- Email: [email protected]
Cardiac MIBG imaging at the edge of clinical application in heart failure
Médecine Nucléaire 35 (2011) 38–41
Review
Cardiac MIBG imaging at the edge of clinical application in heart failure La scintigraphie cardiaque à la 123I-MIBG : applications cliniques récentes dans l’insuffisance cardiaque D. Agostini *, F. Besson, S. Costo, A. Manrique Service de médecine nucléaire, CHU de Caen, 14000 Caen, France Received 19 November 2010; accepted 24 November 2010 Available online 28 December 2010
Abstract Neuronal innervation plays a crucial role in cardiac function. The heart is richly innervated with sympathetic and parasympathetic fibers that work in conjunction with circulating catecholamine mediators, such as norepinephrine (NE), to tightly regulate cardiac output at rest and during periods of increased cardiac demand. An impairment of cardiac autonomic function, most often the result of cardiac disease (ischemic or nonischemic cardiomyopathy), can reflect the severity of the condition, and in many cases is associated with and likely contributing to worsening of the clinical condition, increasing the potential for life-threatening cardiac arrhythmias and death. Because cardiac autonomic function involves numerous molecular processes, use of radiotracers for imaging is an ideal method of assessment. # 2010 Elsevier Masson SAS. All rights reserved. Keywords: Innervation; Imaging; Nuclear; Cardiac; MIBG
Résumé L’insuffisance cardiaque s’accompagne de perturbations importantes du fonctionnement du système nerveux adrénergique, hyperactivation globale de ce système et modifications locales du système nerveux sympathique. La scintigraphie cardiaque à la 123I-MIBG est une technique isotopique explorant la fonction adrénergique présynaptique. La fixation cardiaque de la MIBG est diminuée lors de l’insuffisance cardiaque et est un facteur pronostique déterminant des cardiomyopathies avec FEVG inférieur à 35 % (étude ADMIRE-HF). L’altération du fonctionnement présynaptique est précoce et joue un rôle important dans la pathogénie de l’aggravation de l’insuffisance cardiaque. La scintigraphie cardiaque à la 123I-MIBG pourrait être proposée dans tout bilan d’insuffisance cardiaque, avec dysfonction VG (FEVG < 35 %) chez des patients en classe II et III de la NYHA dans le cadre de la sélection des patients devant bénéficier d’implantation de défibrillateur cardiaque. # 2010 Elsevier Masson SAS. Tous droits réservés. Mots clés : Insuffisance cardiaque ; MIBG ; Pronostic ; Défibrillateur cardiaque implantable
1. 123I-MIBG for imaging cardiac sympathetic innervation Imaging of cardiac sympathetic innervation focuses on the synaptic junction. Most of the radiotracers developed and investigated to this point image presynaptic anatomy and function [1]. The sympathetic mediator NE is synthesized by a
* Corresponding author. E-mail address: [email protected] (D. Agostini).
series of steps originating with tyrosine, and is stored at high concentrations in presynaptic fibers [2–4]. 123 I-meta-iodobenzylguanidine (123I-MIBG) is the most studied radiotracer for cardiac neuronal imaging. Tracer injection is performed at rest and needs only minimal preparation. Medications that might interfere with catecholamine uptake, such as various antidepressants, antipsychotics, and some calcium channel blockers, should be held for 24 hours before tracer injection and imaging [2–5]. The need for administration of thyroid-blocking agents before 123I-MIBG administration provides the shield of the
0928-1258/$ – see front matter # 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.mednuc.2010.11.002
D. Agostini et al. / Médecine Nucléaire 35 (2011) 38–41
thyroid from exposure to unbound radionuclide impurities, such as 124I and 125I. The amount of tracer activity to administer has not been formally established. In several published investigations, a dose of 3 to 5 mCi (111–185 MBq) of 123I-MIBG over one-minute period has been used, and this is generally satisfactory for planar image analysis. Because it is often difficult to obtain satisfactory SPECT images using these tracer doses in patients who have severe cardiac dysfunction and heart failure (HF), a dose of up to 10 mCi (370 MBq) may be appropriate and is under investigation [4]. Parameters for planar and SPECT acquisition of 123I-MIBG are not formally established, but current methods are described in various published reviews and a proposal of standardization of MIBG imaging has been recently published by the European Council of Nuclear Cardiology [6,7]. Planar images are obtained in the anterior view for ten minutes using an energy window of 159 keV 20%. SPECT images are obtained using the 159 keV 20% energy window by way of a 1808 circular acquisition from 458 right anterior oblique to 458 left posterior oblique, using a total of 60 stops (30 stops per head if done with a dual-headed camera) at 30 seconds per stop. Although low-energy collimators have been customarily used for 123I-MIBG acquisition, multiple, low-abundance higher-energy photon emissions (including one of 529 keV) that are emitted by 123I more freely penetrate the septa and degrade image quality. Work is under way using a measured point spread function to perform three-dimensional deconvolution of the septal penetration to compensate for this effect and improve image accuracy, particularly for quantitative parameters. Planar and SPECT images are routinely obtained at approximately 15 minutes following 123I-MIBG administration (early), and again three to five hours later (delayed). Although some believe that only the delayed image should be used for interpretation and analysis because it represents actual neuronal uptake (as opposed to interstitial uptake for the early images), studies mostly from Japan have shown that tracer washout between early and delayed images provides important additional information. 2.
123
I-MIBG image interpretation
Although most published data describe the prognostic usefulness of global myocardial tracer uptake and washout parameters on planar images, one can also perform SPECT imaging to assess regional tracer uptake. When coupled with rest imaging using a standard SPECT perfusion tracer, regional analysis can identify areas of neuronal/perfusion mismatch that may have denervation supersensitivity and increase the risk for cardiac arrhythmias [8–10]. The standard measure of global 123I-MIBG uptake is the heart mediastinal ratio (HMR), derived through regions of interest over the heart and upper mediastinum, created in various ways but all seeming to give similar results in any given patient study. Normal values for HMR range from 1.9 to 2.8, with a mean of about 2.2 [11–14].
39
Another frequently measured quantity from planar images is I-MIBG washout. The washout ratio may reflect turnover of catecholamines attributable to sympathetic drive. A normal washout value in control subjects is reported to be 9.6 8.5% [14]. Although ideally cardiac 123I-MIBG uptake would be homogeneous in normal individuals, there are variations that seem unrelated to cardiac disease. Gill et al. [11] and Morozumi et al. [12] have shown that in normal subjects, there is relatively less uptake (12–18%) of 123I-MIBG in the septum and especially the inferior wall compared with the anterior and lateral walls, attributed to differences in regional myocardial autonomic innervation. Furthermore, these heterogeneities are reported to be more pronounced in older subjects and in men [14]. It has been proposed that such regional variation may be the result of increased vagal tone in the inferior wall, supported in a study by Estorch et al. [15] finding that in athletes who have sinus bradycardia, 123I-MIBG uptake is lower in the inferior wall. 123
3. Cardiac 123I-MIBG imaging and patients with congestive heart failure A consistent finding associated with a poor prognosis in patients who have advanced HF is a decreased HMR [16–18]. The finding was initially reported by Merlet et al. in a prospective study of 90 patients who had moderate to severe CHF and left ventricular ejection fraction (LVEF) less than 45% (mean 22%). Patients who had an HMR less than 1.2 had six- and 12-month survivals of 60 and 40%, respectively, compared with a 100% 12-month survival for patients who had a higher ratio. With multivariate analysis, HMR was a better predictor of mortality than LVEF. A subsequent report from this group studying 112 patients who had idiopathic dilated cardiomyopathy also showed cardiac 123I-MIBG uptake to be independent of and better than LVEF in predicting cardiac death. A study by Nakata et al. [19] of about 400 patients showed a progressive worsening of survival as the HMR decreased, and that HMR was a more powerful predictor of cardiac death than New York Heart Association (NYHA) class, age, prior myocardial infarction (MI), and LVEF. Most recently, Agostini et al. [20] reviewed the records of 290 patients who had HF in six centers in Europe and quantitatively reanalyzed 123 I-MIBG studies. Logistic regression showed that the only significant predictors of major cardiac events (cardiac death, transplant, and potentially fatal arrhythmias) over 24 months were LVEF and HMR. Particularly striking was the ability of HMR to stratify the risk in patients who had LVEF 35% or less, with event rates ranging from less than 5% for those who had HMR 2.18 or greater, to more than 50% for those who had HMR 1.45 or less, as illustrated in Fig. 1. There have been concerns that the cause of congestive HF, especially whether it is ischemic versus nonischemic, may affect the usefulness of 123I-MIBG imaging. As discussed subsequently, ischemic heart disease can by itself, without CHF, result in 123I-MIBG abnormalities, and thus contribute to different findings and implications of image results in these two
[()TD$FIG]40
D. Agostini et al. / Médecine Nucléaire 35 (2011) 38–41
settings. It seems, however, that regardless of the initial cause of HF, there is a common state in which the characteristic cardiac autonomic abnormalities are seen on 123I-MIBG imaging and remain strong correlates of prognosis. In a study of 76 patients who had ischemic cardiomyopathies and 56 patients who had idiopathic cardiomyopathies, Wakabayashi et al. [21] showed that for both groups, late HMR was the most powerful independent predictor of lethal clinical outcome (although there were different HMR threshold values: 1.50 for ischemic compared with 2.02 for idiopathic cardiomyopathies). 4. ADMIRE-HF study Fig. 1. Results of the European retrospective study showing the relationship between the heart mediastinal ratio (HMR) and the two-year major cardiac events MCE rate, including cardiac death, heart transplantation, recurrent heart failure. Résultats d’une étude rétrospective européenne montrant la relation entre le rapport cœur/médiastin et la survenue d’évènements cardiaques majeurs (décès d’origine cardiaque, transplantation cardiaque, réapparition d’épisodes d’insuffisance cardiaque) à deux ans.
Table 1 Clinical comparison of subjects with and without cardiac events in ADMIREHF study. Comparaison des caracte´ristiques cliniques des patients avec et sans e´ve´nements cardiaques dans l’e´tude ADMIRE-HF. Characteristic
Subjects with Subjects without P-value events (n = 237) events (n = 724)
Male sex (%) Age (yr) LVEF (%) ACE-I or ARB (%) Beta blocker (%) Aldosterone antagonist (%) HF class: NYHA II, III (%) HF etiology: ischemic, non-ischemic (%) BNP (ng/L) (n = 926) Plasma NE (pg/mL) (n = 910) Early H/M ratio Late H/M ratio
83.5 61.5 13.4 25.0 6.6 93.7 91.6 38.4 75.1, 24.9 60.3, 39.7
78.9 62.7 11.3 27.8 5.8 94.1 92.1 33.0 85.2, 14.8 68.1, 31.9
0.118 0.181 < 0.001 0.827 0.781 0.130 < 0.001 0.028
397.8 476.8 721.3 407.5 1.53 0.19 1.39 0.18
217.6 339.7 644.1 346.8 1.58 0.20 1.46 0.21
< 0.001 0.006 0.003 < 0.001
ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; BNP: b-type natriuretic peptide; HF: heart failure; H/M: heart/mediastinum ratio; LVEF: left ventricular ejection fraction; NE: norepinephrine; NYHA: New York Heart Association.
ADMIRE-HF study evaluated the usefulness of 123I-MIBG imaging for identifying symptomatic HF patients most likely to experience major cardiac events [22,23]. Nine hundred and sixty-one subjects with NYHA class II and III HF and LVEF inferior or equal to 35% underwent planar and SPECT 123IMIBG myocardial imaging, echocardiography and rest gated SPECT myocardial perfusion imaging. Subjects were then followed for up to two years (Table 1). Time to first occurrence of the composite endpoint of NYHA class progression, potentially life-threatening arrhythmic event, or cardiac death was compared to the heart/mediastinum ratio (H/M) on fourhour delayed planar 123I-MIBG imaging (< 1.60 vs 1.60 or as a continuous variable) using Cox proportional hazards methods. Multivariable Cox proportional hazards analyses using clinical, laboratory, and imaging data were also performed. Two hundred and thirty-seven subjects (25%) experienced events during a median follow-up of 17 months (Table 2). There was a strong inverse relationship between H/M and occurrence of events. Hazard ratio for H/M superior or equal to 1.60 subjects was 0.40 (P < 0.001); hazard ratio for the analysis using the numerical H/M was 0.22 (P < 0.001). Twoyear event rates were 15% for H/M superior or equal to 1.60 versus 37% for H/M inferior to 1.60. Hazard ratios for all event categories were significant: HF progression: 0.49 (P = 0.002); arrhythmic events: 0.37 (P = 0.02); cardiac death: 0.14 (P = 0.006). Significant contributors to the multivariable model were the late H/M, LVEF, BNP, and NYHA class; no other imaging or clinical variables contributed to the prediction model. ADMIRE-HF study provides prospective validation of the independent prognostic value of late cardiac 123I-MIBG
Table 2 Results of Cox model for H/M threshold of 1.60 on cardiac events categories in ADMIRE-HF study. Re´sultats du mode`le de Cox, pour le seuil 1,6 du rapport cardiome´diastinal. (e´tude ADMIRE-HF). Total events Event category
N
n
%
Hazard Ratio. (95 % CI)
P-value
Heart failure progression Potentially life-threatening arrhythmia threatening arrhythmic event Cardiac death
961 961
176 64
18.0 6.6
0.49 (0.32–0.77) 0.77 0.37 (0.16–0.85)
0.002 0.020
961
53
5.5
0.14 (0.03–0.58)
0.006
CI: Confidence interval.
[()TD$FIG]
D. Agostini et al. / Médecine Nucléaire 35 (2011) 38–41
Fig. 2. Results of the prospective multi-trial ADMIRE-HF study showing the relationship between the heart mediastinal ratio (HMR) and the two-year cardiac death rate. Résultats de l’étude prospective ADMIRE-HF montrant la relation entre le rapport cardiomédiastinal et les décès d’origine cardiaque à deux ans.
scintigraphy by using HMR in assessment of patients with HF (Fig. 2). 5. Conclusion Imaging of the cardiac neuronal system with 123I-MIBG shows promise as a potentially powerful tool to evaluate patients who have various cardiac conditions and direct patient management in guiding mechanical devices, and determining the need for cardiac transplant. Conflict of interest statement The authors have not declared any conflict of interest. References [1] Carrio I. Cardiac neurotransmission imaging. J Nucl Med 2001;42:1062– 76. [2] Sisson JC, Wieland DM. Radiolabelled meta-iodo-benzylguanidine pharmacology: pharmacology and clinical studies. Am J Physiol Imaging 1986;1:96–103. [3] Kline RC, Swanson OP, Wieland DM, et al. Myocardial imaging in man with I-123 metaiodobenzylguanidine. J Nucl Med 1981;22:129–32. [4] Flotats A, Carrio I. Cardiac neurotransmission SPECT imaging. J Nucl Cardiol 2004;11:587–602. [5] Wieland DM, Brown LE, Rogers WL, et al. Myocardial imaging with a radioiodinated norepinephrine storage analog. J Nucl Med 1981;22: 22–31.
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[6] Agostini D, Carrio I, Verberne HJ. How to use cardiac MIBG scintigraphy in chronic heart failure. Eur J Nucl Med Mol Imaging 2009;36:555–9. [7] Flotats A, Carrio I, Agostini D, et al. Proposal for standardisation of 123-Imetaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology. Eur J Nucl Med Mol Imaging 2010;37:1802–12. [8] Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of heart. Circulation 1990;82:1095–105. [9] Matsunari L, Schricke U, Bengel FM, et al. Extent of cardiac sympathetic neuronal damage is determined by the area of ischemia in patients with acute coronary syndrome. Circulation 2000;101:2579–85. [10] Simôes MV, Barthel P, Matsunari L, et al. Presence of sympathetically denervated but viable myocardium and its electrophysiologic correlates after early revascularised, acute myocardial infarction. Eur Heart J 2004;25:551–7. [11] Gill JS, Hunter GJ, Gane G, et al. Heterogeneity of the human myocardial sympathetic innervation: in vivo demonstration by iodine 123-labeled metaiodobenzylguanidine scintigraphy. Am Heart J 1993;126:390–8. [12] Morozumi T, Kusuoka H, Fukuchi K, et al. Myocardial iodine-123metaiodobenzylguanidine images and autonomic nerve activity in normal subjects. J Nucl Med 1997;38:49–52. [13] Somsen GA, Verberne HJ, Fleury E, et al. Normal values and withinsubject variability of cardiac I-123 MIBG scintigraphy in healthy individuals: implications for clinical studies. J Nucl Cardiol 2004;11:126–33. [14] Tsuchimochi S, Tamaki N, Tadamura E, et al. Age and gender differences in normal myocardial adrenergic neuronal function evaluated by iodine-123-MIBG imaging. J Nucl Med 1995;36:969–74. [15] Estorch M, Serra-Grima R, Flotats A, et al. Myocardial sympathetic innervation in the athlete’s sinus bradycardia: is there selective inferior myocardial wall denervation? J Nucl Cardiol 2000;1:354–8. [16] Anastasiou-Nana MI, Terrovitis JV, Athanasoulis T, et al. Prognostic value of iodine-123-metaiodobenzylguanidine myocardial uptake and heart rate variability in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2005;96:427–31. [17] Arimoto T, Takeishi Y, Niizeki T, et al. Cardiac sympathetic denervation and ongoing myocardial damage for prognosis in early stages of heart failure. J Card Fail 2007;13:34–41. [18] Merlet P, Benvenuti C, Moyse D, et al. Prognostic value of MIBG imaging in idiopathic dilated cardiomyopathy. J Nucl Med 1999;40:917–23. [19] Merlet P, Valette H, Dubois-Randé J, et al. Prognostic value of cardiac metaiodobenzylguanidine in patients with heart failure. J Nucl Med 1992;33:471–7. [20] Agostini D, Verberne HJ, Burchert W, et al. I-123-MIBG myocardial imaging for assessment of risk for a major cardiac event in heart failure patients: insights from a retrospective European multicenter study. Eur J Nucl Med Mol Imaging 2008;35:535–46. [21] Wakabayashi T, Nakata T, Hashimoto A, et al. Assessment of underlying etiology and cardiac sympathetic innervation to identify patients at high risk of cardiac death. J Nucl Med 2001;42:1757–67. [22] Jacobson AF, Lombard J, Banerjee G, et al. 123I-MIBG scintigraphy to predict risk for adverse cardiac outcomes in heart failure patients: design of two prospective multicenter international trials. J Nucl Cardiol 2009;16:113–21. [23] Jacobson AF, Senior R, Cerqueira M, et al. Myocardial iodine-123-metaiodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (Ad review myocardial imaging for risk evaluation inherit failure) study. J Am Coll Cardiol 2010;55:2212–21.
Review
Cardiac MIBG imaging at the edge of clinical application in heart failure La scintigraphie cardiaque à la 123I-MIBG : applications cliniques récentes dans l’insuffisance cardiaque D. Agostini *, F. Besson, S. Costo, A. Manrique Service de médecine nucléaire, CHU de Caen, 14000 Caen, France Received 19 November 2010; accepted 24 November 2010 Available online 28 December 2010
Abstract Neuronal innervation plays a crucial role in cardiac function. The heart is richly innervated with sympathetic and parasympathetic fibers that work in conjunction with circulating catecholamine mediators, such as norepinephrine (NE), to tightly regulate cardiac output at rest and during periods of increased cardiac demand. An impairment of cardiac autonomic function, most often the result of cardiac disease (ischemic or nonischemic cardiomyopathy), can reflect the severity of the condition, and in many cases is associated with and likely contributing to worsening of the clinical condition, increasing the potential for life-threatening cardiac arrhythmias and death. Because cardiac autonomic function involves numerous molecular processes, use of radiotracers for imaging is an ideal method of assessment. # 2010 Elsevier Masson SAS. All rights reserved. Keywords: Innervation; Imaging; Nuclear; Cardiac; MIBG
Résumé L’insuffisance cardiaque s’accompagne de perturbations importantes du fonctionnement du système nerveux adrénergique, hyperactivation globale de ce système et modifications locales du système nerveux sympathique. La scintigraphie cardiaque à la 123I-MIBG est une technique isotopique explorant la fonction adrénergique présynaptique. La fixation cardiaque de la MIBG est diminuée lors de l’insuffisance cardiaque et est un facteur pronostique déterminant des cardiomyopathies avec FEVG inférieur à 35 % (étude ADMIRE-HF). L’altération du fonctionnement présynaptique est précoce et joue un rôle important dans la pathogénie de l’aggravation de l’insuffisance cardiaque. La scintigraphie cardiaque à la 123I-MIBG pourrait être proposée dans tout bilan d’insuffisance cardiaque, avec dysfonction VG (FEVG < 35 %) chez des patients en classe II et III de la NYHA dans le cadre de la sélection des patients devant bénéficier d’implantation de défibrillateur cardiaque. # 2010 Elsevier Masson SAS. Tous droits réservés. Mots clés : Insuffisance cardiaque ; MIBG ; Pronostic ; Défibrillateur cardiaque implantable
1. 123I-MIBG for imaging cardiac sympathetic innervation Imaging of cardiac sympathetic innervation focuses on the synaptic junction. Most of the radiotracers developed and investigated to this point image presynaptic anatomy and function [1]. The sympathetic mediator NE is synthesized by a
* Corresponding author. E-mail address: [email protected] (D. Agostini).
series of steps originating with tyrosine, and is stored at high concentrations in presynaptic fibers [2–4]. 123 I-meta-iodobenzylguanidine (123I-MIBG) is the most studied radiotracer for cardiac neuronal imaging. Tracer injection is performed at rest and needs only minimal preparation. Medications that might interfere with catecholamine uptake, such as various antidepressants, antipsychotics, and some calcium channel blockers, should be held for 24 hours before tracer injection and imaging [2–5]. The need for administration of thyroid-blocking agents before 123I-MIBG administration provides the shield of the
0928-1258/$ – see front matter # 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.mednuc.2010.11.002
D. Agostini et al. / Médecine Nucléaire 35 (2011) 38–41
thyroid from exposure to unbound radionuclide impurities, such as 124I and 125I. The amount of tracer activity to administer has not been formally established. In several published investigations, a dose of 3 to 5 mCi (111–185 MBq) of 123I-MIBG over one-minute period has been used, and this is generally satisfactory for planar image analysis. Because it is often difficult to obtain satisfactory SPECT images using these tracer doses in patients who have severe cardiac dysfunction and heart failure (HF), a dose of up to 10 mCi (370 MBq) may be appropriate and is under investigation [4]. Parameters for planar and SPECT acquisition of 123I-MIBG are not formally established, but current methods are described in various published reviews and a proposal of standardization of MIBG imaging has been recently published by the European Council of Nuclear Cardiology [6,7]. Planar images are obtained in the anterior view for ten minutes using an energy window of 159 keV 20%. SPECT images are obtained using the 159 keV 20% energy window by way of a 1808 circular acquisition from 458 right anterior oblique to 458 left posterior oblique, using a total of 60 stops (30 stops per head if done with a dual-headed camera) at 30 seconds per stop. Although low-energy collimators have been customarily used for 123I-MIBG acquisition, multiple, low-abundance higher-energy photon emissions (including one of 529 keV) that are emitted by 123I more freely penetrate the septa and degrade image quality. Work is under way using a measured point spread function to perform three-dimensional deconvolution of the septal penetration to compensate for this effect and improve image accuracy, particularly for quantitative parameters. Planar and SPECT images are routinely obtained at approximately 15 minutes following 123I-MIBG administration (early), and again three to five hours later (delayed). Although some believe that only the delayed image should be used for interpretation and analysis because it represents actual neuronal uptake (as opposed to interstitial uptake for the early images), studies mostly from Japan have shown that tracer washout between early and delayed images provides important additional information. 2.
123
I-MIBG image interpretation
Although most published data describe the prognostic usefulness of global myocardial tracer uptake and washout parameters on planar images, one can also perform SPECT imaging to assess regional tracer uptake. When coupled with rest imaging using a standard SPECT perfusion tracer, regional analysis can identify areas of neuronal/perfusion mismatch that may have denervation supersensitivity and increase the risk for cardiac arrhythmias [8–10]. The standard measure of global 123I-MIBG uptake is the heart mediastinal ratio (HMR), derived through regions of interest over the heart and upper mediastinum, created in various ways but all seeming to give similar results in any given patient study. Normal values for HMR range from 1.9 to 2.8, with a mean of about 2.2 [11–14].
39
Another frequently measured quantity from planar images is I-MIBG washout. The washout ratio may reflect turnover of catecholamines attributable to sympathetic drive. A normal washout value in control subjects is reported to be 9.6 8.5% [14]. Although ideally cardiac 123I-MIBG uptake would be homogeneous in normal individuals, there are variations that seem unrelated to cardiac disease. Gill et al. [11] and Morozumi et al. [12] have shown that in normal subjects, there is relatively less uptake (12–18%) of 123I-MIBG in the septum and especially the inferior wall compared with the anterior and lateral walls, attributed to differences in regional myocardial autonomic innervation. Furthermore, these heterogeneities are reported to be more pronounced in older subjects and in men [14]. It has been proposed that such regional variation may be the result of increased vagal tone in the inferior wall, supported in a study by Estorch et al. [15] finding that in athletes who have sinus bradycardia, 123I-MIBG uptake is lower in the inferior wall. 123
3. Cardiac 123I-MIBG imaging and patients with congestive heart failure A consistent finding associated with a poor prognosis in patients who have advanced HF is a decreased HMR [16–18]. The finding was initially reported by Merlet et al. in a prospective study of 90 patients who had moderate to severe CHF and left ventricular ejection fraction (LVEF) less than 45% (mean 22%). Patients who had an HMR less than 1.2 had six- and 12-month survivals of 60 and 40%, respectively, compared with a 100% 12-month survival for patients who had a higher ratio. With multivariate analysis, HMR was a better predictor of mortality than LVEF. A subsequent report from this group studying 112 patients who had idiopathic dilated cardiomyopathy also showed cardiac 123I-MIBG uptake to be independent of and better than LVEF in predicting cardiac death. A study by Nakata et al. [19] of about 400 patients showed a progressive worsening of survival as the HMR decreased, and that HMR was a more powerful predictor of cardiac death than New York Heart Association (NYHA) class, age, prior myocardial infarction (MI), and LVEF. Most recently, Agostini et al. [20] reviewed the records of 290 patients who had HF in six centers in Europe and quantitatively reanalyzed 123 I-MIBG studies. Logistic regression showed that the only significant predictors of major cardiac events (cardiac death, transplant, and potentially fatal arrhythmias) over 24 months were LVEF and HMR. Particularly striking was the ability of HMR to stratify the risk in patients who had LVEF 35% or less, with event rates ranging from less than 5% for those who had HMR 2.18 or greater, to more than 50% for those who had HMR 1.45 or less, as illustrated in Fig. 1. There have been concerns that the cause of congestive HF, especially whether it is ischemic versus nonischemic, may affect the usefulness of 123I-MIBG imaging. As discussed subsequently, ischemic heart disease can by itself, without CHF, result in 123I-MIBG abnormalities, and thus contribute to different findings and implications of image results in these two
[()TD$FIG]40
D. Agostini et al. / Médecine Nucléaire 35 (2011) 38–41
settings. It seems, however, that regardless of the initial cause of HF, there is a common state in which the characteristic cardiac autonomic abnormalities are seen on 123I-MIBG imaging and remain strong correlates of prognosis. In a study of 76 patients who had ischemic cardiomyopathies and 56 patients who had idiopathic cardiomyopathies, Wakabayashi et al. [21] showed that for both groups, late HMR was the most powerful independent predictor of lethal clinical outcome (although there were different HMR threshold values: 1.50 for ischemic compared with 2.02 for idiopathic cardiomyopathies). 4. ADMIRE-HF study Fig. 1. Results of the European retrospective study showing the relationship between the heart mediastinal ratio (HMR) and the two-year major cardiac events MCE rate, including cardiac death, heart transplantation, recurrent heart failure. Résultats d’une étude rétrospective européenne montrant la relation entre le rapport cœur/médiastin et la survenue d’évènements cardiaques majeurs (décès d’origine cardiaque, transplantation cardiaque, réapparition d’épisodes d’insuffisance cardiaque) à deux ans.
Table 1 Clinical comparison of subjects with and without cardiac events in ADMIREHF study. Comparaison des caracte´ristiques cliniques des patients avec et sans e´ve´nements cardiaques dans l’e´tude ADMIRE-HF. Characteristic
Subjects with Subjects without P-value events (n = 237) events (n = 724)
Male sex (%) Age (yr) LVEF (%) ACE-I or ARB (%) Beta blocker (%) Aldosterone antagonist (%) HF class: NYHA II, III (%) HF etiology: ischemic, non-ischemic (%) BNP (ng/L) (n = 926) Plasma NE (pg/mL) (n = 910) Early H/M ratio Late H/M ratio
83.5 61.5 13.4 25.0 6.6 93.7 91.6 38.4 75.1, 24.9 60.3, 39.7
78.9 62.7 11.3 27.8 5.8 94.1 92.1 33.0 85.2, 14.8 68.1, 31.9
0.118 0.181 < 0.001 0.827 0.781 0.130 < 0.001 0.028
397.8 476.8 721.3 407.5 1.53 0.19 1.39 0.18
217.6 339.7 644.1 346.8 1.58 0.20 1.46 0.21
< 0.001 0.006 0.003 < 0.001
ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; BNP: b-type natriuretic peptide; HF: heart failure; H/M: heart/mediastinum ratio; LVEF: left ventricular ejection fraction; NE: norepinephrine; NYHA: New York Heart Association.
ADMIRE-HF study evaluated the usefulness of 123I-MIBG imaging for identifying symptomatic HF patients most likely to experience major cardiac events [22,23]. Nine hundred and sixty-one subjects with NYHA class II and III HF and LVEF inferior or equal to 35% underwent planar and SPECT 123IMIBG myocardial imaging, echocardiography and rest gated SPECT myocardial perfusion imaging. Subjects were then followed for up to two years (Table 1). Time to first occurrence of the composite endpoint of NYHA class progression, potentially life-threatening arrhythmic event, or cardiac death was compared to the heart/mediastinum ratio (H/M) on fourhour delayed planar 123I-MIBG imaging (< 1.60 vs 1.60 or as a continuous variable) using Cox proportional hazards methods. Multivariable Cox proportional hazards analyses using clinical, laboratory, and imaging data were also performed. Two hundred and thirty-seven subjects (25%) experienced events during a median follow-up of 17 months (Table 2). There was a strong inverse relationship between H/M and occurrence of events. Hazard ratio for H/M superior or equal to 1.60 subjects was 0.40 (P < 0.001); hazard ratio for the analysis using the numerical H/M was 0.22 (P < 0.001). Twoyear event rates were 15% for H/M superior or equal to 1.60 versus 37% for H/M inferior to 1.60. Hazard ratios for all event categories were significant: HF progression: 0.49 (P = 0.002); arrhythmic events: 0.37 (P = 0.02); cardiac death: 0.14 (P = 0.006). Significant contributors to the multivariable model were the late H/M, LVEF, BNP, and NYHA class; no other imaging or clinical variables contributed to the prediction model. ADMIRE-HF study provides prospective validation of the independent prognostic value of late cardiac 123I-MIBG
Table 2 Results of Cox model for H/M threshold of 1.60 on cardiac events categories in ADMIRE-HF study. Re´sultats du mode`le de Cox, pour le seuil 1,6 du rapport cardiome´diastinal. (e´tude ADMIRE-HF). Total events Event category
N
n
%
Hazard Ratio. (95 % CI)
P-value
Heart failure progression Potentially life-threatening arrhythmia threatening arrhythmic event Cardiac death
961 961
176 64
18.0 6.6
0.49 (0.32–0.77) 0.77 0.37 (0.16–0.85)
0.002 0.020
961
53
5.5
0.14 (0.03–0.58)
0.006
CI: Confidence interval.
[()TD$FIG]
D. Agostini et al. / Médecine Nucléaire 35 (2011) 38–41
Fig. 2. Results of the prospective multi-trial ADMIRE-HF study showing the relationship between the heart mediastinal ratio (HMR) and the two-year cardiac death rate. Résultats de l’étude prospective ADMIRE-HF montrant la relation entre le rapport cardiomédiastinal et les décès d’origine cardiaque à deux ans.
scintigraphy by using HMR in assessment of patients with HF (Fig. 2). 5. Conclusion Imaging of the cardiac neuronal system with 123I-MIBG shows promise as a potentially powerful tool to evaluate patients who have various cardiac conditions and direct patient management in guiding mechanical devices, and determining the need for cardiac transplant. Conflict of interest statement The authors have not declared any conflict of interest. References [1] Carrio I. Cardiac neurotransmission imaging. J Nucl Med 2001;42:1062– 76. [2] Sisson JC, Wieland DM. Radiolabelled meta-iodo-benzylguanidine pharmacology: pharmacology and clinical studies. Am J Physiol Imaging 1986;1:96–103. [3] Kline RC, Swanson OP, Wieland DM, et al. Myocardial imaging in man with I-123 metaiodobenzylguanidine. J Nucl Med 1981;22:129–32. [4] Flotats A, Carrio I. Cardiac neurotransmission SPECT imaging. J Nucl Cardiol 2004;11:587–602. [5] Wieland DM, Brown LE, Rogers WL, et al. Myocardial imaging with a radioiodinated norepinephrine storage analog. J Nucl Med 1981;22: 22–31.
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