International Journal of Cardiology xxx (2013) xxx–xxx

IJCA-15696; No of Pages 3

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International Journal of Cardiology

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Letter to the Editor

Quantitative 123I-MIBG SPECT/CT assessment of cardiac sympathetic innervation— Anew diagnostic tool for heart failure☆,☆☆

Shmuel Rispler a,b,c, Alex Frenkel b, Eleonora Kuptzov b, Yafim Brodov a,b, Ora Israel b,c, Zohar Keidar b,c,⁎a Department of Cardiology, Rambam Health Care Campus, Haifa, Israelb Department of Nuclear Medicine, Rambam Health Care Campus, Haifa, Israelc B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

☆ All the above authors take responsibility for all aspdom from bias of the data presented and their discusse☆☆ Funding sources: This work was supported in part

⁎ Corresponding author at: Department of Nuclear MCampus, POB 9602, Haifa 31096, Israel. Tel.: +972 4 85

E-mail address: z_keidar@rambam.health.gov.il (Z.

0167-5273/$ – see front matter © 2013 Elsevier Irelandhttp://dx.doi.org/10.1016/j.ijcard.2012.12.077

Please cite this article as: Rispler S, et al, Qutic tool for heart failure, Int J Cardiol (2013

a r t i c l e i n f o

Article history:

Received 8 November 2012Accepted 25 December 2012Available online xxxx

Keywords:MIBGHeart failureSPECT/CT

tools for measurements of cardiac MIBG kinetics. The purpose of thepresent study was to develop a quantitative index for the assessmentof cardiac MIBG uptake kinetics for diagnosis of HF using SPECT/CTmeasurements.

Fifty-three patients (27 males, 26 females; mean age, 58±12 y;age range, 37–80 y), who were referred for MIBG scintigraphy forassessment of known or suspected neuroendocrine tumors wererecruited. The patients were interviewed and examined specificallyfor the presence of HF according to the NYHA classification. Forty

The sympathetic and parasympathetic innervation of the heartplays a major role in the regulation of cardiac function. Sympatheticnerve activity is associated with unfavorable prognosis of left ventric-ular dysfunction [1,2]. Iodine-123 labeled metaiodobenzyl-guanidine(MIBG) shares many cellular uptake and storage properties with nor-epinephrine (NE), and has been used to evaluate cardiac sympatheticnervous distribution and function [3]. Myocardial distribution andwashout of MIBG from the heart differ significantly between controlsand patients with severe, nonischemic, dilated cardiomyopathy [4].MIBG imaging of the heart also appears to have significant prognosticvalue [5]. Semiquantitative assessment of cardiac MIBG uptake usingthe heart to mediastinum ratio (HMR) has been performed on earlyplanar static scintigraphy, at 10 min after tracer administration. A re-duced HMR was an indicator of poor prognosis in cardiomyopathy,regardless of the etiology [6] and a predictor of death in New YorkHeart Association (NYHA) class II–IV patients with dilated cardiomy-opathy [7]. However, in cases of scatter from organs such as the liverand in patients with severe heart failure (HF) and a significant de-crease in cardiac MIBG uptake, drawing region of interest (ROI) onplanar scans may be inaccurate. HMR measurement may be furtherinfluenced by a high inter-individual and within-subject variability[8]. These limitations of the HMR technique as well as the clinicalneed for accurate data regarding the sympathetic innervation of the

ects of the reliability and free-d interpretation.by GE Healthcare.edicine, Rambam Health Care43009; fax: +972 4 8543011.Keidar).

Ltd. All rights reserved.

antitative 123I-MIBG SPECT/), http://dx.doi.org/10.1016/

heart provide a compelling rationale to develop precise quantitative

one patients had no known or proven heart disease (non-HF) while12 patients were diagnosed as having HF. In conformity to the ethicalguidelines of the 1975 Declaration of Helsinki, this investigation wasconducted with the approval of the Institutional and Ethical ReviewBoard at Rambam Medical Center in respect to clinical care, laborato-ry investigation, informed consent of all patients and study protocol.The authors of this manuscript have certified that they comply withthe Principles of Ethical Publishing in the International Journal ofCardiology [9]. Imaging was performed after an intravenous (IV)injection of 148 MBq (4 mCi) of 123I-MIBG (123I MIBG — AdreView,GE Healthcare). In addition to the routine neuroendocrine tumor as-sessment protocol, all patients underwent a sequence of three cardiacSPECT/CT studies at 15 min, 4 h and 24 h post injection using a hybridSPECT/CT device (GE Millennium VG/Hawkeye). Low dose CT datawere used for photon attenuation correction as well as for preciseanatomical localization of the boundaries of the heart. In a subgroupof 41 patients (34 without HF and 7 with HF) planar images of thechest were also performed at 10 min after the injection for an acquisi-tion time of 5 min for calculation of the HMR. Total cardiac MIBGuptake was measured in a bullet shaped volume of interest (VOI)centered on the left ventricle as determined on the correspondingCT image (Fig. 1). The percent of injected dose per cm3 (%ID/cm3) ofMIBG were measured for each study, and corrected for decay. Foreach patient data obtained in the 3 consecutive studies were used tocalculate the slope values. The %ID/cm3 calculated for all three timepoints were fitted using linear regression analysis and the standarderror of estimate (SEE) was evaluated. The MIBG clearance slope wasobtained from the regression analysis (%ID/cm3/h), representing theclearance rate of MIBG from the heart. HMR was calculated on planarchest images obtained 10 min after injection. The mediastinum ROIand the myocardial ROI including the left ventricular cavity weredrawn according to previously described methodology [10].

CT assessment of cardiac sympathetic innervation — A new diagnos-j.ijcard.2012.12.077

Fig. 1. A bullet shaped ROI over the heart is defined using the CT. The ROI in the three planes are used to calculate the VOI of the whole heart. a) non-HF patient 4 h after MIBGadministration. b) HF patient 4 h after MIBG administration. Total cardiac MIBG counts can be measured on the tomographic slices within the boundaries of the heart delineatedby the CT component even in cases in which the MIBG uptake is very low, as is the case in many of the patients with HF.

2 S. Rispler et al. / International Journal of Cardiology xxx (2013) xxx–xxx

The MIBG clearance slope was evaluated for its ability to sepa-rate patients with and without HF. The non-parametric Mann–Whitney U test was used to compare HF and non-HF patients. A pvalue b0.05 was considered statistically significant. Receiver Oper-ating Curve (ROC) analysis was performed in order to obtain athreshold clearance slope value for further assessment of perfor-mance indices of quantitative cardiac MIBG SPECT/CT for the diag-nosis of HF.

The MIBG clearance slope obtained in HF patients was 0.13±0.06 (SEE=0.06) vs. 0.29±0.09 (SEE=0.06) %ID/cm3/h in non-HFpatients (pb0.001). Using ROC analysis, a threshold value of0.23%ID/cm3/h, gave the best performance of 100% sensitivity and76% specificity for differentiating between HF and non-HF patients.In the subgroup of patients in whom the HMR was calculatedthere was no statistically significant difference in HMR between

Please cite this article as: Rispler S, et al, Quantitative 123I-MIBG SPECT/tic tool for heart failure, Int J Cardiol (2013), http://dx.doi.org/10.1016/

patients with and without HF (1.8±0.3 vs. 1.9±0.2, p=N.S.). TheMIBG clearance slope distribution for HF and non-HF patients isshown in Fig. 2.

This study demonstrated that total cardiac MIBG counts can bemeasured on the tomographic slices within the boundaries of theheart delineated by the CT component even in cases in which theMIBG uptake is very low. In contrary to most of the studies aimedat evaluating the prognostic value of cardiac MIBG uptake in heartfailure patients, the present study assessed and compared this pa-rameter in heart failure and normal patients. In the current studypatients with HF were found to have a significantly lower MIBGclearance slope as compared with non-HF patients. If confirmed byfurther studies SPECT/CT measured cardiac MIBG clearance may po-tentially represent an accurate index for early diagnosis and moni-toring response to treatment in patients with HF.

CT assessment of cardiac sympathetic innervation — A new diagnos-j.ijcard.2012.12.077

Fig. 2. The MIBG clearance slope distribution for HF (red columns) and non-HF (purple columns) patients. The solid black horizontal line represents the threshold value of 0.23obtained from ROC analysis.

3S. Rispler et al. / International Journal of Cardiology xxx (2013) xxx–xxx

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Please cite this article as: Rispler S, et al, Quantitative 123I-MIBG SPECT/tic tool for heart failure, Int J Cardiol (2013), http://dx.doi.org/10.1016/

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CT assessment of cardiac sympathetic innervation — A new diagnos-j.ijcard.2012.12.077