Functional Changes After Partial Left Ventriculectomy and Mitral Valve Repair Assessed by Gated Perfusion SPECT

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Oct, 2004  |  Pubmed ID: 15471822

A myocardial remodeling in dilated cardiomyopathy (DCM) after partial left ventriculectomy (PLV) has been previously discussed. The aim of this study was to investigate the functional changes in the follow-up of patients with DCM undergoing PLV using electrocardiographically triggered perfusion SPECT (gated SPECT).

High-density Lipoprotein Stimulates Myocardial Perfusion in Vivo

Circulation. Nov, 2004  |  Pubmed ID: 15545521

Several clinical studies have demonstrated a close association between plasma HDL cholesterol levels and endothelium-dependent vasodilation in peripheral arteries. In isolated arteries, HDL has been shown to mediate vasodilation via NO release. In vivo, administration of reconstituted HDL restored abnormal endothelial function of the brachial artery in hypercholesterolemic patients. However, no data are currently available on the effect of HDL on myocardial perfusion.

ECG-triggered High-resolution Positron Emission Tomography: a Breakthrough in Cardiac Molecular Imaging of Mice

European Journal of Nuclear Medicine and Molecular Imaging. Mar, 2005  |  Pubmed ID: 15791447

Monitoring Left Ventricular Dilation in Mice with PET

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Sep, 2005  |  Pubmed ID: 16157535

Molecular imaging by small-animal PET is an important noninvasive means to phenotype transgenic mouse models in vivo. When investigating pathologies of the left ventricular (LV) myocardium, the serial assessment of LV volumes is important. By this, the presence of LV dilation as a sign of developing heart failure can be detected. Whereas PET is usually used to derive biochemical and molecular information, functional parameters such as ventricular volumes are generally measured using echocardiography or MRI. In this study, a novel method to monitor LV dilation in mice with PET is presented and evaluated using cardiac MRI.

[Scintigraphic Molecular Imaging]

Zeitschrift Für Medizinische Physik. 2005  |  Pubmed ID: 16171035

Modern medicine is currently focusing its basic and clinical research towards "molecular medicine". This trend, together with the decoding of the human genome and the resulting design and use of transgenic mouse models of human diseases, demands that innovative imaging approaches are developed for man and mice. Non-invasive imaging modalities capable of quantifying molecular processes in vivo (collectively defined as "molecular imaging" techniques) are extremely interesting in this respect. This review focuses on the clinical and experimental scintigraphic molecular-imaging modalities SPECT and PET, and summarizes their actual and future impact in medicine.

Successful High-resolution Animal Positron Emission Tomography of Human Ewing Tumours and Their Metastases in a Murine Xenograft Model

European Journal of Nuclear Medicine and Molecular Imaging. Dec, 2006  |  Pubmed ID: 16896672

As primary osseous metastasis is the main adverse prognostic factor in patients with Ewing tumours, a NOD/scid mouse model for human Ewing tumour metastases has been established to examine the mechanisms of metastasis. The aim of this study was to evaluate the feasibility of diagnostic molecular imaging by small animal PET in this mouse model.

High-density Lipoproteins and Their Constituent, Sphingosine-1-phosphate, Directly Protect the Heart Against Ischemia/reperfusion Injury in Vivo Via the S1P3 Lysophospholipid Receptor

Circulation. Sep, 2006  |  Pubmed ID: 16982942

All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport-independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury.

Accurate Noninvasive Measurement of Infarct Size in Mice with High-resolution PET

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Nov, 2006  |  Pubmed ID: 17079817

Reliable, repeatable, and time-efficient noninvasive measurement of infarct size in mice with PET would benefit studies aimed at the exploration of biochemical and functional changes associated with acute myocardial infarction (MI). PET with the radioactively labeled glucose derivative (18)F-FDG is used in humans to distinguish between viable but dysfunctional and nonviable myocardium. In this study, the feasibility, accuracy, and time efficiency of (18)F-FDG PET for quantification of infarct size in mice using a high-resolution animal PET device was evaluated in comparison with histomorphometry.

Molecular Cardiovascular Imaging Using Scintigraphic Methods

European Radiology. Jun, 2007  |  Pubmed ID: 17206422

Molecular cardiovascular imaging plays an increasingly important role both in basic research and in clinical diagnosis. Scintigraphic methods have long been used to study pathophysiological changes on a cellular and molecular level, and they are likely to remain important molecular imaging modalities in the foreseeable future. This article provides an overview over current developments in cardiovascular molecular imaging using scintigraphic methods. The focus lies on imaging of cardiac innervation, plaque instability, hypoxia and angiogenesis, gene expression and stem and progenitor cell migration and proliferation.

Stress and High Heart Rate Provoke Ventricular Tachycardia in Mice Expressing Triadin

Journal of Molecular and Cellular Cardiology. May, 2007  |  Pubmed ID: 17408688

Reduced function of the cardiac ryanodine receptor or calsequestrin causes catecholaminergic ventricular tachycardia (VT). These proteins regulate sarcoplasmic Ca(2+) release in close conjunction with two accessory proteins, triadin and junctin. Based on data from cardiomyocytes, we hypothesized that enhanced triadin expression could cause VT. We assessed arrhythmias and electrophysiological changes in vivo and in the beating heart in mice expressing junctin, triadin, or both proteins (TRDxJCN), and measured calcium transients in isolated ventricular cardiomyocytes. TRDxJCN mice were studied to compensate the down-regulation of junctin expression in triadin-expressing mice. Exercise or stress provoked repetitive VT in freely roaming TRDxJCN mice whenever heart rate increased above approximately 600 bpm (p<0.05 vs. the three other genotypes). TRDxJCN mice expressed total triadin 2.9-fold (p<0.05) and total junctin not different to wildtype (p=ns). Left ventricular systolic function was not different between lineages. beta-adrenoreceptor stimulation (orciprenaline 1.7 microM) provoked early-coupled ventricular ectopy and repetitive VT in isolated, Langendorff-perfused TRDxJCN hearts (p<0.05). Under conditions associated with VT (high pacing rate, catecholamine stimulation), action potential duration was shorter in TRDxJCN with VT than in the other genotypes and shorter than in TRDxJCN hearts without VT (p<0.05). Ca(2+) transient duration was prolonged in Indo1-loaded TRDxJCN cardiomyocytes under VT-provoking conditions. Action potential prolongation by mexiletine (2 microM or 4 microM) or clarithromycine (150 microM) suppressed VT. Expression of triadin provokes stress- and tachycardia-related ventricular arrhythmias in mice. An imbalance between prolonged intracellular calcium release and shortening of the ventricular action potential may contribute to genesis of arrhythmias in this model.

Impaired Myocardial Perfusion and Perfusion Reserve Associated with Increased Coronary Resistance in Persistent Idiopathic Atrial Fibrillation

European Heart Journal. Sep, 2007  |  Pubmed ID: 17604290

Patients with atrial fibrillation (AF) present with symptoms of myocardial ischaemia despite exclusion of coronary artery disease. A small vessel disease has been suggested. We quantified myocardial perfusion, perfusion reserve, and coronary vascular resistance (CVR) in AF patients using positron emission tomography (PET).

Clinical Molecular Imaging in Intestinal Graft-versus-host Disease: Mapping of Disease Activity, Prediction, and Monitoring of Treatment Efficiency by Positron Emission Tomography

Blood. Mar, 2008  |  Pubmed ID: 18057227

Gastrointestinal graft-versus-host disease (GVHD) is a common and potentially life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Noninvasive tests for assessment of GVHD activity are desirable but lacking. In the present study, we were able to visualize intestinal GVHD-associated inflammation in an allogeneic murine transplantation model by (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in vivo. A predominant localization of intestinal GVHD to the colon was verified by histology and fluorescence reflectance imaging of enhanced green fluorescent protein (EGFP)-expressing donor cells. Colonic infiltration by EGFP(+) donor lymphocytes matched increased FDG uptake in PET examinations. These preclinical data were prospectively translated into 30 patients with suspected intestinal GVHD beyond 20 days after transplantation. A total of 14 of 17 patients with a diagnostic histology showed significant FDG uptake of the gut, again predominantly in the colon. No increased FDG uptake was detected in 13 patients without histologic evidence of intestinal GVHD. Our findings indicate that FDG-PET is a sensitive and specific noninvasive imaging technique to assess intestinal GVHD, map its localization, and predict and monitor treatment responsiveness. Novel targeted tracers for PET may provide new insights into the pathophysiology of GVHD and bear the potential to further improve GVHD diagnosis.

Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number

Circulation. Mar, 2008  |  Pubmed ID: 18332262

Survivin inhibits apoptosis and regulates cell division in many organs, but its function in the heart is unknown.

Dynamic 18F-fluoride Small Animal PET to Noninvasively Assess Renal Function in Rats

European Journal of Nuclear Medicine and Molecular Imaging. Dec, 2008  |  Pubmed ID: 18622612

Renal function can be quantified by both laboratory and scintigraphic methods. In the case of small animal diagnostics, scintigraphic image-based methods are ideal since they can assess split renal function, work noninvasively, and can be repeated. The aim of this study is to validate a (18)F-PET-based method to quantify renal function in rats.

Sepsis Causes Neuroinflammation and Concomitant Decrease of Cerebral Metabolism

Journal of Neuroinflammation. 2008  |  Pubmed ID: 18793399

Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death.

Transgenic Model of Cardiac Rhabdomyosarcoma Formation

The Journal of Thoracic and Cardiovascular Surgery. Nov, 2008  |  Pubmed ID: 19026800

Cardiac rhabdomyosarcomas are rare, and the pathogenesis of this detrimental disease is widely unknown. Most data are obtained from case reports or small series, and models for systematic pathogenetic studies are lacking. We aimed to establish a transgenic mouse model of cardiac rhabdomyosarcoma formation.

Myocardial Perfusion in Nonischemic Dilated Cardiomyopathy with and Without Atrial Fibrillation

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Mar, 2009  |  Pubmed ID: 19223407

Recent studies have shown that idiopathic atrial fibrillation (AF) is associated with diminished myocardial perfusion and perfusion reserve, which are also impaired in various forms of cardiomyopathies. In many cases, AF develops during progression of dilated cardiomyopathy (DCM) and may aggravate heart failure. This study compared myocardial perfusion between patients with nonischemic DCM with and without AF.

Molecular Imaging of Apoptosis in Vivo with Scintigraphic and Optical Biomarkers--a Status Report

Anti-cancer Agents in Medicinal Chemistry. Nov, 2009  |  Pubmed ID: 19663786

The balance between proliferation and programmed cell death--apoptosis--is essential for multicellular organisms which use apoptosis to regulate and maintain the number and type of their cells during embryogenesis, growth and homeostasis. Increased cell proliferation or enhanced cell loss can be caused by dysregulated apoptosis and are observed in various diseases: in clinical scenarios such as neurodegenerative disorders, myocardial infarction and stroke the rate of apoptosis is upregulated compared to the physiological situation, while in clinical scenarios such as cancer or autoimmune diseases which are connected with pathological proliferation, apoptosis is often downregulated. Therefore, non-invasive imaging of apoptosis is of great clinical interest as patients would clearly benefit from the diagnosis of cell loss post infarction or from monitoring apoptosis triggered by chemotherapy or radiation therapy of tumours. Several biochemical transformations occur in apoptotic cells offering different biological targets for the development of specific molecular biomarkers of apoptosis. Key steps that occur during apoptosis have already been evaluated; among these are the externalisation of phospholipid phosphatidylserine to the outer leaflet of the cell membrane, which can be visualized by labeled annexin A5 and the activation of caspases, especially effector caspase-3, which can be addressed by labeled enzyme substrates or synthetic caspase inhibitors. Here, recent advances in tracer development for the molecular imaging techniques PET, SPECT and optical imaging are presented, the discussion of breakthroughs is involved, drawbacks and methodological issues of apoptosis imaging are highlighted.

Multimodal Vessel Visualization of Mouse Aorta PET/CT Scans

IEEE Transactions on Visualization and Computer Graphics. Nov-Dec, 2009  |  Pubmed ID: 19834228

In this paper, we present a visualization system for the visual analysis of PET/CT scans of aortic arches of mice. The system has been designed in close collaboration between researchers from the areas of visualization and molecular imaging with the objective to get deeper insights into the structural and molecular processes which take place during plaque development. Understanding the development of plaques might lead to a better and earlier diagnosis of cardiovascular diseases, which are still the main cause of death in the western world. After motivating our approach, we will briefly describe the multimodal data acquisition process before explaining the visualization techniques used. The main goal is to develop a system which supports visual comparison of the data of different species. Therefore, we have chosen a linked multi-view approach, which amongst others integrates a specialized straightened multipath curved planar reformation and a multimodal vessel flattening technique. We have applied the visualization concepts to multiple data sets, and we will present the results of this investigation.

Autonomic Modulation and Antiarrhythmic Therapy in a Model of Long QT Syndrome Type 3

Cardiovascular Research. Jul, 2010  |  Pubmed ID: 20110334

Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). Beta-adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease.

Radiofluorinated Pyrimidine-2,4,6-triones As Molecular Probes for Noninvasive MMP-targeted Imaging

ChemMedChem. May, 2010  |  Pubmed ID: 20373323

Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent endopeptidases. Representing a subfamily of the metzincin superfamily, MMPs are involved in the proteolytic degradation of components of the extracellular matrix. Unregulated MMP expression, MMP dysregulation and locally increased MMP activity are common features of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific visualization of such pathologies, in particular by using radiolabeled MMP inhibitors (MMPIs). The aim of this work was to develop a radiofluorinated molecular probe for noninvasive in vivo imaging for the detection of up-regulated levels of activated MMPs in the living organism. Fluorinated MMPIs (26, 31 and 38) based on the pyrimidine-2,4,6-trione lead structure RO 28-2653 (1) were synthesized, and their MMP inhibition potency was evaluated in vitro. The radiosynthesis and the in vivo biodistribution of the first (18)F-labeled prototype, MMP-targeted tracer [(18)F]26, suitable for molecular imaging by means of positron emission tomography (PET) were realized.

Matrix-metalloproteinases As Imaging Targets for Inflammatory Activity in Atherosclerotic Plaques

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. May, 2010  |  Pubmed ID: 20439506

Cardiovascular events such as myocardial infarction or stroke resulting from atherosclerosis still account for the majority of deaths worldwide. New imaging approaches focusing on the visualization of inflammation in the vessel wall may emerge as tools for individualized risk assessment and prevention of events. Enzymes such as matrix-metalloproteinases (MMPs) are involved in several steps in plaque progression driving plaques into vulnerable, rupture-prone states. Targeting of MMPs for imaging is therefore a promising strategy. The rationale, potential, and current status of imaging MMPs in the clinical context of stroke and myocardial infarction are reviewed here from a clinical viewpoint.

Isochronous Assessment of Cardiac Metabolism and Function in Mice Using Hybrid PET/MRI

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Aug, 2010  |  Pubmed ID: 20660390

Recently, integrated small-animal PET/MRI prototypes that provide isochronous and coregistered datasets of morphology and function through the simultaneous acquisition of PET and MRI data have been developed. However, the need for MRI compatibility can constrain the technical design of the PET components and may lead to a lower sensitivity and lower spatial and temporal resolutions. The aim of this study was to evaluate the suitability of a prototype preclinical PET/MRI system for the simultaneous assessment of cardiac metabolism and function in mice. A stand-alone high-resolution small-animal PET scanner using the same evaluation protocols was used as a reference.

Small-animal PET: a Promising, Non-invasive Tool in Pre-clinical Research

European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V. Jan, 2010  |  Pubmed ID: 19482080

Today, non-invasive imaging techniques are significantly contributing to the understanding of molecular processes in vivo. Positron emission tomography (PET) is a scintigraphic medical imaging modality that uses radiolabelled molecules (tracers), provides quantitative tomographic images and allows non-invasive assessment of the biodistribution of radioactive substances in vivo. The assessment of pathological glucose metabolism is the clinically best-established application of PET today; however, a multitude of different tracers are available to assess diverse physiological processes. The growing interest in pre-clinical imaging studies, in biological and medical basic research, as well as in pharmaceutical research, has fostered the recent growth in small-animal PET. Small-animal PET can be applied to enable the transfer from molecular findings in vitro to in vivo applications in humans, from bench to bed side.

Cellular Organization of Adult Neurogenesis in the Common Marmoset

Aging Cell. Feb, 2011  |  Pubmed ID: 21040399

Adult neurogenesis within the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricle (LV) has been most intensely studied within the brains of rodents such as mice and rats. However, little is known about the cell types and processes involved in adult neurogenesis within primates such as the common marmoset (Callithrix jacchus). Moreover, substantial differences seem to exist between the neurogenic niche of the LV between rodents and humans. Here, we set out to use immunohistochemical and autogradiographic analysis to characterize the anatomy of the neurogenic niches and the expression of cell type-specific markers in those niches in the adult common marmoset brain. Moreover, we demonstrate significant differences in the activity of neurogenesis in the adult marmoset brain compared to the adult mouse brain. Finally, we provide evidence for ongoing proliferation of neuroblasts within both the SGZ and SVZ of the adult brain and further show that the age-dependent decline of neurogenesis in the hippocampus is associated with a decrease in neuroblast cells.

Development and Evaluation of Endothelin-A Receptor (radio)ligands for Positron Emission Tomography

Journal of Medicinal Chemistry. Feb, 2011  |  Pubmed ID: 21275367

The expression and function of endothelin (ET) receptors are abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. A previously reported promising radioligand for positron emission tomography (PET) based on the non-peptide ET(A) receptor antagonist PD 156707 showed specific binding to target receptors in the myocardium but high accumulation in bile and intestine, probably because of its high lipophilicity. In this study we describe the synthesis of a series of fluorinated derivatives with hydrophilic building blocks. All compounds were evaluated as high affinity ET(A) receptor ligands (16, 17, 23-26, K(i) = 1.4-7.9 nM) with high subtype selectivity over the ET(B) receptor. [(18)F]3-Benzo[1,3]dioxol-5-yl-4-{3-[1-(2-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}ethyl)-1H-[1,2,3]triazol-4-ylmethoxy]-4,5-dimethoxybenzyl}-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one ([(18)F]17) was synthesized as one of the radioligands of this series that possesses a higher hydrophilicity and an excellent stability in human serum. Improved clearance properties and specific uptake in target organs have been confirmed by biodistribution studies and small animal PET imaging.

The Role for Decorin in Delayed-type Hypersensitivity

Journal of Immunology (Baltimore, Md. : 1950). Dec, 2011  |  Pubmed ID: 22043007

Decorin, a small leucine-rich proteoglycan, regulates extracellular matrix organization, growth factor-mediated signaling, and cell growth. Because decorin may directly modulate immune responses, we investigated its role in a mouse model of contact allergy (oxazolone-mediated delayed-type hypersensitivity [DTH]) in decorin-deficient (Dcn(-/-)) and wild-type mice. Dcn(-/-) mice showed a reduced ear swelling 24 h after oxazolone treatment with a concurrent attenuation of leukocyte infiltration. These findings were corroborated by reduced glucose metabolism, as determined by (18)fluordeoxyglucose uptake in positron emission tomography scans. Unexpectedly, polymorphonuclear leukocyte numbers in Dcn(-/-) blood vessels were significantly increased and accompanied by large numbers of flattened leukocytes adherent to the endothelium. Intravital microscopy and flow chamber and static adhesion assays confirmed increased adhesion and reduced transmigration of Dcn(-/-) leukocytes. Circulating blood neutrophil numbers were significantly increased in Dcn(-/-) mice 24 h after DTH elicitation, but they were only moderately increased in wild-type mice. Expression of the proinflammatory cytokine TNF-α was reduced, whereas syndecan-1 and ICAM-1 were overexpressed in inflamed ears of Dcn(-/-) mice, indicating that these adhesion molecules could be responsible for increased leukocyte adhesion. Decorin treatment of endothelial cells increased tyrosine phosphorylation and reduced syndecan-1 expression. Notably, absence of syndecan-1 in a genetic background lacking decorin rescued the attenuated DTH phenotype of Dcn(-/-) mice. Collectively, these results implicated a role for decorin in mediating DTH responses by influencing polymorphonuclear leukocyte attachment to the endothelium. This occurs via two nonmutually exclusive mechanisms that involve a direct antiadhesive effect on polymorphonuclear leukocytes and a negative regulation of ICAM-1 and syndecan-1 expression.

A New Generation of Radiofluorinated Pyrimidine-2,4,6-triones As MMP-targeted Radiotracers for Positron Emission Tomography

Journal of Medicinal Chemistry. Jan, 2012  |  Pubmed ID: 22118188

Radiolabeled C-5-disubstituted pyrimidine-2,4,6-triones have recently been suggested by our group as a class of potent matrix metalloproteinase (MMP) targeted radiotracers that can noninvasively visualize activated MMPs by means of positron emission tomography (PET). MMPs belong to the zinc- and calcium-dependent endopeptidases which are involved in the proteolytic degradation of components of the extracellular matrix (ECM) but also are capable of processing and releasing bioactive molecules such as growth factors, proteinase inhibitors, and cytokines. Locally increased levels of activated MMPs modulate and contribute to the progression of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific and noninvasive visualization of aforementioned pathologies in vivo. On the basis of our recent results, we here describe a series of new fluorinated pyrimidine-2,4,6-triones of the second generation with maintained MMP inhibition potencies (IC(50) = 4-605 nM), which are fine-tuned toward more hydrophilic versions, and show the improved biodistribution behavior of one selected radiofluorinated pyrimidine-2,4,6-trione by means of small-animal PET.