Introduction
Heart failure (HF) is characterized by several abnormalities of sympathetic cardiac activity: an increased sympathetic response is initially favorable by serving as compensation for decreased cardiac output, but as HF progresses this response leads to deleterious neurohormonal and myocardial structural changes that worsen the condition and increase the likelihood of adverse cardiac events.
1
Iodine123-Metaiodobenzylguanidine (
123I-mIBG), an analog of norepinephrine, is a useful tool for detecting abnormalities in the myocardial adrenergic nervous system in HF patients and can be successfully used to assess their prognosis.
2–4123I-mIBG represents a tracer of sympathetic neuron integrity and function and the most widely used imaging agent for studying the causes and effects of cardiac sympathetic hyperactivity.
5 Semi-quantitative myocardial
123I-mIBG parameters have proved to be of prognostic value in HF.
6,
7 Specifically, some trials were designed to assess the capability of the heart to mediastinum ratio (H/M) on
123I-mIBG planar scintigraphy for predicting prognosis for significant adverse cardiac events in subjects with HF.
8 Currently, the H/M is the basis for the clinical decision-making diagnostic work-up, enabling the common application of a single standardized parameter beyond worldwide institutions.
9,
10 Several single and multicenter studies demonstrated and confirmed its potent prognostic role in the clinical evaluation and risk stratification in HF.
11,
12 HF patients with impaired myocardial
123I-mIBG parameters had a worse prognosis compared with those with relatively preserved parameters (i.e., reduced late H/M and increased myocardial wash-out rate (WR)).
13 However, it has become progressively more common to include single-photon emission computerized tomography (SPECT) imaging in clinical and research protocol.
14 Myocardial SPECT imaging allows evaluation of the regional sympathetic activity and polar maps of the myocardium could be obtained by SPECT images, providing an assessment of the defect extent and severity.
15,
16 Furthermore, the ability of
123I-mIBG SPECT to provide regional information not available on planar images remains a driver for efforts to incorporate this procedure into assessments of HF patients with arrhythmic events (AE) and sudden cardiac death (SCD) specific risk.
17,
18 Despite PET imaging holds higher spatial resolution and superior quantitative capabilities,
19,
20 for the forthcoming future
123I-mIBG SPECT accounts for the most widely available nuclear imaging technique for an accurate assessment of the regional myocardial sympathetic innervation.
21 Nonetheless, a shared and established consent of these
123I-mIBG SPECT parameters is found to be hard to get according to the present knowledge. Therefore, to date, there is an urgent need for improved risk stratification for patients developing HF and growing evidence that
123I-mIBG SPECT imaging should gain greater clinical relevance. The aim of this systematic review is to evaluate the prognostic value of
123I-mIBG SPECT myocardial imaging in patients with HF and to assess whether semi-quantitative SPECT scores can be useful for accurate risk stratification with regard to AE and SCD.
Discussion
In patients with chronic HF, sympathetic hyperactivity initially represents a compensatory mechanism for coping with impaired myocardial function. However, long-term elevated adrenergic stimulation generates a vicious circle which leads in the end to detrimental myocardial remodeling, decline in left ventricular function, and increased morbidity and mortality.
27 Cardiac sympathetic activity could be non-invasively assessed with
123I-mIBG myocardial SPECT imaging since the internalization of this tracer in presynaptic endings of post-ganglionic neuronal cells.
28,
29 Several studies proved that parameters derived by myocardial planar scintigraphy with
123I-mIBG play a significant prognostic role in chronic HF, with particular regard to the H/M value.
30–32 However, in recent times, following the conversion from planar to SPECT tomographic techniques in clinical nuclear myocardial perfusion imaging (MPI), also
123I-mIBG SPECT imaging it has become progressively more common in clinical and research protocols.
5,
33 Early and late
123I-mIBG SPECT images were scored visually with 20- and 17-segment regional polar maps, also known as
bull’s-eye maps. Additionally, segmental counts data were used to calculate regional wash-out rate (rWO) in some studies. In patients with HF, the reduced uptake of norepinephrine in presynaptic neurons determines a lower mIBG uptake (decreased H/M) and an increased WR, due to an increased release rate. Such patients are eligible for implantable cardioverter-defibrillator (ICD) implantation. The dominant observation was that the larger the extent of the
123I-mIBG SPECT abnormality, the higher the likelihood of ventricular tachyarrhythmia.
34123I-mIBG scintigraphy was approved after the multicenter prospective study ADMIRE-HF showed a significant correlation between decreased late H/M and increased risk of HF progression, ventricular tachyarrhythmia, and death.
26 Several studies investigated the prognostic value of
123I-mIBG scintigraphy in patients with chronic HF. A systematic review explored the prognostic significance of
123I-mIBG planar-imaging-derived parameters and indicated that patients with HF and decreased late H/M or increased WO, have a worse prognosis compared with patients with normal parameters.
27
To date few studies, mainly evaluating relatively small samples of patients, focused on the prognostic significance of
123I-mIBG SPECT imaging derived parameters. Basically, data obtained by SPECT tomographic imaging have been applied in the same way as planar scintigraphic ones: to evaluate the potential correlation between
123I-mIBG semi-quantitative uptake scores and specific outcomes, like the occurrence of AE and SCD.
35,
36 Therefore, this systematic review aimed to collect sets of SPECT quantitative data from published studies to derive more accurate evidence of their prognostic value; a systematic process was adopted to avoid all possible selection bias. The methodological work-up in conducting a systematic review carries unavoidably with it some biases and limitations. First of all publication itself represents a primary source of bias as studies showing significant results are more likely to be published than studies reporting non-significant findings, therefore only complete studies taking into account the role of
123I-mIBG SPECT imaging in relation with planar imaging were considered. Therapy could represent another potential source of bias. In most of the studies included in this systematic review, the authors stated that the patient population was treated with either beta-blockers, Angiotensin-converting-enzyme inhibitors (ACE), or Angiotensin II Receptor Blockers (ARBs), but this was not homogeneous criteria. Only some authors specified that the patients were not undergoing treatment with tricyclic antidepressants or other medications that are known to interfere with mIBG uptake.
37,
38 The inclusion criteria were homogeneous for most but not all studies (NYHA class II or III, left ventricular ejection fraction LVEF ≤35%, indication for ICD implantation) hence the heterogeneity of the patient population can represent an additional source of bias. In particular, since most of the samples were extracted from patients affected by chronic HF, the absent discrimination between ischemic and non-ischemic events among such patients could be a source of error. 12 out of 16 studies assembling SPECT slices in polar maps of 17 segments were performed on patients with chronic HF, in order to predict AE or SCD in such patients. In these studies, the tracer uptake was graded on a scale of 0-4 (0=normal; 1=mildly reduced; 2=moderately reduced; 3=severely reduced; 4 = absent), and the SDS was calculated by summing the scores for each segment. All these studies stated that an increased summed score is suggestive of an increased risk for AE or SCD and associated with a worse prognosis in such patients. Most of the patients with an increased summed score also show a H/M ratio < 1.60, therefore demonstrating a good correlation between the tomographic and the planar imaging parameters. Another parameter, the regional
123I-mIBG rWO, calculated on SPECT imaging, was considered in one of these studies. It was calculated by subtracting the minimum rWO among 17 segments. The abnormal rWO was defined as both the rWO range and maximum rWO > mean value + 2SD obtained in 15 subjects.
39 This SPECT parameter was significantly associated with SCD. An increased rWO, according to Doi et al.,,
40 is associated with cardiac events in patients with chronic HF, suggesting a good prognostic value of this parameter.
Nevertheless, controversies remain on whether the best parameter to assess such risks remains the H/M on planar images. Indeed, most of the authors recognize as a major limitation to their studies the low sample size and the fact that additional studies are needed to establish the role of
123I-mIBG SPECT. Furthermore, the population of patients was heterogeneous since it doesn’t discriminate the etiology of chronic HF between ischemic and non-ischemic.
13 A recent study
41 assembling SPECT slices in polar maps of 20 instead of 17 segments was included in this review,
42 having similar outcomes in terms of SPECT SDS in correlation with prognosis in patients with chronic HF.
43 Several studies tried to apply
123I-mIBG SPECT in different ways. Somsen et al.
44 described a new method to quantitative myocardial mIBG uptake, considering eighteen
123I-mIBG SPECT studies of patients with chronic HF. Myocardial uptake is calculated from the myocardial to left ventricular cavity count density ratio and the
123I activity in a blood sample. This was performed employing single-slice SPECT and multi-slice SPECT methods. The first compares different ROIs: mediastinum (M), right lung (L), left ventricular cavity (C), and the entire myocardium (MYO). The second analyzes semi-automatically drawn volumes of interest (VOIs). The single-slice SPECT method showed poor reproducibility than the multi-slice SPECT method that is a reproducible and accurate technique for the assessment of myocardial
123I-mIBG uptake but further evaluations of this method are needed.
45–48 Another study
49 examined the association between left ventricular mechanical dyssynchrony and cardiac sympathetic denervation with potential SCD events in the ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) trial. The ADMIRE-HF subject had rest gated SPECT Technetium-99 metastable (
99mTc)-Tetrofosmin and
123I-mIBG imaging. Thanks to SPECT myocardial perfusion imaging, it was possible to determine the phase standard deviation, an index of mechanical dyssynchrony, through which it was observed an association between left ventricular mechanical dyssynchrony and SCD events in symptomatic patients with HF and reduced EF.
Conclusions
Data from this systematic review suggest that patients affected by chronic HF, including those receiving an ICD, with a high SPECT SDS, an increased rWO, or, either way, reduced tracer uptake in specific segments of the myocardium, have an increased risk of developing AE or SCD, with a worse prognosis with respect to patients with a low SDS. In any case, it seems clear that additional studies must be performed and an automated quantitative analysis system must be adopted for 123I-mIBG SPECT since the lack of standardized methods makes the comparison difficult between different studies and the sharing of data between different centers, to reach the same reliable prognostic value as planar 123I-mIBG scintigraphy.
Disclosures
Mariano Pontico, Gabriele Brunotti, Miriam Conte, Ferdinando Corica, Laura Cosma, Cristina De Angelis, Maria Silvia De Feo, Julia Lazri, Antonio Matto, Melissa Montebello, Arianna Di Rocco, Viviana Frantellizzi, Alessio Farcomeni, and Giuseppe De Vincentis have no conflicts of interest to declare.
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