Fluorescence Tomography and Magnetic Resonance Imaging of Myocardial Macrophage Infiltration in Infarcted Myocardium In Vivo

Sosnovik, David E.; Nahrendorf, Matthias; Deliolanis, Nikolaos C.; Новиков, Михаил С.; Aikawa, Elena; Josephson, Lee; Rosenzweig, Anthony; Weissleder, Ralph; Ntziachristos, Vasilis

doi:10.1161/circulationaha.106.663351

Cited by 176 publications

(182 citation statements)

References 41 publications

(62 reference statements)

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“…Fluorescence molecular tomography (FMT) is a technology developed to quantitatively image the up-regulation and function of tumoral proteases, cellular receptors, and other proteins (4). Recently this technology has been applied to in vivo imaging of brain, mammary, and lung tumors and for studying tumor angiogenesis and chemotherapeutic effects in entire animals (5,6). The technique may be ideally also suited for studying lung diseases and responses to environmental stimuli noninvasively and in vivo in small animals, especially if multi-projection approaches are implemented (5).…”

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confidence: 99%

Optical Imaging of Molecular Signatures in Pulmonary Inflammation

Ntziachristos

2009

Proceedings of the American Thoracic Society

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Biomedical imaging has become an important tool in the study of ''-omics'' fields by allowing the noninvasive visualization of functional and molecular events using in vivo staining and reporter gene approaches. This capacity can go beyond the understanding of the genetic basis and phenotype of such respiratory conditions as acute bronchitis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and asthma and investigate the development of disease and of therapeutic events longitudinally and in unperturbed environments. Herein, we show how the application of novel quantitative optical imaging methods, using transillumination and fluorescence molecular tomography (FMT), can allow visualization of pulmonary inflammation in small animals in vivo. The results confirm prior observations using a proteasesensitive probe. We discuss how this approach enables in vivo insights at the system level as to the dynamic role of proteases in respiratory pathophysiology and their potential as therapeutic targets. Overall, the proposed imaging method can be used with a significantly wider range of possible targets and applications in lung imaging.Keywords: fluorescence; tomography; proteases; lung; inflammation, in vivo Investigation of the respiratory system at the cellular, biochemical, and molecular level is critical in understanding lung disease and designing effective and novel strategies for prevention and intervention. Our knowledge of the cells and mediators that are involved in lung diseases has increased immensely during the last decade (1-3). This knowledge provides the basis for improving the rational development of therapeutic strategies that may relieve or prevent the development of symptoms.Coupled to the importance of understanding the genetic basis and phenotype of the disease is the ability to visualize the associated molecular processes in vivo. Fluorescence molecular tomography (FMT) is a technology developed to quantitatively image the up-regulation and function of tumoral proteases, cellular receptors, and other proteins (4). Recently this technology has been applied to in vivo imaging of brain, mammary, and lung tumors and for studying tumor angiogenesis and chemotherapeutic effects in entire animals (5, 6). The technique may be ideally also suited for studying lung diseases and responses to environmental stimuli noninvasively and in vivo in small animals, especially if multi-projection approaches are implemented (5). This is in contrast to the mainstay of fluorescence imaging techniques currently available, such as microscopy, which does not penetrate under the tissue surface for more than about 500 mm, or photographic methods that penetrate to only superficial depths (z2-3 mm) and yield single projection qualitative images. The FMT application to lung imaging is foreseen to play a markedly different role than microscopy, since the method achieves macroscopic resolutions similar to the ones of nuclear imaging. The benefits of FMT are associated with its ability for three...

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confidence: 99%

Optical Imaging of Molecular Signatures in Pulmonary Inflammation

Ntziachristos

2009

Proceedings of the American Thoracic Society

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“…As alluded to earlier, the application of targeted drugs (i.e., specifically targeting infarct expansion as opposed to non-ischemic infarct extension or compensatory hypertrophy) will rely greatly on the development of diagnostic techniques capable of monitoring the efficacy of that specific therapy. For example, molecular imaging techniques have already been developed to assess macrophage accumulation [68] and collagen deposition [69] in the heart after MI. However, it may take some time for the necessary contrast agents to gain FDA approval, and it is conceivable that blood-borne biomarkers [70] could provide similar information on the progression of scar formation at lower cost with absolutely no risk to the patient.…”

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confidence: 99%

Mechanisms of postinfarct left ventricular remodeling

French

Kramer

2007

Drug Discovery Today: Disease Mechanisms

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Heart failure secondary to myocardial infarction (MI) remains a major source of morbidity and mortality. Long-term outcome after MI can be largely be defined in terms of its impact on the size and shape of the left ventricle (i.e., LV remodeling). Three major mechanisms contribute to LV remodeling: 1) early infarct expansion, 2) subsequent infarct extension into adjacent noninfarcted myocardium, and 3) late hypertrophy in the remote LV. Future developments in preventing post-MI heart failure will depend not only on identifying drugs targeting each of these individual mechanisms, but also on diagnostic techniques capable of assessing efficacy against each mechanism.

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“…26,58,59 In a recent study, mice were injected intravenously with 3 to 20 mg Fe/kg of the MNP, CLIO-Cy5.5, 48 hours after the infarct and then imaged with conventional T2*-weighted MRI a further 48 hours later. Negative contrast, consistent with the uptake of the probe by infiltrating macrophages, was seen in the infarcted anterolateral myocardium of all mice and at all doses (Fig.…”

Section: Applications: Myocardiummentioning

confidence: 99%

“…25,26 This can be advantageous and be used to image inflammation but can also limit the specificity of targeted imaging with MNPs in tissues that have become highly infiltrated by macrophages. In tissues without a significant macrophage infiltrate, ligand-mediated binding of an MNP to either the cell surface or an appropriate receptor often results in their internalization into the cell.…”

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Molecular Imaging in Cardiovascular Magnetic Resonance Imaging

Sosnovik

2008

Topics in Magnetic Resonance Imaging

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The development of novel imaging agents and techniques is allowing some biological events to be imaged in vivo with magnetic resonance imaging (MRI) at the cellular and subcellular level. In this paper, the use of novel gadolinium chelates and superparamagnetic iron oxide nanoparticles for molecular MRI of the cardiovascular system is extensively reviewed. The physical properties of these imaging agents and the pulse sequences best suited to their visualization are extensively discussed. The application of molecular MRI in diseases of the vasculature and myocardium is then reviewed. The clinical experience to date, as well as the promise and potential impact of molecular MRI, is extensively discussed.Keywords magnetic resonance imaging; molecular imaging; cardiovascular; iron oxide; nanoparticles; myocardium; atherosclerosis Molecular magnetic resonance imaging (MRI) refers to the noninvasive imaging of events at the cellular and subcellular level with MRI in vivo. Although the experience to date with nuclear-based molecular imaging techniques is greater, the advantages of an MRI-based approach to cardiovascular imaging include its high spatial resolution, excellent soft tissue contrast, and ability to simultaneously image cardiovascular anatomy, physiology, and molecular events. 1 Molecular MRI is already playing an important role in preclinical investigation and has the potential to play a major role in the clinical arena in the near future. 1 The present paper focuses on the role of MRI in cardiovascular molecular imaging, and the interested reader is referred to several broad reviews of the field for a more detailed discussion of other molecular imaging modalities as well. 1-3 MOLECULAR MRI AGENTSThe principal challenge of molecular MRI, in comparison with other molecular imaging techniques such as single photon emission computed tomography/positron emission tomography (PET) and fluorescence, lies in its lower sensitivity. Conventional gadolinium chelates have a sensitivity in the micromolar range, which is significantly better than iodinated contrast agents (millimolar range) but significantly worse than radiotracer and fluorescence techniques (picomolar or better). 1,3,4 Two approaches have been developed to deal with this problem. The first involves the selection of highly expressed molecular targets, such as fibrin in thrombi or type 1 collagen in areas of fibrosis. 5,6 Because these targets are so abundant, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript small gadolinium chelates with relatively low relaxivity values can be used for their detection. These agents are also similar in size to clinically approved gadolinium chelates, simplifying some aspects of their pharmacokinetic and toxicological evaluation. The principal disadvantage of this approach, however, lies in its low sensitivity per binding event (low level of signal generated for each unit ligand that binds to the target). This limits the applicability of this approach to highly expressed targets and also re...

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Fluorescence Tomography and Magnetic Resonance Imaging of Myocardial Macrophage Infiltration in Infarcted Myocardium In Vivo

Cited by 176 publications

References 41 publications

Optical Imaging of Molecular Signatures in Pulmonary Inflammation

Optical Imaging of Molecular Signatures in Pulmonary Inflammation

Mechanisms of postinfarct left ventricular remodeling

Molecular Imaging in Cardiovascular Magnetic Resonance Imaging

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