfunction, which can be characterized with ¹²³I-MIBG imaging. We will now discuss studies that demonstrate the utility of ¹²³I-MIBG scans in the previously described disorders.