Cardiac Perfusion and Innervation Assessment by CZT-SPECT: Have a Look to Simultaneous Dual-isotope Protocol

The purpose of this review is to provide a summary on the status of the art of simultaneous perfusion-innervation imaging by CZT-SPECT and to clarify its potential applications in clinical practice. Introduction of CZT cameras represented a critical breakthrough in nuclear cardiology. Although it has been demonstrated that cardiac innervation may be easily assessed by CZT-SPECT, as for now, there are only few studies investigating cardiac perfusion and innervation with simultaneous dual-isotope imaging by CZT cameras. Perfusion and innervation assessment by CZT camera is a feasible tool, allowing to reduce radiation dose exposure and acquisition time, thanks to CZT better spatial, temporal, and energy resolution, with higher compliance by patients. Moreover, this technique allows to integrate regional evaluation of myocardial perfusion/innervation status, providing more accurate information for risk stratification of different cardiac disease.


Introduction
Cardiac adrenergic innervation imaging by 123I-metaiodobenzylguanidine (mIBG) single-photon emission computed tomography (SPECT) is recognized as a useful tool in risk stratification and disease assessment in patients with heart failure (HF), ischemic heart disease (IHD), and other conditions affecting cardiac sympathetic activity [1][2][3][4][5]. AdreView Myocardial Imaging Evaluation in Heart Failure (ADMIRE-HF) is the first multicentric study to demonstrate that 123I-mIBG imaging-derived parameters, such as late heart-to-mediastinum ratio (HMR) and washout rate (WR), may suggest the presence of sympathetic dysfunction and are linked to the HF worsening, worst response to implantable cardiac device (ICD) therapy, and increased occurrence of fatal cardiac events [5]. The 123I-mIBG HMR and WR are easily obtained by a static planar acquisition of chest, including in the field of view (FOV) both heart and mediastinum. Moreover, a further SPECT acquisition may provide a regional evaluation of 123I-mIBG distribution allowing to combine and compare these findings with parameters obtained by myocardial perfusion imaging (MPI), such as extent and severity of myocardial perfusion defect and dyssynchrony [6][7][8]. Although the combined assessment of myocardial perfusion and innervation could provide more information compared to the only HMR evaluation in risk assessment of HF patients, the dual protocol with 123I-mIBG and a perfusion tracer is still not widely feasible in clinical practice, because of the high radiation exposure required by standard Anger camera and long SPECT acquisition time. On the other hand, there is increasing evidence that solid-state cameras with cadmium-zinc-telluride (CZT) detectors may overcome some of the standard Anger camera limitations, due to the higher spatial and energy resolution, providing the possibility for a low-dose protocol with higher image quality both for perfusion and innervation imaging, lower imaging acquisition time, and scatter correction availability [9][10][11][12]. Considering all these aspects, it is reasonable to expect that simultaneous global and regional myocardial perfusion, innervation, and functional assessment by CZT-SPECT may be a valuable tool, along with a significant benefit for patients [12,13]. The field of application of simultaneous dual-isotope (SDI) cardiac imaging by CZT-SPECT seems to be wide but, as for our knowledge, is still uncharted and only few studies documented the value of CZT-SPECT SDI-derived parameters and the feasibility of this acquisition protocol in clinical practice [14•, 15•, 16•, 17•]. Thus, this review article aims to provide the state of the art of combined dual myocardial perfusion/innervation imaging, underling the effective advantages and potential applications of SDI by CZT-SPECT in clinical practice.

Technical Features of Dual Acquisition: Limitations and Possible Solutions
According to the recommendations of the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology, 123I-mIBG imaging acquisition protocol with Anger camera consists of two planar acquisitions of the chest performed 15 min (early) and 4 h (delay) after 123I-mIBG administration, allowing the assessment of, respectively, early and late HMR and WR. These parameters are derived from planar images, drawing manually two regions of interest (ROIs), one on the heart and one on the mediastinum, and comparing each pixel's radioactivity counts [1]. The protocol described in literature as simultaneous perfusion/innervation imaging by Anger camera consists in two separate imaging acquisitions, with the administration of a perfusion tracer, 99mTc-Sestamibi or 99mTc-tetrofosmin, after a variable interval time (ranging from 15 min to 7 days, according to different authors) since 123I-mIBG injection (Fig. 1) [5][6][7][8]. Despite that this technique including two separate imaging studies seemed quite easy to perform, its clinical use is still negatively affected by lack of standardization in injection dose, protocol acquisition, imaging time, and imaging elaboration, causing low reproducibility among different centers [18,19]. One of the main limiting factors is due to the presence of 123I high-energy photon emission, over the main photopeak of 159 keV, which may penetrate collimator septa and affect image quality, especially when using low-energy (LE) collimators instead of medium energy (ME) ones [20][21][22]. This phenomenon, known as scatter effect, may be particularly impacting when acquiring perfusion/innervation studies in the same day, since the energy window of Anger camera is about 20% symmetrical and the main photopeak of 99mTc (140 keV) and 123I (159 keV) may overlap [23]. Thus, collimator choice, energy window width, and detector sensitivity have a dramatic impact on both image quality and semiquantitative parameters' reliability. The introduction of new CZT technology opened also new frontiers in the dual-isotope imaging approach. Two commercially available CZT cameras (D-SPECT by Spectrum Dynamics and DNM by GE) differ right in detector and collimator features: D-SPECT camera is equipped with 9 mobile detectors and tungsten wide-angle square parallel collimators, while GE camera features 19 fixed detectors with tungsten multi-pinhole collimators, both focused on heart [24,25]. Both cameras collect data by list-mode acquisition, which allows to perform SDI acquisition and to obtain two different images in one acquisition (Fig. 2), retrospectively selecting specific asymmetric energy windows: D-SPECT   [26][27][28][29][30][31][32]. By the CZT-SPECT cameras, the derived HMR is not calculated on planar images but on a planar equivalent image, planogram, obtained with different modalities according to each CZT-camera. D-SPECT planogram is the sum of two series of 2D images for each angular position [28]. GE DNM planogram may be obtained by reprojection of planar equivalent images or by using trans axial images. The use of trans axial images determines that more reliable values can be obtained, as it may avoid some truncation artifacts related to the multi-pinhole collimation and affect reprojection planogram [15•]. When performing SDI by CZT-SPECT, early and late HMR are obtained drawing manually the ROIs (if using planogram) or the volumes of interest (if using trans axial images) including the heart and the mediastinum on perfusion images. Then, the ROI is automatically copied on 123I-mIBG images corrected or non-corrected for scatter (Fig. 3), and HMR is calculated. Accordingly, the values obtained may be corrected according to attenuation, scatter, or a conversion factor to make them comparable with standard Anger camera [22,26,28]. As showed in Figs. 1 and 2, the overall time for a combined acquisition is completely different using the two different protocols. It should be outlined that CZT cameras directly provide a SPECT acquisition of 10 min compared to a further acquisition by Anger camera of 30-45 min [10, 12]. Previous studies compared the two different CZT cameras to an Anger camera, using both phantoms and clinical data acquired separately or simultaneously, demonstrating that 99mTc crosstalk into 123I energy window is irrelevant when SDI acquisition is performed by CZT camera [26][27][28][29][30][31][32]. Moreover, early and late HMR values obtained by this technique showed good agreement with those obtained by Anger camera especially when a correction factor is applied to uniform CZT camera values to those obtained by ME collimators [29]. Similarly, perfusion and LV functional assessment by SDI CZT-SPECT showed high overall agreement with single isotope imaging results, especially when using 99mTc tracers, the crosstalk, scatter effect, and tailing effect of 123I into 99mTc photopeak are negligible [30]. In fact, it has been demonstrated that perfusion/innervation defect size and mismatch quantification are neither influenced by the type of CZT camera, nor by acquisition time or mode [15 •]. Moreover, only a slight difference was found in LV volume assessment according to the type of camera, but this was not linked to the acquisition mode. Anyway, LV wall motion and thickening assessment showed a high agreement between perfusiononly and SDI acquisitions [30,31]. However, as showed in Table 2, most of the different clinical studies available  have provided combined data using a protocol with two different acquisitions, both by Anger camera and, as well, by CZT cameras. Thus, the main advantage to use a CZT camera allowing to perform two studies using one acquisition has not been fully utilized.

Clinical Applications: Emerging Evidence
From a clinical point of view, major goal of simultaneous imaging using dual-isotope approach allows to evaluate simultaneously global and regional perfusion/innervation defect severity, extent, and matching/mismatching, along with a functional assessment of LV parameters such LVEF, volumes, and mechanical dyssynchrony. Considering the promising results of previous phantom feasibility studies, researchers' interest is growing on SDI CZT-SPECT (one imaging for two tracers) for possible clinical applications [26][27][28][29][30][31][32]. In Table 3 are summarized the most recent clinical studies on CZT-SPECT SDI protocol (Fig. 2) IHD is characterized by both myocardial perfusion and adrenergic impairment, but usually LV 123I-mIBG uptake is reduced not only in necrotic regions (perfusion/innervation match), but also in ischemic and/or still viable regions (perfusion/innervation mismatch), which are more sensitive to catecholamine and may trigger VA. Using cardiac MRI as standard reference, the authors demonstrated that 201Tl and 123I-mIBG SDI is useful to evaluate the presence and the extent of these trigger zones, and to better stratify IHD patients according to their risk of developing VA. Moreover, this study highlighted the necessity of scatter correction for a reliable estimation of trigger zone extent, although clinical implications are not investigated yet. Recently, Assante et al. assessed the feasibility   MPI. Innervation defect on infero-lateral wall (red arrows) appears more severe than perfusion defect (white arrows) both at visual analysis and at semi-quantitative evaluation, suggesting a potential perfusion/innervation mismatch in infero-lateral region (yellow arrow) correlation with 123I-mIBG WR, which reflects adrenergic neuronal retention system impairment and is an independent predictor of fatal cardiac events. These preliminary studies are promising and enforce the need for wide prospective multicentric standardized trials to standardize the technical aspects of this approach and its possible clinical usefulness. Thus, the combined evaluation of late 123I-mIBG HMR and perfusion/innervation mismatch by CZT-SPECT may provide a useful tool to further stratify HF patients according to risk of VA and to ICD therapy response [33][34][35][36][37][38]. Clearly, the technique should be further standardized, and large prospective multicentric studies are required to investigate the real added value of SDI-derived novel parameters in diagnosis and prognosis of patients with HF. Other patients' categories could be involved in a SDI protocol, despite that lack of evidence till now does not support this hypothesis, considering that cardiac adrenergic innervation may result impaired in some conditions, like chronic kidney failure, obesity, and diabetes mellitus, where perfusion defect could be observed also in the absence of known CAD [2, 3, [39][40][41]. Some authors evaluated obesity impact on cardiac innervation assessment in a cohort of obese and non-obese HF patients concluding that obesity is associated with reduced early and late HMR [42]. Similarly, diabetes mellitus complications could include not only macrovascular and microvascular dysfunction, but also cardiac autonomic neuropathy, which may lead to silent myocardial ischemia and increased risk of fatal arrythmia [43,44]. It has been demonstrated that regional assessment of cardiac 123I-mIBG distribution is useful in diabetic patients with known CAD where perfusion assessment has important implications [43]. Moreover, 123I-mIBG imaging resulted useful also in documenting diabetes therapy response and in risk stratification even before the onset of microvascular impairment [44]. In such clinical scenarios, the opportunity to perform serial simultaneous global and regional perfusion/innervation assessment in a single 10-min acquisition seems to be very cost-effective in the management of diabetic patients. Similarly, some evidence reported the use of 123I-mIBG imaging in diagnosing cardiomyophaties like cardiac amyloidosis or chronic Chagas disease, both conditions that may lead to HF and fatal arrhythmia [45][46][47][48]. Moreover, it has been demonstrated that a massive catecholamine release, which happens typically in Tako-Tsubo cardiomyopathy, may cause myocardial stunning and reduce myocardial 123I-mIBG uptake [49].
Since each of these conditions may require further myocardial perfusion assessment, it appears clear the need for large, multicentric, and standardized trials to assess the real diagnostic and prognostic added value of performing perfusion/innervation SDI imaging by CZT-SPECT in different clinical scenarios [50][51][52]. Lastly, considering that CZT cameras allow high-quality listmode dynamic image acquisition for myocardial blood flow and perfusion reserve assessment [53,54], some preliminary studies on animals evaluated the feasibility of dynamic innervation imaging combined with gated MPI performed immediately before 123I-mIBG administration [55,56]. The authors concluded that dynamic 123I-mIBG kinetic analysis, considering tracer's uptake peak, may integrate the standard evaluation parameters like late HMR and WR, adding more information of 123I-mIBG myocardial distribution [55].

Conclusions
Simultaneous assessment of myocardial perfusion and innervation by dual-isotope CZT-SPECT is a feasible technique, proved to have many possible advantages over single-isotope evaluation in HF management, and promising data are emerging about its usefulness in many cardiac and systemic disease involving myocardial perfusion and innervation impairment. CZT cameras allow a dramatic reduction in dose exposure and acquisition time, with great patient's comfort and benefit. Thus, more studies are mandatory to standardize and validate this technique in clinical practice and to evaluate its real value in patients with cardiac disease. The farther the research goes, more applications may be implemented.
Funding Open access funding provided by Università degli Studi di Napoli Federico II within the CRUI-CARE Agreement.

Data Availability
The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information.

Conflict of Interest
The authors declare no competing interests.

Human and Animal Rights This article does not contain any studies with human or animal subjects performed by any of the authors.
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