I -123 metaiodobenzylguanidine imaging for predicting ventricular arrhythmia in heart failure patients

Weihua Zhou, Ji Chen

Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA 30322, USA.Received 04 September 2013, Accepted 16 September 2013, Epub 25 September 2013

INTRODUCTION

Heart failure (HF)is a prevalent, costly, and potentially deadly disease[1]. Around 5.1 million people in the United States had HF in 2009[2]. In developed countries, around 2% of adults suffer from HF[1,3]and about one-third of them are admitted to hospital each year[4]. The most common cause of HF is coronary artery disease (CAD), which is the main cause in nearly 70% of patients[5]. In the United States, more than half of all cardiac deaths are sudden deaths[6]and more than 80% of sudden deaths are caused by arrhythmia[7].

Therapies with antiarrhythmic drugs (AAD)and implantable cardioverter defibrillator (ICD)have been developed to prevent arrhythmias. A number of clinical trials have demonstrated the superiority of ICD over AAD in the prevention of death from ventricular arrhythmias[6,7]. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)[8]showed that HF patients with ICD therapy had an all-cause death risk of 23% lower than placebo and an absolute decrease in mortality of 7.2% after 5-year follow-up in the overall population.

Left ventricular ejection fraction (LVEF)is the main criterion used for ICD patient selection[9]. An LVEF of less than 40% may confirm a diagnosis of HF. An LVEF of less than 35% represents an increase of the risk of life-threatening arrhythmia. ICD therapy may be recommended for these patients. The updated 2009 guidelines of ACC/AHA associated with other institutes suggest[10]: ICD therapy is recommended for primary prevention of sudden cardiac death to reduce total mortality in patients with non-ischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-myocardial infarction (MI), a LVEF less than or equal to 35%, and New York Heart Association (NYHA)functional class II or III symptoms while receiving chronic optimal medical therapy, and who have reasonable expectation of survival with a good functional status for more than 1 year (Class I, Level of Evidence: A).

Although the recommendations based on LVEF provide an important guide in ICD installation, pivot trials and post-hoc studies have demonstrated that this predictor has numerous limitations. On one hand, ICD never discharges in a considerable number of patients who received ICD. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT)II, only 35%of patients received appropriate ICD shocks within 3-year follow-up. On the other hand, many arrhythmic deaths occur in a population who have a higher LVEF but are not qualified for ICD according to the guidelines. Moreover, the complications of ICD therapy during the surgery and long-term management limitations[8]may cause serious problems, including a 4%post-procedural complication rate[11], infection, device malfunction, worsened quality of life, psychiatric problems and life style restrictions[12,13].

Therefore, selection criteria better than LVEF are needed to improve patient selection for ICD therapy.Abnormalities of the sympathetic nervous system are thought to play an important role in the development of ventricular tachyarrhythmia[14,15]. It was found that the inducibility of ventricular tachyarrhythmia is related to regional cardiac sympathetic denervation as assessed by I-123 metaiodobenzylguanidine (MIBG)imaging[16,17]. Thus, cardiac I-123 MIBG imaging may improve the selection of heart failure patients who are at a high risk of ventricular arrhythmia and may benefit from ICD therapy[18].

This review paper introduces the recent advances in I-123 MIBG imaging for the prediction of ventricular arrhythmias and discusses the clinical value of I-123 MIBG imaging in patient selection for ICD therapy.

I-123 MIBG: AN AUTONOMIC TRACER TO ASSESS THE SYMPATHETIC NERVOUS SYSTEM

The neurohormonal system plays an important role in HF[19-22]. Initially, neurohormonal feedback mechanisms tend to compensate the hemodynamic consequences of cardiac dysfunction via positive inotropic and chronotropic effects. Consequently, these chronic neurohormonal effects may cause cardiac hypertrophy and fibrosis, thereafter remodeling. Moreover, downregulation of myocardial-adrenoceptors and alterations in postsynaptic signaling lead to further decline in cardiac function, creating arrhythmias.

In addition, a dysfunctional cardiac autonomic nervous system may also be related to the development of ventricular arrhythmias[23]. The regions with impaired innervation may be viable and hypersensitive to catecholamine, resulting in increased automaticity and enhanced triggering. In particular, the border zone of myocardial scar tissue may be predisposed to the development of re-entrant circuits because these regions are viable but may have damaged sympathetic nerves. The viable peri-infarct region can be partially denervated because sympathetic nerve fibers are more vulnerable to ischemia than cardiomyocytes. Consequently, important clinical and prognostic information in HF patients can be provided by assessment of cardiac sympathetic innervation.

MIBG, an analogue of norepinephrine, has been extensively applied to investigate sympathetic innervation[23]. After administration, MIBG is primarily transported into the pre-synaptic nerve terminal by sodium- and ATP-dependent transporters, referred to as uptake-1. In the nerve terminal, MIBG does notdegrade, resulting in an accumulation of MIBG with high signal intensity. The signals of MIBG labeled with I-123 permits visualization of myocardial sympathetic neuronal uptake. Thereafter, cardiac sympathetic nerve innervation can be analyzed by analyzing I-123 MIBG images, including review of planar images for global cardiac tracer uptake and tomographic images for regional cardiac trace uptake.

I-123 MIBG PLANAR IMAGING

Imaging protocols

I-123 MIBG planar images are usually obtained at approximately 15 minutes after MIBG administration (early scan), and again 3-5 hours later (late scan).There were several slightly different I-123 MIBG planar imaging protocols. In the pivot study by Kasama et al.[18], patients were injected intravenously with I-123 MIBG (111 MBq)in a supine position. At 15 min and at 4 h after injection, static data were acquired in the anterior view with a single-head gamma-camera.In the study by Boogers et al.[17], patients were pretreated with 120 mg of sodium iodide to block uptake of free I-123 by the thyroid gland. Sodium iodide was given orally 1 h before intravenous administration of 185 MBq I-123. I-123 MIBG planar imaging was performed in the supine position. A planar image was acquired for 10 minutes from an anterior thoracic view 10 to 15 min after tracer administration. Planar imaging was repeated after 3 to 4 hours of tracer administration. In both studies, 128×128 planar images were acquired with a 20% energy window centered around the 159-keV energy peak of I-123 MIBG.

Image processing and analysis

The standard parameters of I-123 MIBG planar imaging are heart-to-mediastinum ratio (HMR)and washout rate (WR)[9,16-18]. Using regions of interest(ROI)of the entire heart and upper mediastinum on planar images, the HMR is computed by dividing the mean pixel value within the myocardium by the mean pixel value within the mediastinum as shown in Fig. 1.

A high HMR value denotes greater tracer uptake and indicates normal heart conditions, while lower value signifies reduced adrenergic density and may have abnormal condition. HMR can be calculated for both early and late planar images, respectively.WR indicates the capability of the myocardium to retain tracer uptake. High WR is associated with increased risk. WR was calculated using the following equation[18]:

The HMR and WR in the planar image are considerably influenced by imaging systems, and location and size of the selected cardiac and mediastinal ROIs[24-27]. The normal HMR has been reported to be quite different in recent studies. A questionnaire survey is shown in Table 1. Taking into account the variation of these HMR, careful consideration should be taken when investigating HMR and WR with varied imaging systems and observations. A semi-automated method would be beneficial to reduce the interobserver variability. In a study by Okuda et al.[24], the only step requiring manual operation is specifying the center of circular cardiac contour. Automatic threshold and search of cardiac ROI and mediastinal ROI showed high reproducibility of this new method when tested in 37 patients.

Clinical results

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I-123 MIBG planar imaging may be useful for making decisions about patient selection for ICD therapy. A few studies evaluated the association of HMR with ICD discharges. Arora et al.[28]performed a pilot study in 17 advanced HF patients with ICD therapy. Patients with a recorded ICD discharge showed significantly greater early HMR than those without an ICD discharge. Nagahara et al.[29]evaluated 54 HF patients with an ICD. During a mean follow-up of 15 months, late HMR was independently associated with appropriate ICD discharge.

Fig. 1 ROI selection and HMR calculation by I-123 MIBG planar imaging. The normal subject has prominently higher MIBG uptake in the heart than the heart failure patient, as compared to the corresponding mediastinal MIBG uptakes. ROI: region of interest; HMR: heart-to-mediastinum ratio

Recently, AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF)[30], a multi-center clinical study was completed to confirm the findings of extensive single-center trials and assess the prognostic role of I-123 MIBG imaging. A total of 961 subjects with NYHA class II/III HF and LVEF≤35% were enrolled. Time to occurrence of the first cardiac event (NYHA class progression, potentially life-threatening arrhythmic event, or cardiac death)was compared in patients with HMR≥1.6 vs. HMR< 1.6. The ADMIRE-HF study reported that patients with HMR≥1.6 had significantly lower cardiac event risk than patients with HMR<1.6. The 2-year event rates were 38% vs. 15% for these two groups. Noteworthy, a total of 86 subjects had either non-fatal arrhythmic events or sudden cardiac deaths.These combined arrhythmic events were significantly more common in the subjects with HMR <1.6 (76 of 790, 10.4%)than in the subjects with HMR ≥1.6 (7 of 201, 3.5%).

Some groups also evaluated WR in HF patients. In the study by Kasama,[18]WR in HF patients was significantly lower in the non-cardiac death group than in the cardiac death group. The cardiac death-free rate was significantly higher in patients with WR< 25%than in those with WR≥25%. Furthermore, the sudden death-free rate was significantly higher in the patients with WR< 22% than in those with WR≥22%.Kioka et al.[31]also reported that abnormal WR could predict sudden cardiac death in patients with mild-tomoderate HF.

I-123 MIBG SPECT IMAGING

Imaging protocols

I-123 MIBG SPECT images were usually acquired immediately after the completion of the I-123 MIBG planar imaging. Important imaging parameters include collimator choice, energy window and reconstruction algorithms[32]. The largest clinical trial of I-123 MIBG,ADMIRE-HF, used low-energy/high-resolution collimators, with a symmetric 20% energy window peaked at 159 keV, and the projection images were reconstructed using filtered back-projection algorithm[30].

The denervated but viable myocardium, causing innervation supersensitivity, is considered to create dangerous ventricular arrhythmias; therefore, I-123 MIBG SPECT imaging was usually acquired in conjunction with myocardial perfusion imaging (MPI). In the ADMIRE-HF trial[30], patients underwent resting99mTc tetrofosmin SPECT MPI on a separate day. The SPECT MPI was acquired at a minimum of 15 minutes post administration with a conventional protocol[30]. All the projection images were also reconstructed using filtered back-projection algorithm.

Image processing and analysis

The other important parameter is innervation perfusion mismatch score. An innervation/ perfusion mismatch that creates innervation supersensitivity indicates the risk of ventricular arrhythmias[33]. A similar method based on the 17-segment model is usually used to calculate a perfusion defect score from supercriptTc SPECT MPI images. Then, a MIBG-perfusion mismatch score can be calculated by subtracting the perfusion defect score from the MIBG defect score to represent the size of mismatch, i.e., myocardium with abnormal MIBG uptake but normal perfusion uptake.

I-123 MIBG SPECT images can also be used to measure HMR. Similar to the definition of ROIs in planar imaging, volumes of interest (VOIs)of the heart and mediastinum are drawn on reconstructed SPECT transaxial images, and then the ratio between mean counts within and the two VOIs is measured as HMR. Chen et al.[32]demonstrated that SPECT imaging produced more accurate HMR than planar imaging. In another further quantitative SPECT study[34],they measured HMR of 67 pilot patients and 1,051 validation patients, and found that SPECT HMR has similar capability to planar HMR to differentiate HF patients from normal controls.

Clinical results

I-123 MIBG SPECT imaging has been used for prognosis in HF patients by a number of clinicalstudies. Boogers et al.[17]measured the innervation/perfusion mismatch score in 50 patients with LV systolic dysfunction referred for electrophysiologic testing. The study showed that innervation/perfusion mismatch score was associated with the occurrence of ventricular arrhythmias in univariable analysis; however, no significant association was found in multivariable analysis. On the other hand, it revealed that regional cardiac denervation was significantly higher in patients with positive electrophysiologic tests than patients with negative electrophysiologic tests. Mitrani et. al.[35]reported that patients with ventricular tachycardia showed significantly more regional sympathetic denervation as compared to patients without ventricular tachycardia. This study also demonstrated that regional cardiac sympathetic denervation derived from late I-123 MIBG SPECT was significantly associated with ventricular arrhythmias causing appropriate ICD therapy. Fig. 2 shows case examples,where the HF patient with ICD discharges had more extensive MIBG defect as well as MIBG-perfusion mismatch.

Table 1 Normal HMR values

Fig. 2 MIBG and perfusion SPECT images of two HF patients with ICD. (Courtesy of Mark I. Travin, MD, Montefiore Medical Center, Bronx, NY, USA). A: A representative HF patient with ICD, but not experiencing ICD shocks. Both MIBG and perfusion SPECT images show good myocardial uptakes of the MIBG and perfusion tracers, respectively, indicating a low risk of ventricular arrhythmia in this patient. B: A representative HF patient with ICD, and experiencing ICD shocks. The MIBG SPECT images show low myocardial uptakes of MIBG in the anterior and inferior wall (red arrows). Good myocardial perfusion is observed in the inferior wall as shown by the perfusion SPECT images (green arrows).Therefore, this patient has large MIBG defects in both anterior and inferior walls and prominent MIBG/perfusion mismatch in the inferior wall, indicating a high risk of ventricular arrhythmia.

SUMMARY

The selection of HF patients for ICD therapy is a challenging clinical problem. The current methods are mainly based on LVEF, which has many limitations. I-123 MIBG imaging provides a useful tool for the assessment of the sympathetic nervous system.Several parameters given by I-123 MIBG planar and SPECT imaging, such as heart-to-mediastinum ratio,MIBG defect score, and MIBG-perfusion mismatch score, have been shown to predict ventricular arrhythmia and are promising in selecting HF patients for ICD therapy. Further studies are needed to establish these clinical applications of I-123 MIBG planar and SPECT imaging.

[1]McMurray JJ, Pfeffer MA. Heart failure. Lancet 2005;365: 1877-89.

[2]Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Executive summary: heart disease and stroke statistics - 2013 update: a report from the American Heart Association. Circulation 2013; 127:143-52.

[3]Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ,Ponikowski P, Poole-Wilson PA, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the task force for the diagnosis and treatment of acute and chronic heart failure 2008. Eur Heart J 2008; 29: 2388-442.

[4]Eriksson H. Heart failure: a growing public health problem. J Intern Med 1995; 237: 135-41.

[5]Gheorghiade M, Bonow R. Chronic heart failure in the United States: a manifestation of coronary artery disease.Circulation 1998; 97: 282-9.

[6]Myerburga RJ, Spooner PM. Opportunities for sudden death prevention: Directions for new clinical and basic research. Cardiovasc Res 2001; 50: 177-85.

[7]Zipes DP, Hein JJW. Sudden cardiac death. Circulation 1998; 98: 2334-51.

[8]Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL,Boineau R, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352: 225-37.

[9]Kelesidis I, Travin MI. Use of cardiac radionuclide imaging to identify patients at risk for arrhythmic sudden cardiac death. J Nucl Cardiol 2012; 19: 142-52.

[10]Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults:a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119: e391-e479.

[11]Lee DS, Krahn AD, Healey JS, Birnie D, Crystal E, Dorian P, et al. Evaluation of early complications related to de novo cardioverter defibrillator implantation insights from the Ontario ICD database. J Am Coll Cardiol 2010;55: 774-82.

[12]Anderson KP. Estimates of implantable cardioverterdefibrillator complications Caveat emptor. Circulation 2009; 119: 1069-71.

[13]Anderson KP. Risk assessment for defibrillator therapy.J Am Coll Cardiol 2007; 50: 1158-60.

[14]Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia.Circulation 1990; 822 Suppl: I103-13.

[15]Zipes DP. Sympathetic stimulation and arrhythmias. N Engl J Med 1991; 325: 656-7.

[16]Bax JJ, Kraft O, Buxton AE, Fjeld JG, Parízek P, Agostini D, et al. 123I-mIBG scintigraphy to predict inducibility of ventricular arrhythmias on cardiac electrophysiology testing: a prospective multicenter pilot study.Circ Cardiovasc Imaging 2008; 1: 131-40.

[17]Boogers MJ, Borleffs CJ, Henneman MM, van Bommel RJ, van Ramshorst J, Boersma E, et al. Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients. J Am Coll Cardiol 2010; 55: 2769-77.

[18]Kasama S, Toyama T, Sumino H, Nakazawa M, Matsumoto N, Sato Y, et al. Prognostic value of serial cardiac 123I-MIBG imaging in patients with stabilized chronic heart failure and reduced left ventricular ejection fraction.J Nucl Med 2008; 49: 907-14.

[19]Chou CC, Zhou S, Hayashi H, Nihei M, Liu YB, Wen MS, et al. Remodelling of action potential and intracel-lular calcium cycling dynamics during subacute myocardial infarction promotes ventricular arrhythmias in langendorff-perfused rabbit hearts. J Physiol 2007; 580:895-906.

[20]Naud P, Guasch E, Nattel S. Physiological versus pathological cardiac electrical remodelling: Potential basis and relevance to clinical management. J Physiol 2010; 588:4855-6.

[21]Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart failure:Current concepts in clinical significance and assessment.J Am Coll Cardiol Imaging 2011; 4: 98-108.

[22]Kelesidis I, Travin MI. Use of cardiac radionuclide imaging to identify patients at risk for arrhythmic sudden cardiac death. J Nucl Cardiol 2012; 19: 142-52.

[23]Boogers MM, Bengel FM, Knuuti JK, Bax JJ. Cardiac Iodine-123 Metaiodobenzylguanidine Imaging for Risk Stratification in Heart Failure Patients. European Cardiology 2008; 4: 42-45.

[24]Okuda K, Nakajima K, Hosoya T, Ishikawa T, Konishi T,Matsubara K, et al. Semi-automated algorithm for calculating heart-to-mediastinum ratio in cardiac Iodine-123 MIBG imaging. Journal of Nuclear Cardiology 2010;18: 82-9.

[25]Verberne HJ, Habraken JB, van Eck-Smit BL, Agostini D,Jacobson AF. Variations in 123I-metaiodobenzylguanidine (MIBG)late heart mediastinal ratios in chronic heart failure: a need for standardisation and validation. Eur J Nucl Med Mol Imaging 2008; 35: 547-53.

[26]van der Veen L, Scholte A, Stokkel M. Mathematical methods to determine quantitative parameters of myocardial 123I-MIBG studies: A review of the literature.Nucl Med Commun 2010; 31: 617-28.

[27]Nishimura T, Sugishita Y, Sasaki Y. The results of questionnaire on quantitative assessment of 123I-metaiodobenzylguanidine myocardial scintigraphy in heart failure.Kaku Igaku 1997; 34: 1139-48.

[28]Arora R, Ferrick KJ, Nakata T, Kaplan RC, Rozengarten M, Latif F, et al. I-123 MIBG imaging and heart rate variability analysis to predict the need for an implantable cardioverter defibrillator. J Nucl Cardiol 2003; 10: 121-31.

[29]Nagahara D, Nakata T, Hashimoto A, Wakabayashi T,Kyuma M, Noda R, et al. Predicting the need for an implantable cardioverter defibrillator using cardiac metaiodobenzylguanidine activity together with plasma natriuretic peptide concentration or left ventricular function. J Nucl Med 2008; 49: 225-33.

[30]Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, et al. Myocardial Iodine-123 Meta-Iodobenzylguanidine imaging and cardiac events in heart failure. J Am Coll Cardiol 2010; 55: 2212-21.

[31]Kioka H, Yamada T, Mine T, Morita T, Tsukamoto Y,Tamaki S, et al. Prediction of sudden death in patients with mild-to-moderate chronic heart failure by using cardiac iodine-123 metaiodobenzylguanidine imaging.Heart 2007; 93: 1213-8.

[32]Chen J, Garcia EV, Galt JR, Folks RD, Carrio I. Optimized acquisition and processing protocols for I-123 cardiac SPECT imaging. J Nucl Cardiol 2006; 13: 251-60.

[33]Minardo JD, Tuli MM, Mock BH, , Weiner RE, Pride HP, Wellman HN, et al. Scintigraphic and electrophysiologic evidence of canine myocardial sympathetic denervation and reinnervation produced by myocardial infarction or phenol application. Circulation 1988; 78:1008-19.

[34]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.

[35]Mitrani RD, Klein LS, Miles WM, Hackett FK, Burt RW, Wellman HN, et al. Regional cardiac sympathetic denervation in patients with ventricular tachycardia in the absence of coronary artery disease. J Am Coll Cardiol 1993; 22: 1344-53.

[36]Nakajima K. Normal values for nuclear cardiology: Japanese databases for myocardial perfusion, fatty acid and sympathetic imaging and left ventricular function. Ann Nucl Med 2010; 24: 125-35.

[37]Parthenakis FI, Prassopoulos VK, Koukouraki SI, Zacharis EA, Diakakis GF, Karkavitsas NK, et al. Segmental pattern of myocardial sympathetic denervation in idiopathic dilated cardiomyopathy: Relationship to regional wall motion and myocardial perfusion abnormalities. J Nucl Cardiol 2002; 9: 15-22.

[38]Somsen GA, Verberne HJ, Fleury E, Righetti A. Normal values and within-subject variability of cardiac I-123 MIBG scintigraphy in healthy individuals: Implications for clinical studies. J Nucl Cardiol 2004; 11: 126-33.