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123I-metaiodobenzylguanidine (MIBG) is a radiolabeled norepinephrine analog that can be used to investigate myocardial sympathetic innervation. 123I MIBG scintigraphy has been investigated with interest in many disease settings. In patients with systolic heart failure (HF), 123I MIBG scintigraphy can capture functional impairment and rarefaction of sympathetic terminals (which manifest as reduced early and late heart-to-mediastinum [H/M] ratio on planar scintigraphy), and increased sympathetic outflow (which can be visualized as high washout rate). These findings have been consistently associated with a worse outcome: most notably, a phase 3 trial found that patients with a late H/M 1.60 have a higher incidence of all-cause and cardiovascular mortality and life-threatening arrhythmias over a follow-up of less than 2 years. Despite these promising findings, 123I MIBG scintigraphy has not yet been recommended by major HF guidelines as a tool for additive risk stratification, and has then never entered the stage of widespread adoption into current clinical practice. 123I MIBG scintigraphy has been evaluated also in patients with myocardial infarction, genetic disorders characterized by an increased susceptibility to ventricular arrhythmias, and several other conditions characterized by impaired sympathetic myocardial innervation. In the present chapter we will summarize the state-of-the-art on cardiac 123I MIBG scintigraphy, the current unresolved issues, and the possible directions of future research.

123I-metaiodobenzylguanidine (MIBG) is a radiolabeled norepinephrine analog that can be used to investigate myocardial sympathetic innervation. 123I MIBG scintigraphy has been investigated with interest in many heart disease settings. In patients with systolic heart failure (HF), 123I MIBG scintigraphy can capture functional impairment and rarefaction of sympathetic terminals (which manifest as reduced early and late heart-to-mediastinum [H/M] ratio on planar scintigraphy), and increased sympathetic outflow (which can be visualized as high washout rate). These findings have been consistently associated with a worse outcome: most notably, a phase 3 trial found that patients with a late H/M 1.60 have a higher incidence of all-cause and cardiovascular mortality and life-threatening arrhythmias over a follow-up of less than 2years. Despite these promising findings, 123I MIBG scintigraphy has not yet been recommended by major HF guidelines as a tool for additive risk stratification, and has then never entered the stage of widespread adoption into current clinical practice. 123I MIBG scintigraphy has been evaluated also in patients with myocardial infarction, genetic disorders characterized by an increased susceptibility to ventricular arrhythmias, and several other conditions characterized by impaired sympathetic myocardial innervation. Across different disorders, scintigraphy evidence increased sympathetic outflow and a mismatch between innervation and perfusion emerged quite consistently as predictors of a worse outcome. In the present article we will summarize the state-of-the-art on cardiac 123I MIBG scintigraphy, the applications in various heart diseases, the current unresolved issues, and the possible directions of future research.

The CZT-cameras (DNM 530c and DSPECT) have only recently been introduced, and the impact of the increased energy resolution remains unknown. This paper summarizes the evidence on the assessment of: (i) the left ventricular function, (ii) the 123I/99mTc mismatch, and (iii) the heart-to-mediastinum ratio (HMR) of 123I-metaiodobenzylguanidine (MIBG) uptake under dual-isotope conditions (99mTc and 123I) using cadmium-zinc-telluride (CZT) technology. The diagnostic accuracy of CZT cameras for myocardial sympathetic innervation imaging, left ventricular function and perfusion assessment using perfusion-gated SPECT have only been established in a few studies, under single-isotope conditions. Limited evidence is available regarding simultaneous dual-isotope acquisition using CZT-cameras. However, recently reported data have shown that CZT cameras allow, in dual-isotope (123I and 99mTc) acquisitions and under routine conditions: (i) a simultaneous and accurate segmental study of myocardial innervation and perfusion (match and mismatch), (ii) the ventricular function assessment (EDV, ESV and LVEF), and (iii) the determination of the late HMR of cardiac 123I-MIBG uptake in patients with heart failure. However, this latter should be performed using transaxial reconstructed images and a linear correction based on phantom data acquisitions. Conclusion With an increased energy resolution, the CZT cameras should become the one-stop shop SPECT for simultaneous dual-isotope 123I/99mTc acquisitions in heart failure patients, permitting to perform LV function, myocardial perfusion and innervation.

Pulmonary arterial hypertension (PAH) is characterized by the right ventricle (RV) remodeling and pulmonary endothelial dysfunction. We studied cardiac perfusion and innervation in PAH with a cadmium-zinc-telluride (CZT) scanner and lung uptake impairment of 123I-metaiodobenzylguanidine (123I-MIBG). In 13 patients with newly diagnosed PAH and 11 dilated cardiomyopathies (DCM, for comparative purposes), we assessed early and delayed 123I-MIBG uptake ratios of lung-to-mediastinum (L/M) and heart-to-mediastinum (H/M) on anterior planar images. A quantitative myocardial innervation with 123I-MIBG and perfusion with 99mTc-tetrofosmin using CZT-SPECT was performed. All patients underwent right heart catheterization. Early and delayed L/M ratios in PAH were lower than DCM (1.47 ± 0.14 vs 1.98 ± 0.11 and 1.40 ± 0.13 vs 1.83 ± 0.09; P

Cardiac positron emission tomography (PET) is mainly applied in myocardial perfusion and viability detection. Noninvasive imaging of myocardial innervation using PET is a valuable additional methodology in cardiac imaging. Novel methods and different PET ligands have been developed to measure presynaptic and postsynaptic function of the cardiac neuronal system. Obtained PET data can be analysed quantitatively or interpreted qualitatively. Thus far, PET is not a widely used clinical application in autonomic heart imaging; however, due to its technical advantages, the excellent properties of the imaging agents, and the availability of tools for quantification, it deserves a better position in the clinic. From a historical point of view, the focus of PET software packages for image analysis was mainly oncology and neurology driven. Actually, commercially available software for cardiac PET image analysis is still only available for the quantification of myocardial blood flow. Thus far, no commercial software package is available for the interpretation and quantification of PET innervation scans. However, image data quantification and analysis of kinetic data can be performed using adjusted generic tools. This paper gives an overview of different neuronal PET ligands, interpretation and quantification of acquired PET data.

Mismatch between areas of reduced myocardial blood flow (MBF) and reduced myocardial innervation (defect areas) may be used to estimate the risk for ventricular arrhythmias. The presence of a mismatch zone can be derived using a combined protocol consisting of both an MBF scan and an (11)C-meta-hydroxyephedrine ((11)C-HED) scan. The rate of influx from blood to myocardium (K1) of (11)C-HED is proportional to MBF and can potentially be used as an index for defining MBF defects. The aim of this study was to assess whether K1 derived from an (11)C-HED scan can be used as an index of MBF, potentially allowing for an assessment of MBF-innervation mismatch areas from a single (11)C-HED scan.Seventeen patients with known ischemic cardiomyopathy underwent dynamic (15)O-water and (11)C-HED scans. Discrete arterial blood samples were taken during (11)C-HED scans for metabolite correction of the image-derived input function. (11)C-HED influx rate was obtained using a single-tissue-compartment model and compared with transmural MBF (MBFT), defined as MBF as measured with (15)O-water multiplied by perfusable tissue fraction. Defect sizes were obtained from parametric K1 and MBFT images, using 50% of a remote control segment as the cutoff value.There was a significant correlation between MBFT and K1 (y = 0.40x + 0.05 mL·g(-1)·min(-1), r = 0.80, P0.001), although K1 was significantly lower than MBFT (slope of the regression line significantly different from 1, P0.001). Correlation between MBFT and K1 defect sizes was high (y = 0.89x + 1.38%, r = 0.95, P0.001), with no significant difference in mean defect size based on K1 or MBFT (20.9% ± 11.3% and 20.1% ± 10.7% for MBFT and K1, respectively, P = 0.41).(11)C-HED influx rate K1 can be used as an alternative to a separate MBF scan for assessing mismatch areas between MBF and myocardial innervation.

A possible relationship between cardiac sympathetic denervation and left ventricular (LV) diastolic dysfunction has been suggested. However, an evaluation of the interactions between myocardial adrenergic tone and LV perfusion and diastolic function is lacking.Seventy-two patients underwentThe burden of LV regions showing an innervation/perfusion mismatch associates with the occurrence of overt diastolic dysfunction.

New dedicated-cardiac cameras using CZT detectors have dramatically transformed the routine of myocardial perfusion imaging. With a better count detection sensitivity, an improved spatial and energy resolution, they potentially enable combined assessment of myocardial innervation (123I) and perfusion (99mTc) within a single imaging session. These cameras images with different sharpness and contrast-to-noise ratios.Using two CZT cameras with anthropomorphic phantom, and clinical studies in heart failure patients, our work focused on (i) the left ventricular function assessment within the 99mTc window in presence of 123I, (ii) the evaluation of regional myocardial innervation (123I) and perfusion (99mTc) match and mismatch with single- (separate 123I and 99mTc acquisition) and simultaneous dual-isotope acquisitions, and (iii) the late heart-to-mediastinal ratio (HMR) of 123I-MIBG uptake determined using dual-isotope CZT acquisition with that determined using conventional planar imaging in patients with heart failure.Our results found no impact of the acquisition mode (single vs dual) or the type of CZT camera on 123I and 99mTc defect size and mismatch, LVEF, and HMR of 123I-MIBG uptake.This work provides a new step toward simultaneous dual-isotope acquisition for combined innervation, perfusion and ventricular function assessment., Les nouvelles gamma-caméras à semi-conducteurs utilisant des détecteurs au CZT sont dédiées aux explorations cardiaques. Leurs sensibilité, résolution spatiale et en énergie nettement améliorées comparativement aux gamma-caméras conventionnelles sont une révolution en médecine nucléaire. Ces gamma-caméras utilisent de nouvelles géométries d’acquisition, de nouveaux algorithmes de reconstruction, et ouvrent de nouvelles perspectives dans les études simultanées en double-isotope de l’123I et du 99mTc, dont les pics énergétiques sont proches.Nous avons étudié l’impact de l’amélioration de la résolution en énergie en comparant deux modèles de gamma-caméras à détecteurs semi-conducteurs aux gamma-caméras conventionnelles. A l’aide d’études sur fantômes anthropomorphes et chez des patients porteurs d’insuffisance cardiaque, notre travail s’est concentré sur les acquisitions scintigraphiques (i) de la fonction ventriculaire gauche (99mTc) en présence d’123I, (ii) de la perfusion myocardique (99mTc) en présence d’123I (innervation), et (iii) du rapport cardiomédiastinal de la fixation d’123I- métaiodobenzylguanidine (123I-MIBG) lors d’acquisitions double-isotope (123I-MIBG/99mTc- tétrofosmine) chez les patients souffrant d’insuffisance cardiaque.Nos résultats montrent que la meilleure résolution en énergie des gamma-caméras CZT permet en étude double-isotope (i) une évaluation de la FEVG et du mouvement régional dans les différentes fenêtres d'énergie (123I ou 99mTc) et les types d'acquisition (simple- vs double-isotope), (ii) une évaluation simultanée et combinée de la perfusion (99mTc) et de l’innervation (123I) du myocarde, et (iii) l’évaluation du rapport cardiomédiastinal de la fixation d’123I-MIBG. Chacune de ces trois parties a fait l’objet d’une publication.

In recent years, heart failure has been recognized as a major and increasing public health issue. In the context of the shortage of heart donors and increasing waiting time on the transplantation list, nonpulsatile left ventricular assist devices (LVAD) have shown their efficiency in reducing mortality and improving quality of life in patients with end-stage heart failure. Among LVAD recipients, a minority of patients will recover a normal cardiac function, allowing pump weaning. However, the evaluation of intrinsic cardiac function is particularly challenging and still a matter of debate in LVAD recipients.

The usefulness of imaging the cardiac sympathetic nervous system is increasingly supported by prospective clinical studies. The future success of this molecular imaging technique, however, will depend on careful design of additional trials. But preclinical and clinical use requires a thorough understanding of the underlying biology, which defines the relationship between neuronal tracer kinetics, disease mechanisms, and appropriate study interpretation. This review focuses on basic methodologic aspects considered relevant for successful continuation of the translation of cardiac neuronal imaging from a research tool toward a clinical test.

The sympathetic innervation of the hypertrophied myocardium was investigated by the histochemical fluorescence method for biogenic monoamines and electron microscopy. Cardiac hypertrophy was induced by renal hypertension, aortic stenosis and swimming exercise. An increase in the density of adrenergic structures was observed in relation to small vessels in the left cardiac wall in swimming exercised rats and, although to a much less extent, in the hypertensive rats. In relation to the larger myocardial vessels an increased density was observed in swimming exercised rats and in rats with long-term hypertension. In the electron microscope, nerve structures were seen adjacent to growing capillaries. The number of nerve fibres and filaments related to each vessel was not increased. No change was observed in the rats with aortic stenosis. The observations indicate that in cardiac hypertrophy secondary to swimming exercise the newly formed myocardial blood vessels aquire a normal adrenergic nerve supply.

Molecular imaging holds the promise of becoming a key diagnostic modality in cardiovascular medicine by allowing visualization of specific targets and pathways that precede or underlie changes in morphology, physiology, and function. As such, molecular imaging aims at detecting precursors or early stages of cardiovascular disease and at monitoring and guiding novel, increasingly specific and versatile cardiovascular therapies. Imaging of myocardial metabolism and autonomic innervation are already used in current practice, and a wide variety of other targets and probes is on the horizon. This focused review provides an overview of the opportunities and challenges that molecular imaging faces to fulfill its promises in clinical cardiovascular medicine.

Cardiac autonomic innervation imaging has been focused on assessing molecular, electrophysiologic, and pathophysiologic processes of various cardiac disorders. Iodine radiotracer (I-123)-labeled metaiodobenzylguanidine (MIBG), as a marker of adrenergic neuron function, plays an important role in risk stratification and treatment monitoring of heart failure patients. In addition, MIBG has a potential value for predicting fatal arrhythmias that may require implantable cardioverter-defibrillator treatment. Among various positron emission tomography (PET) tracers for probing autonomic neuronal function, C-11 hydroxyephedrine (HED), has been used for precise assessment of heart failure and arrhythmias, similar to MIBG. More studies are needed to confirm the clinical utility of these molecular imaging modalities for the management of patients with heart failure, coronary artery disease and arrhythmias.

Non-invasive imaging of myocardial innervation using positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) is a valuable methodology in cardiac imaging. Although it never entered the clinical arena in an extent as single-photon emission computed tomography (SPECT) imaging for this purpose did, its technical advantages, the excellent properties of the imaging agents, and the availability of tools for quantification combine into an occasionally underrated approach.

Coronary artery disease is a major cause of mortality and morbidity in the western world. Despite successive revascularization procedures, a large number of patients ends up with end-stage coronary artery disease, not amenable for conventional revascularization. These patients often have stress-inducible myocardial ischemia, resulting in disabling complaints of angina, refractory to medical treatment. Intramyocardial bone marrow cell injection is currently under investigation as a new therapeutic option for these patients. This treatment aims to improve myocardial perfusion and contractile function (and decrease anginal complaints) through administration of bone marrow cells into ischemic myocardium. In the current thesis, the use of intramyocardial bone marrow cell injection for the treatment of chronic myocardial ischemia is evaluated several studies. First, the results of a randomized, placebo controlled, double-blinded trial are described, demonstrating that bone marrow cell injection is associated with a reduction in angina complaints, improved myocardial perfusion and increased left ventricular function. Furthermore, the effects of intramyocardial bone marrow cell injection were further explored by evaluating changes in diastolic function, cardiac innervation, and left ventricular synchronicity. In addition, the long term effects of bone marrow cell injection are described.

(123)I-meta-iodobenzyl-guanidine ((123)I-MIBG) scintigraphy is used to visualize and quantify the sympathetic nerve activity. Although it has been used since 1980 to identify myocardial innervation, it is not yet regarded a routine sympathetic imaging agent in this respect. The lack of large multicentre studies and the presence of variations in the protocols that are used for planar MIBG acquisition confines the comparability of study results and application of normal values. Therefore, the aim of this study was to assess the variations in mathematical methods that are currently used to quantify the heart-to-mediastinum ratio and washout rate (WOR). In addition, normal values were evaluated in concordance with these methods. A systematic literature search yielded 169 unique manuscripts, of which 30 contained a complete description of the acquisition protocol for planar MIBG acquisition, image analysis and quantification of the parameters. The results indicate not only large variations in mathematical methods, but also in various aspects of the protocols that are used during acquisition. In many manuscripts method-specific normal values were used; however, these values were generally generated from small, single-centre studies. This study stresses the need to produce guidelines to achieve a standardized method for MIBG acquisition, image analysis and methods to quantify parameters.