Phase dyssynchrony and 123I-meta-iodobenzylguanidine innervation imaging towards standardization

Journal of Nuclear Cardiology, Sep 2017

Kenichi Nakajima MD, PhD, Koichi Okuda PhD, Hein J. Verberne MD, PhD

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Phase dyssynchrony and 123I-meta-iodobenzylguanidine innervation imaging towards standardization

Received Sep 123 Phase dyssynchrony and I-meta- iodobenzylguanidine innervation imaging towards standardization Kenichi Nakajima 0 3 Koichi Okuda 1 3 Hein J. Verberne 3 0 Department of Nuclear Medicine, Kanazawa University Hospital, Kanazawa University , Kanazawa , Japan 1 Department of Physics, Kanazawa Medical University , Uchinada, Kahoku , Japan 2 Department of Radiology and Nuclear Medicine, Academic Medical Center, University of Amsterdam , Amsterdam , The Netherlands 3 Reprint requests: Kenichi Nakajima , MD, PhD , Department of Nuclear Medicine, Kanazawa University Hospital, Kanazawa University , 13-1 Takara-machi, Kanazawa, ZIP 920-8641 , Japan - Over the last decades, semi-quantitative analysis has become crucial in the assessment of myocardial perfusion scintigraphy. Through widely available software packages, electrocardiographically (ECG) gated myocardial perfusion single-photon emission computed tomography (SPECT) quantitative parameters of left ventricular (LV) function are easily obtainable. These software algorithms have increased worldwide consistency and improved quality of myocardial perfusion scintigraphy in the assessment of the total ischemic burden, left ventricular (LV) volumes, and left ventricular ejection fraction (LVEF). In general, these software algorithms have standardized the interpretation of ECG gated myocardial perfusion SPECT. However, for other parameters of left ventricular function such as phase analysis of ECG gated myocardial perfusion SPECT and regional analysis of cardiac sympathetic imaging with 123I-meta-iodobenzylguanidine (123I-mIBG), standardization is still not reached. This lack of standardization hampers the widespread clinical use of the potentially very valuable parameters obtained with phase analysis and 123I-mIBG quantitation methods. GLOBAL AND REGIONAL 123I-MIBG MYOCARDIAL UPTAKE PARAMETERS The necessity of standardizing global 123I-mIBG myocardial uptake, has already been emphasized.1?3 In particular for the assessment of the heart-to-mediastinum ratio (HMR) on planar images, it has been shown that the accuracy of the HMR is significantly influenced by variations in camera-collimator systems.4 However, the recent development of a calibration phantom-based standardization method provides optimal conversion coefficients for most of the Anger-type camera-collimator combinations.5,6 The standardization method could be applied to cadmium-zinc-telluride (CZT) cameras, either by empirical conversion equation between two systems with a phantom study7,8 or calibration phantom experiments as described for Anger cameras.9 On the other hand, the assessment of regional 123ImIBG uptake with SPECT has not been standardized so rigorously yet. Scoring methods as used in myocardial perfusion SPECT with a 17-segment model and percent of voxels with counts below the lower limit of normal have been described.10,11 Important to realize is that the normal distribution of 123I-mIBG on SPECT shows lower uptake in the inferior and apical regions (Figure 1). This lower uptake is not explained by attenuation as seen in myocardial perfusion images. A number of studies used a visual semi-quantitative approach partly aided by percent uptake of each segment and mismatch between perfusion and innervation as well.12,13 Normal databases as commonly used in myocardial perfusion SPECT could be an option for a standardized 123I-mIBG SPECT analysis. However, the 123I-mIBG databases as used by the Japanese Society of Nuclear Medicine working groups have not been created for clinical use outside of Japan.14 These databases would be of interest as they use the same approach as used for myocardial perfusion SPECT. However, when there is an overall decreased 123I-mIBG myocardial uptake, myocardial regions corresponding to 100% count cannot be determined appropriately. In other words, this quantification assumes that at least one myocardial region has normal sympathetic activity. In this respect, imaging with CZT could provide high resolution and sensitivity, which could potentially enhance the accuracy of regional scores based on 123I-mIBG SPECT imaging. 15 Obviously, nearly complete decreased 123I-mIBG uptake as seen in Lewy-body disease and very severe heart failure may result in the maximal defect score of 68 (17 segments 9 4 points). In addition, perfusion images combined with 123I-mIBG images may be helpful for a better risk analysis.12 Another approach for SPECT is the summation of all myocardial slices to calculate myocardial uptake, and then calculate the uptake in relation to the mediastinal uptake, similar to the planar approach.11,16 Although such whole-heart SPECT analysis has been reported, the impact on the diagnosis or prognosis has not yet been demonstrated.16 Most promising seems the use of x-ray computed tomography-based attenuation and scatter corrections resulting in absolute quantification in Bq/ cm3 for 123I-mIBG SPECT, similar to the standardized uptake value as used in positron emission tomography. However, the exact role of this exciting methodology for the calculation of absolute 123I-mIBG uptake in establishing diagnosis and prognosis needs to be investigated first before it can be applied to clinical practice. GLOBAL PHASE VS REGIONAL PHASE ANALYSIS The principle of phase analysis was developed in 1980s, and subsequently applied to gated SPECT.17 The application of phase analysis has also been described for modern CZT technology-driven cameras.18 Whereas phase dyssynchrony parameters have provided potentially promising results, such as for the prediction of response to cardiac resynchronization therapy,19 it is not yet standardized. Variations of the phase values, namely differences in timing of contraction, using standard deviation (SD) and 95% bandwidth of the phase histogram are most often included.20 Time-activity curves in 17 segments may also be used to evaluate regional variations of time to end-systole.21 Although phase distribution is usually analyzed using a histogram, peak phase value is influenced by the shape of regional time-activity curves. When the shape is symmetric, the peak value will be around 180 (for example, during tachycardia), and when asymmetric (for example, low heart rate with a long diastolic phase), the peak value will be around 140 -160 . Therefore, SD and bandwidth are commonly used for the dyssynchrony analysis. However, all these parameters are influenced by the administrated tracer dose, body weight, statistical noise, sampling method over the myocardium, filtering, and the number of bins used for the histogram.22 There are several commercial software programs available, including Emory Cardiac Toolbox (Emory University/Syntermed, Atlanta, GA, USA), QGS (Cedars Sinai Medical Center, Los Angeles, CA, USA), Corridor 4DM (INVIA Medical Imaging Solutions, Ann Arbor, MI, USA), cardioREPO (FUJIFILM RI Pharma, Tokyo, Japan), and Heart Function View (or Heart Risk View-F, Nihon MediPhysics, Tokyo, Japan). It is important to realize that normal values depend on software programs.21 Therefore, the characteristics of each software program including normal ranges should be carefully established before use in clinical practice.23 Figure 2 shows phase maps created in a patient with a myocardial infarction of the apical anterior wall and apex. The images clearly show the variation between the different software programs used. In order to evaluate regional phase abnormalities, deviance of the mean segmental value of a control segment/region may be analyzed. This kind of analysis may be used to identify the earliest phase in ventricular pacing sites, may help to establish the presence of a preexcitation syndrome, and to determine the latest phase in a dyssynchronous area.15 COMPARISON BETWEEN 123I-MIBG AND PHASE PARAMETERS To integrate parameters of innervation, perfusion, and phase values, various combinations could be selected. When global 123I-mIBG and phase parameters are compared, standardized HMR and ??standardized?? (but not yet validated) phase values such as SD, bandwidth, and entropy may be used. In typical situations of myocardial infarction, defect score is large, HMR is decreased, 123I-mIBG defect score is high, and phase variations will be large, resulting in some correlation among these parameters. When regional 123I-mIBG and perfusion are compared, the simplest approach is visual analysis of match and mismatch. In this issue of the Journal of Nuclear Cardiology, Gimelli et al have compared different parameters of perfusion, innervation, and dyssynchrony.15 LV walls with delayed mechanical activation showed a higher burden of innervation/perfusion mismatch than normally contracting walls. The extent of mismatch was the only predictor of delayed mechanical activation. How this mismatch relates to specific pathophysiology, diagnosis, or prognosis including arrhythmogenicity needs to be further investigated. While the results are intriguing, the dyssynchrony analysis is dependent on the cut-off values used. More importantly, variation between different software algorithms makes extrapolation of the findings troublesome. This only further stresses the necessity for standardized approaches for myocardial perfusion imaging, 123ImIBG innervation imaging, and assessment of left ventricular dyssynchrony. Acknowledgments SPECT data were from Kanazawa University Hospital, Kanazawa, Japan, and Kaga Medical Center, Kaga City, Japan. Disclosure K. Nakajima collaborates with FUJIFILM RI Pharma, Tokyo, Japan to develop cardioREPO and 123I-mIBG software. K. Okuda and H. Verberne have nothing to declare. 1. Verberne HJ . Assessment of cardiac sympathetic innervation with 123I-mIBG SPECT comes to life: Need for standardization ! Eur Heart J Cardiovasc Imaging 2016 ; 17 : 391 - 2 . 2. Nakajima K , Verschure DO , Okuda K , Verberne HJ . Standardization of 123I-meta-iodobenzylguanidine myocardial sympathetic activity imaging: Phantom calibration and clinical applications . Clin Transl Imaging 2017 ; 5 : 255 - 63 . 3. Nakajima K , Yamada M. 123I-meta-iodobenzylguanidine sympathetic imaging: Standardization and application to neurological diseases . Chonnam Med J 2016 ; 52 : 145 - 50 . 4. Verberne HJ , Feenstra C , de Jong WM , Somsen GA , van Eck-Smit BL , Busemann Sokole E. Influence of collimator choice and simulated clinical conditions on 123I-MIBG heart/mediastinum ratios: A phantom study . Eur J Nucl Med Mol Imaging 2005 ; 32 : 1100 - 7 . 5. Nakajima K , Okuda K , Yoshimura M , Matsuo S , Wakabayashi H , Imanishi Y , Kinuya S . Multicenter cross-calibration of I-123 metaiodobenzylguanidine heart-to-mediastinum ratios to overcome camera-collimator variations . J Nucl Cardiol 2014 ; 21 : 970 - 8 . 6. Verschure DO , Poel E , Nakajima K , Okuda K , van Eck-Smit BL , Somsen GA , Verberne HJ . A European myocardial 123I-mIBG cross-calibration phantom study . J Nucl Cardiol . 2017 . doi: 10 .1007/s12350-017-0782-6. 7. Bellevre D , Manrique A , Legallois D , Bross S , Baavour R , Roth N , Blaire T , Desmonts C , Bailliez A , Agostini D. First determination of the heart-to-mediastinum ratio using cardiac dual isotope 123I-MIBG / 99mTc-tetrofosmin) CZT imaging in patients with heart failure: The ADRECARD study . Eur J Nucl Med Mol Imaging 2015 ; 42 : 1912 - 9 . 8. Blaire T , Bailliez A , Ben Bouallegue F , Bellevre D , Agostini D , Manrique A . Determination of the heart-to-mediastinum ratio of 123I-MIBG uptake using dual-isotope (123I-MIBG/99mTc-tetrofosmin) multi-pinhole CZT SPECT in patients with heart failure . J Nucl Med 2017 . doi: 10 .2967/jnumed.117.194373. 9. Nakajima K , Okuda K , Yokoyama K , Yoneyama T , Tsuji S , Oda H , Yoshita M , Kubota K. Cross calibration of 123I-metaiodobenzylguanidine heart-to-mediastinum ratio with D-SPECT planogram and Anger camera . Ann Nucl Med 2017 . doi: 10 .1007/s12149-017-1191-2. 10. Boogers MJ , Borleffs CJ , Henneman MM , van Bommel RJ , van Ramshorst J , Boersma E , Dibbets-Schneider P , Stokkel MP , van der Wall EE , Schalij MJ , Bax JJ . Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverterdefibrillator patients . J Am Coll Cardiol 2010 ; 55 : 2769 - 77 . 11. Clements IP , Kelkar AA , Garcia EV , Butler J , Chen J , Folks R , Jacobson AF . Prognostic significance of (123)I-mIBG SPECT myocardial imaging in heart failure: Differences between patients with ischaemic and non-ischaemic heart failure . Eur Heart J Cardiovasc Imaging 2016 ; 17 : 384 - 90 . 12. Travin MI , Henzlova MJ , van Eck-Smit BL , Jain D , Carrio I , Folks RD , Garcia EV , Jacobson AF , Verberne HJ . Assessment of ImIBG and Tc-tetrofosmin single-photon emission computed tomographic images for the prediction of arrhythmic events in patients with ischemic heart failure: Intermediate severity innervation defects are associated with higher arrhythmic risk . J Nucl Cardiol 2016 ; 24 : 377 - 91 . 13. Verschure DO , de Groot JR , Mirzaei S , Gheysens O , Nakajima K , van Eck-Smit BLF , Somsen GA , Verberne HJ . Cardiac 123ImIBG scintigraphy predicts freedom of appropriate ICD therapy in stable chronic heart failure patients . Int J Cardiol 2017 . doi: 10 .1016/j.ijcard. 2017 . 08 .003. 14. Nakajima K , Matsumoto N , Kasai T , Matsuo S , Kiso K , Okuda K. Normal values and standardization of parameters in nuclear cardiology: Japanese Society of Nuclear Medicine working group database . Ann Nucl Med 2016 ; 30 : 188 - 99 . 15. Gimelli A , Liga R , Menichetti F , Soldati E , Bongiorni MG , Marzullo P . Interactions between myocardial sympathetic denervation and left ventricular mechanical dyssynchrony: A CZT analysis . J Nucl Cardiol 2017 . doi: 10 .1007/s12350-017-1036-3. 16. Chen J , Folks RD , Verdes L , Manatunga DN , Jacobson AF , Garcia EV . Quantitative I-123 mIBG SPECT in differentiating abnormal and normal mIBG myocardial uptake . J Nucl Cardiol 2012 ; 19 : 92 - 9 . 17. Chen J , Garcia EV , Folks RD , Cooke CD , Faber TL , Tauxe EL , Iskandrian AE . Onset of left ventricular mechanical contraction as determined by phase analysis of ECG-gated myocardial perfusion SPECT imaging: Development of a diagnostic tool for assessment of cardiac mechanical dyssynchrony . J Nucl Cardiol 2005 ; 12 : 687 - 95 . 18. Gimelli A , Liga R , Giorgetti A , Favilli B , Pasanisi EM , Marzullo P . Determinants of left ventricular mechanical dyssynchrony in patients submitted to myocardial perfusion imaging: A cardiac CZT study . J Nucl Cardiol 2016 ; 23 : 728 - 36 . 19. Boogers MM , Van Kriekinge SD , Henneman MM , Ypenburg C , Van Bommel RJ , Boersma E , Dibbets-Schneider P , Stokkel MP , Schalij MJ , Berman DS , Germano G , Bax JJ . Quantitative gated SPECT-derived phase analysis on gated myocardial perfusion SPECT detects left ventricular dyssynchrony and predicts response to cardiac resynchronization therapy . J Nucl Med 2009 ; 50 : 718 - 25 . 20. Van Kriekinge SD , Nishina H , Ohba M , Berman DS , Germano G . Automatic global and regional phase analysis from gated myocardial perfusion SPECT imaging: Application to the characterization of ventricular contraction in patients with left bundle branch block . J Nucl Med 2008 ; 49 : 1790 - 7 . 21. Nakajima K , Okuda K , Matsuo S , Kiso K , Kinuya S , Garcia EV . Comparison of phase dyssynchrony analysis using gated myocardial perfusion imaging with four software programs: Based on the Japanese Society of Nuclear Medicine working group normal database . J Nucl Cardiol 2016 ; 24 : 611 - 21 . 22. Nakajima K , Okuda K , Matsuo S , Slomka P. Making the invisible visible: Phase dyssynchrony has potential as a new prognostic marker . J Nucl Cardiol 2017 . doi: 10 .1007/s12350-017-0929-5. 23. Okuda K , Nakajima K , Matsuo S , Kashiwaya S , Yoneyama H , Shibutani T , Onoguchi M , Hashimoto M , Kinuya S . Comparison of diagnostic performance of four software packages for phase dyssynchrony analysis in gated myocardial perfusion SPECT . EJNMMI Res . 2017 ; 7 : 27 .

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Kenichi Nakajima MD, PhD, Koichi Okuda PhD, Hein J. Verberne MD, PhD. Phase dyssynchrony and 123I-meta-iodobenzylguanidine innervation imaging towards standardization, Journal of Nuclear Cardiology, 2017, 1-5, DOI: 10.1007/s12350-017-1069-7