Derk O. Verschure

For what endpoint does myocardial 123I-MIBG scintigraphy have the greatest prognostic value in patients with chronic heart failure? Results of a pooled individual patient data meta-analysis

AIMS The purpose of this study was to determine the most appropriate prognostic endpoint for myocardial (123)I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with chronic heart failure (CHF) based on aggregate results from multiple studies published in the past decade. METHODS AND RESULTS Original individual late (3-5 h) heart/mediastinum (H/M) ratio data of 636 CHF patients were retrieved from six studies from Europe and the USA. All-cause mortality, cardiac mortality, arrhythmic events, and heart transplantation were investigated to determine which provided the strongest prognostic significance for the MIBG imaging data. The majority of patients was male (78%), had a decreased left ventricular ejection fraction (31.1 ± 12.5%), and a mean late H/M of 1.67 ± 0.47. During follow-up (mean 36.9 ± 20.1 months), there were 83 deaths, 67 cardiac deaths, 33 arrhythmic events, and 56 heart transplants. In univariate regression analysis, late H/M was a significant predictor of all event categories, but lowest hazard ratios (HRs) were for the composite endpoint of any event (HR = 0.30, 95% CI 0.19-0.46), all-cause (HR = 0.29, 95% CI 0.16-0.53), and cardiac mortality (HR = 0.28, 95% CI 0.14-0.55). In multivariate analysis, late H/M was an independent predictor for all event categories, except for arrhythmias. CONCLUSIONS This pooled individual patient data meta-analysis showed that, in CHF patients, the late H/M ratio is not only useful as a dichotomous predictor of events (high vs. low risk), but also has prognostic implication over the full range of the outcome value for all event categories except arrhythmias.

A European myocardial 123I-mIBG cross-calibration phantom study

AimPlanar myocardial 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy is a highly reproducible technique. However, differences in collimator use are one of the most important factors that cause variation among institutions and studies in heart-to-mediastinum (H/M) ratio. Therefore, standardization among various gamma camera-collimator combinations is needed. Previously, a phantom has been developed to cross-calibrate different acquisition conditions in Japan. For further cross-calibration of European myocardial 123I-mIBG imaging, the aim of this study was to collect 123I-mIBG data for H/M ratios from common European gamma camera vendors.Methods210 experiments were performed in 27 European institutions. Based on these experiments, conversion coefficients for each gamma camera-collimator combination were calculated. An averaged conversion coefficient of 0.88 was used to calculate a standardized H/M ratio.ResultsOn average, LE-collimator-derived H/M ratios were significantly lower compared to ME-collimator-derived H/M ratios. The mean conversion coefficients ranged from 0.553 to 0.605 for the LE-collimator group and from 0.824 to 0.895 for the ME-collimator group.ConclusionClinically established H/M ratios can be converted into standardized H/M ratios using cross-calibrated conversion coefficients. This standardization is important for identifying appropriate thresholds for adequate risk stratification. In addition, this cross-calibration enables comparison between different national and international data.

Tako-tsubo cardiomyopathy: how to understand possible pathophysiological mechanism and the role of (123)I-MIBG imaging.

Tako-tsubo cardiomyopathy (TCM) is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction, commonly preceded by exposure to severe physical or emotional stress. In this review, we give a short overview on clinical presentation and treatment of TCM and discuss the possible pathophysiological mechanisms of TCM and the role of various non-invasive imaging modalities in TCM with a focus on the potential role of 123I-meta-iodobenzylguanidine (MIBG) scintigraphy. Currently, the dominating hypothesis on the pathophysiology of TCM postulates that high levels of the neurotransmitter epinephrine may trigger a change in intracellular signaling in ventricular myocytes. More specific, epinephrine stimulates G-protein coupled β2 adenoreceptors (β2AR) which are located on ventricular myocytes. Normal levels of this neurotransmitter predominantly stimulate the intracellular G-protein, and induce a positive inotropic effect. However, with significant increasing levels of epinephrine, the predominance of stimulation is shifted from G-stimulating to the G-inhibitor protein coupling, which leads to a negative inotropic effect. Interestingly, this negative inotropic effect is the largest in the apical myocardium where the β2AR:β1AR ratio is the highest within the heart. Echocardiography and ventriculography are essential to diagnose TCM, but new imaging tools are promising to diagnose TCM and to evaluate therapeutic efficacy. Cardiovascular magnetic resonance can be used to differentiate TCM from other myocardial diseases, such as myocarditis. 123I-meta-iodobenzylguanidine (123I-MIBG) scintigraphy can be used to assess ventricular adrenergic activity and may guide optimization of individual (pharmacological) therapy. These new insights into the possible pathophysiological mechanisms and novel diagnostic imaging modalities can be used as starting point for the development of international guidelines of TCM which may increase the awareness, and optimize the treatment of TCM.

Cardiac 123I-mIBG scintigraphy is associated with freedom of appropriate ICD therapy in stable chronic heart failure patients

AIM Chronic heart failure (CHF) is a life-threatening clinical syndrome, partly due to sudden cardiac death (SCD). Implantable cardioverter defibrillators (ICD) for primary prevention of SCD have improved overall survival of CHF patients. However, a high percentage of patients never receives appropriate ICD therapy. This prospective multicentre study evaluated whether cardiac sympathetic activity assessed by 123I-mIBG scintigraphy could be helpful in selecting patients for ICD implantation. MATERIALS AND METHODS 135 stable CHF subjects (age 64.5±9.3years, 79% male, LVEF 25±6%) referred for prophylactic ICD implantation were enrolled in 13 institutions. All subjects underwent planar and SPECT 123I-mIBG scintigraphy. Early and late heart-to-mediastinum (H/M) ratio, 123I-mIBG washout (WO) and late summed scores were calculated. The primary endpoint was appropriate ICD therapy. The secondary endpoint was defined as the combined endpoint of all first cardiac events: appropriate ICD therapy, progression of heart failure (HF) and cardiac death. RESULTS During a median follow-up of 30months (6-68months), 24 subjects (17.8%) experienced a first cardiac event (appropriate ICD therapy [12], HF progression [6], cardiac death [6]). Late H/M ratio and defect size of 123I-mIBG SPECT were not associated with appropriate ICD therapy. However, late H/M ratio was independently associated with the combined endpoint (HR 0.135 [0.035-0.517], p=0.001). Post-hoc analysis showed that the combination of late H/M ratio (HR 0.461 [0.281-0.757]) and LVEF (HR 1.052 [1.021-1.084]) was significantly associated with freedom of appropriate ICD therapy (p<0.001). CONCLUSION 123I-mIBG scintigraphy seems to be helpful in selecting CHF subjects who might not benefit from ICD implantation.

123i-mibg heart-to-mediastinum ratio is influenced by high-energy photon penetration of collimator septa from liver and lung activity

AimThe 123I-metaiodobenzylguanidine (123I-MIBG) late heart-to-mediastinum ratio (H/M) is a well-established prognostic parameter in patients with chronic heart failure (CHF). However, 123I presents imaging problems owing to high-energy photon emission leading to penetration of collimator septa and subsequent reduction in image quality. Most likely this affects the H/M ratio and may subsequently lead to incorrect patient risk classification. In this prospective study we assessed the intrapatient variation in late H/M ratio between low-energy high-resolution (LEHR) and medium-energy (ME) collimators in patients with CHF. Materials and methodsFifty-three patients with CHF (87% male, age 63±8.3 years, left ventricular ejection fraction 29±7.8) referred for 123I-MIBG scintigraphy were enrolled in the study. In each patient, after the administration of 185 MBq 123I-MIBG, early (15 min after injection) and late (4 h after injection) planar anterior thoracic images were acquired with both LEHR and ME collimators. Early and late H/M ratios were calculated on the basis of the mean count densities from the manually drawn regions of interest (ROIs) over the left ventricle and a predefined fixed ROI placed in the upper mediastinum. Additional ROIs were drawn over the liver and lungs. Liver/lung to myocardium and liver/lung to mediastinal ratios were calculated to estimate the effect of collimator septa penetration from liver and lung activity on the myocardial and mediastinal ROIs. ResultsThe mean LEHR collimator-derived parameters were lower compared with those from the ME collimator (late H/M 1.41±0.18 vs. 1.80±0.41, P<0.001). Moreover, Bland–Altman analysis showed that with increasing late H/M ratios the difference between the ratios from the two collimator types increased (R2=0.73, P=0.001). Multivariate regression analysis showed that almost 90% of the variation in the difference between ME and LEHR late H/M ratios could be explained by scatter from the liver in both the mediastinal and myocardial ROIs (R2=0.90, P=0.001). Independent predictors for the difference in the late H/M between ME and LEHR were the liver-to-heart ratio and the liver-to-mediastinum ratio assessed by ME (standardized coefficient of −1.69 and 1.16, respectively) and LEHR (standardized coefficient of 1.24 and −0.90, respectively) (P<0.001 for all). ConclusionIntrapatient comparison in H/M between the ME and LEHR collimators in patients with CHF showed that with increasing H/M the difference between the ratios increased in favour of the ME collimator. These differences could be explained by septal penetration of high-energy photons from both the liver and the lung in the mediastinum and myocardium, being lowest when using the ME collimator. These results strengthen the importance of the recommendation to use ME collimators in semiquantitative 123I-MIBG studies.

Standardization of 123I-meta-iodobenzylguanidine myocardial sympathetic activity imaging: phantom calibration and clinical applications

PurposeMyocardial sympathetic imaging with 123I-meta-iodobenzylguanidine (123I-mIBG) has gained clinical momentum. Although the need for standardization of 123I-mIBG myocardial uptake has been recognized, the availability of practical clinical standardization approaches is limited. The need for standardization includes the heart-to-mediastinum ratio (HMR) and washout rate with planar imaging, and myocardial defect scoring with single-photon emission computed tomography (SPECT).MethodsThe planar HMR shows considerable variation due to differences in collimator design. These camera–collimator differences can be overcome by cross-calibration phantom experiments. The principles of these cross-calibration phantom experiments are summarized in this article. 123I-mIBG SPECT databases were compiled by Japanese Society of Nuclear Medicine working group. Literature was searched based on the words “123I-mIBG quantification method”, “standardization”, “heart-to-mediastinum ratio”, and its application to “risk model”.ResultsCalibration phantom experiments have been successfully performed in Japan and Europe. The benefit of these cross-calibration phantom experiments is that variation in the HMR between institutions is minimized including low-energy, low–medium-energy and medium-energy collimators. The use of myocardial 123I-mIBG SPECT can be standardized using 123I-mIBG normal databases as a basis for quantitative evaluation. This standardization method can be applied in cardiac event prediction models.ConclusionStandardization of myocardial 123I-mIBG outcome parameters may facilitate a universal implementation of myocardial 123I-mIBG scintigraphy.

Cardiac sympathetic activity in hypertrophic cardiomyopathy and Tako-tsubo cardiomyopathy

Abstract123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy has been established as an important technique to evaluate cardiac sympathetic function and it has been shown to be of clinical value, especially for the assessment of prognosis, in many cardiac diseases. The majority of 123I-mIBG scintigraphy studies have focused on patients with cardiac dysfunction due to hypertension, ischemic heart disease, or valvular disease. However less is known about the role of 123I-mIBG scintigraphy in primary cardiomyopathies. This overview shows the clinical value of 123I-mIBG scintigraphy in two types of primary cardiomyopathy: The genetic hypertrophic cardiomyopathy (HCM) and the acquired Tako-tsubo cardiomyopathy (TCM). Cardiac sympathetic activity is increased in HCM and correlates to the septal wall thickness and consequently to the LVOT obstruction. Moreover, increased cardiac sympathetic activity correlates with impaired diastolic and systolic LV function. In addition, 123I-mIBG scintigraphy may be useful for determining the risk of developing congestive heart failure and ventricular tachycardia in these patients. In TCM 123I-mIBG scintigraphy can be used to assess cardiac sympathetic hyperactivity. In addition, 123I-mIBG scintigraphy may identify those patients who are prone to TCM recurrence and may help to identify responders to individual (pharmacological) therapy.

Renal Function in Relation to Cardiac (123)I-MIBG Scintigraphy in Patients with Chronic Heart Failure.

The aim of this study was to explore if estimates of renal function could explain variability of 123I-metaiodobenzylguanidine (123I-MIBG) assessed myocardial sympathetic activity. Furthermore estimates of renal function were compared to 123I-MIBG as predictors of cardiac death in chronic heart failure (CHF). Semi-quantitative parameters of 123I-MIBG myocardial uptake and washout were calculated using early heart/mediastinum ratio (H/M), late H/M and washout. Renal function was calculated as estimated Creatinine Clearance (e-CC) and as estimated Glomerular Filtration Rate (e-GFR). Thirty-nine patients with CHF (24 males; age: 64.4 ± 10.5 years; NYHA II/III/IV: 17/20/2; LVEF: 24.0 ± 11.5%) were studied. Variability in any of the semi-quantitative 123I-MIBG myocardial parameters could not be explained by e-CC or e-GFR. During follow-up (60 ± 37 months) there were 6 cardiac deaths. Cox proportional hazard regression analysis showed that late H/M was the only independent predictor for cardiac death (Chi-square 3.2, regression coefficient: −4.095; standard error: 2.063; hazard ratio: 0.17 [95% CI: 0.000–0.950]). Addition of estimates of renal function did not significantly change the Chi-square of the model. Semi-quantitative 123I-MIBG myocardial parameters are independent of estimates of renal function. In addition, cardiac sympathetic innervation assessed by 123I-MIBG scintigraphy seems to be superior to renal function in the prediction of cardiac death in CHF patients.

Role of cardiac 123I-mIBG imaging in predicting arrhythmic events in stable chronic heart failure patients with an ICD

BackgroundDespite therapeutic improvement, the prognosis of chronic heart failure (CHF) remains unfavorable partly due to arrhythmia and sudden cardiac death (SCD). This prospective study evaluated myocardial 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy as a predictor of arrhythmic events (AE) in CHF patients.Methods170 CHF patients referred for implantable cardioverter-defibrillator (ICD) implantation for both primary and secondary prevention were enrolled. All patients underwent planar and SPECT imaging. Early and late heart-to-mediastinum (H/M) ratio, 123I-mIBG washout (WO), early and late summed SPECT scores were calculated The primary endpoint was an AE: sustained ventricular tachycardia, resuscitated cardiac arrest, appropriate ICD therapy or SCD. The secondary endpoint was appropriate ICD therapy.ResultsDuring a median follow-up of 23.3 months, 69 patients experienced an AE. Early summed score (ESS) was the only independent predictor of AE [HR 1.023 (1.003-1.043)]. Focussing on only patients with an ICD for primary prevention, ESS was the only independent predictor of AE [HR 1.028 (1.007-1.050)]. 123I-mIBG-derived parameters failed to be independent predictors of appropriate ICD therapy. However there was a “bell-shaped” relation between 123I-mIBG scintigraphy-derived parameters and AE and appropriate ICD therapy, i.e., those with intermediate 123I-mIBG abnormalities tended to be at higher risk of events.ConclusionAlthough SPECT 123I-mIBG scintigraphy was associated with AE in CHF patients with ICD implantation for primary and secondary prevention, no association was found between 123I-mIBG scintigraphy-derived parameters and appropriate ICD therapy.

The use of Cardiac 123I-mIBG Scintigraphy in Clinical Practice: The Necessity to Standardize!

A avaliacao da atividade adrenergica cardiaca atraves de exames de imagem apresenta grande potencial em uma ampla variedade de aplicacoes clinicas. A cintilografia miocardica com 123I-mIBG desempenha papel importante na avaliacao de insuficiencia cardiaca cronica (ICC) ao estratificar o risco de pacientes para eventos cardiacos. A mIBG, um analogo da norepinefrina (NE), pode ser utilizada para avaliar a atividade simpatica cardiaca ao se analisar a diminuicao da expressao do adrenorreceptor (AR) β na ICC. Alem disso, a cintilografia miocardica com 123I-mIBG em combinacao com outros parâmetros de funcao ventricular esquerda pode ser usada para identificar o melhor respondedor a dispositivos cardiacos implantaveis, assim como avaliar cardiotoxicidade oncologica. Ainda que util, a cintilografia miocardica com 123I-mIBG nao e amplamente realizada devido a falta de padronizacao entre as diferentes instituicoes. Portanto, sua padronizacao e validacao podem contribuir para sua aceitacao na pratica clinica.Mailing Address: Euclides Timóteo da Rocha Rua Antenor Duarte Vilela, 1331. Postal Code: 14784-700 – Bairro Dr. Paulo Prata, Barretos, São Paulo, SP – Brazil. E-mail: euclidestimoteo@uol.com.br The use of Cardiac 123I-mIBG Scintigraphy in Clinical Practice: The Necessity to Standardize! Euclides Timóteo da Rocha,1 Wilson Eduardo Furlan Matos Alves,1 Derk O. Verschure2 e Hein J Verberne2 Departamento de Medicina Nuclear, Hospital do Câncer de Barretos,1 Barretos, São Paulo, Brasil; Departamento de Radiologia e Medicina Nuclear, Academic Medical Center,2 Amsterdã the Netherlands