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Editorial

Can cardiac [123I] m-iodobenzylguanidine imaging be used for risk stratication of patients with acute myocardial infarction?
Mark J Boogers,1,2 Jeroen J Bax1
The sympathetic nervous system of the heart is critically involved in the maintenance of cardiovascular homoeostasis by regulation of cardiac contractility, conduction, heart frequency and peripheral vasoconstriction.1 It has been shown that a dysfunctional cardiac sympathetic nervous system exerts detrimental effects on the structural and functional integrity of the myocardium, leading to a marked increase in the morbidity and mortality rates of patients with cardiac disease.2 3 For this reason, the cardiac sympathetic nervous system has been used for prognostication of patients with cardiovascular disease.2e6 Evaluation of the cardiac sympathetic nervous system can be performed with radionuclide imaging of [123I]m-iodobenzylguanidine ([123I]MIBG). [123I]MIBG is a norepinephrine analogue which uses similar uptake and storage mechanisms within the sympathetic neuron as norepinephrine. Cardiac uptake of [123I] MIBG is predominantly determined by two pathways: it can be cleared from the synaptic cleft by (1) the norepinephrine transporter protein located at the dilated endings of the sympathetic neuron or (2) the non-neuronal transport mechanism located at the post-synaptic site of the cleft. Importantly, once taken up by the sympathetic neuron, [123I]MIBG is not metabolised by proteolytic enzymes. As a consequence, [123I]MIBG is preserved with its original molecular structure, which makes [123I]MIBG suitable for visualisation of cardiac sympathetic innervation and activation. A complete [123I]MIBG imaging protocol consists of planar and single photon emission computed tomography (SPECT) imaging performed at 10e20 min (early imaging) and 3e4 h (delayed imaging) after administration of the tracer. Planar imaging provides information on global sympathetic innervation or activation, whereas SPECT imaging can be used for assessment of regional cardiac sympathetic innervation or activation (gure 1). On planar imaging, the heartto-mediastinum (H/M) ratio is determined by dividing the mean counts per pixel within the cardiac region of interest by the mean counts per pixel within mediastinal region of interest. In addition, the myocardial [123I]MIBG washout rate can be assessed by comparing early and delayed myocardial uptake of [123I]MIBG. The [123I]MIBG washout rate reects the degree of sympathetic activation of the heart.7

At present, several studies have demonstrated that cardiac [123I]MIBG imaging can be used for risk stratication of patients with chronic heart failure, regardless of their underlying aetiology.4e6 Sympathetic nerve imaging with [123I] MIBG has predominantly been used for the prediction of cardiac death or worsening heart failure.4e6 One of the rst studies was performed by Merlet et al,4 who evaluated the prognostic value of cardiac [123I]MIBG imaging in 90 patients with heart failure. A delayed H/M ratio was identied as the most powerful predictor for survival over a follow-up period of 1e27 months. Recently, the ADMIRE-HF trial was performed that aimed to prospectively validate the prognostic value of [123I]MIBG imaging in 961 patients with heart failure. Over the 2-year follow-up period, 237 (25%) patients experienced an adverse cardiac event, dened as progression of heart failure, occurrence of life-threatening ventricular arrhythmias or cardiac death. Patients with adverse events showed a signicantly lower H/M ratio (p<0.01) as well as higher myocardial washout rate (p<0.01) than patients without adverse events. Impairment of cardiac sympathetic innervation is also thought to have a considerable role in the development of life-threatening ventricular arrhythmias and sudden cardiac death.8 9 More specically, regions with deprived sympathetic innervation but preserved viability (the socalled innervation/perfusion mismatch) may serve as arrhythmogenic substrate as these regions may show an enhanced automaticity and increased triggering as compared with regions with preserved

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 2The Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Correspondence to Jeroen J Bax, Department Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands; j.j.bax@lumc.nl Heart January 2011 Vol 97 No 1

Figure 1 Cardiac [123I]m-iodobenzylguanidine imaging can be used to evaluate sympathetic innervation of the heart. Planar imaging (A) provides information on global sympathetic innervation, whereas single photon emission Computed Tomography imaging (B) provides information on regional sympathetic innervation. The heart-to-mediastinum (H/M) ratio was calculated by dividing the mean counts per pixel within the myocardial region of interest (H) by the mean counts per pixel within the upper mediastinum (M).
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Editorial
sympathetic innervation.8 10 Additionally, regions with impaired sympathetic innervation can exhibit an increased electromechanical instability due to myocardial catecholamine overexposure.10 The presence of myocardial electrical instability, which is referred to as electrophysiological heterogeneity, has been related to the initiation of re-entrant arrhythmias within the myocardium.11 Various studies have demonstrated the ability of cardiac [123I] MIBG imaging to identify patients at high risk for potentially lethal ventricular arrhythmias or sudden cardiac death.6 7 12 Recently, the value of cardiac [123I] MIBG imaging for prediction of appropriate implantable cardioverter-debrillator (ICD) therapy (surrogate for potential lethal ventricular arrhythmias) was studied in 116 patients receiving ICD treatment.12 ICD indication (secondary vs primary) and cardiac sympathetic denervation were independently associated with appropriate ICD therapy over a mean follow-up of 23615 months (p<0.01). Furthermore, the cardiac sympathetic drive is presumed to be signicantly involved in the ventricular arrhythmogenesis of patients with heart failure.7 9 Tamaki et al7 showed that the myocardial washout of [123I]MIBG was an independent predictor for sudden cardiac death in 106 patients with stable chronic heart failure. Although the majority of studies have conrmed the predictive value of cardiac [123I]MIBG imaging in patients with heart failure, its role for prediction of outcome in patients with unstable clinical conditions (eg, acute myocardial infarction (AMI)) has not been elucidated. Accordingly, the study from Kasama et al13 published in this issue of Heart represents an interesting study as it evaluates whether [123I]MIBG imaging is predictive for adverse outcome in patients with ST-segment elevation myocardial infarction (STEMI) (see page 20). Patients with chest pain for more than 30 min, ST-segment elevation of >2 mm and increased levels of serum creatine phosphokinase were diagnosed with STEMI, for which they received standard medical care. Cardiac [123I]MIBG imaging and echocardiography (or left ventriculography) were performed 3 weeks after the onset of STEMI. Adverse cardiac events were documented during follow-up, including cardiac death, nonfatal myocardial infarction and hospitalisation due to worsening heart failure. The study was based on 213 patients with STEMI who had undergone cardiac [123I] MIBG imaging. A total of 54 (25%) patients experienced an adverse cardiac
2

event during a median follow-up of 982 days. Of the 54 patients, cardiac death was documented in 18 (33%). Multivariate Cox regression analyses demonstrated that high myocardial [123I]MIBG washout rate, reduced left ventricular ejection fraction and not having percutaneous coronary intervention were independent predictors for any adverse events and cardiac death. Finally, KaplaneMeier analyses showed that patients with a washout rate of $40% showed signicantly lower cardiac death free-rate than patients with a washout rate of <40% (p<0.01). Accordingly, the study showed that cardiac [123I]MIBG imaging can be used for risk stratication of patients with STEMI. Thus far, the hypothesis that the cardiac sympathetic nervous system as assessed with [123I]MIBG imaging has an essential role in the prediction of long-term outcome has only been evaluated in patients with stable and chronic heart failure, while patients with AMI were excluded.4e6 The study by Kasama et al13 represents the rst study evaluating the value of cardiac [123I]MIBG imaging for prediction of long-term outcome in patients with AMI. In these patients, cardiac [123I]MIBG imaging has only been used to assess the extent of post-infarct sympathetic denervation or to evaluate the relation between cardiac sympathetic denervation and ventricular remodelling shortly after myocardial infarction.14 15 In 50 patients with AMI, Sakata et al14 showed that changes in sympathetic defect on [123I]MIBG SPECT imaging were predictive for ventricular remodelling 4 weeks after infarction. Although this study clearly demonstrated the prognostic value of cardiac [123I]MIBG imaging in patients with AMI, some limitations need to be considered. First, the level of plasma norepinephrine and its spillover were not measured in the study. As these variables are predictive for adverse outcome in patients with AMI,16 it would be interesting to evaluate the relation between plasma norepinephrine levels (or its spillover) and cardiac [123I] MIBG imaging variables. Furthermore, the reproducibility of [123I]MIBG imaging variables was not assessed. Although the authors used a standardised approach for assessment of [123I]MIBG imaging parameters, intra- and interobserver reproducibility analyses would have considerably improved the robustness of the current analyses. Finally, the study did not evaluate cardiac regions with deprived sympathetic innervation but preserved viability (the socalled innervation/perfusion mismatch),

which has been identied as myocardium at risk for development of life-threatening ventricular arrhythmias or sudden cardiac death.8e10 Despite these study limitations, the study by Kasama et al13 contributes signicantly to the current literature as it provides evidence that cardiac [123I]MIBG imaging can be used for risk stratication of patients with AMI. Additional studies are needed that will examine the role of innervation/perfusion mismatch for prediction of long-term outcome in patients with AMI.
Funding MJB supported by the Dutch Heart Foundation, grant 2006T102. JJB received research grants from Medtronic, Boston Scientic, Edwards Lifesciences, BMS Medical Imaging, St Jude Medical and GE Healthcare. Competing interests None. Provenance and peer review Commissioned; not externally peer reviewed. Published Online First 11 November 2010 Heart 2011;97:1e3. doi:10.1136/hrt.2010.209007

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Heart January 2011 Vol 97 No 1

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Can cardiac [123I]m-iodobenzylguanidine imaging be used for risk stratification of patients with acute myocardial infarction?
Mark J Boogers and Jeroen J Bax Heart 2011 97: 1-3 originally published online November 11, 2010

doi: 10.1136/hrt.2010.209007

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