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Temme S, Kleimann P, Tiren ZB, Bouvain P, Zielinski A, Dollmeyer W, Poth S, Görges J, Flögel U. Imaging of Thromboinflammation by Multispectral 19F MRI. Int J Mol Sci 2025; 26:2462. [PMID: 40141106 PMCID: PMC11942564 DOI: 10.3390/ijms26062462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/24/2025] [Accepted: 03/05/2025] [Indexed: 03/28/2025] Open
Abstract
The close interplay between thrombotic and immunologic processes plays an important physiological role in the immune defence after tissue injury and has the aim to reduce damage and to prevent the spread of invading pathogens. However, the uncontrolled or exaggerated activation of these processes can lead to pathological thromboinflammation. Thromboinflammation has been shown to worsen the outcome of cardiovascular, autoinflammatory, or even infectious diseases. Imaging of thromboinflammation is difficult because many clinically relevant imaging techniques can only visualize either inflammatory or thrombotic processes. One interesting option for the noninvasive imaging of thromboinflammation is multispectral 19F magnetic resonance imaging (MRI). Due to the large chemical shift range of the 19F atoms, it is possible to simultaneously visualize immune cells as well as thrombus components with specific 19F tracer that have individual spectral 19F signatures. Of note, the 19F signal can be easily quantified and a merging of the 19F datasets with the anatomical 1H MRI images enables precise anatomical localization. In this review, we briefly summarize the background of 19F MRI for inflammation imaging, active targeting approaches to visualize thrombi and specific immune cells, introduce studies about multispectral 19F MRI, and summarize one study that imaged thromboinflammation by multispectral 19F MRI.
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Affiliation(s)
- Sebastian Temme
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (Z.-B.T.); (A.Z.); (W.D.); (J.G.)
| | - Patricia Kleimann
- Experimental Cardiovascular Imaging, Institute of Molecular Cardiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (P.K.); (P.B.); (S.P.); (U.F.)
| | - Zeynep-Büsra Tiren
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (Z.-B.T.); (A.Z.); (W.D.); (J.G.)
| | - Pascal Bouvain
- Experimental Cardiovascular Imaging, Institute of Molecular Cardiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (P.K.); (P.B.); (S.P.); (U.F.)
| | - Arthur Zielinski
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (Z.-B.T.); (A.Z.); (W.D.); (J.G.)
| | - William Dollmeyer
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (Z.-B.T.); (A.Z.); (W.D.); (J.G.)
| | - Sarah Poth
- Experimental Cardiovascular Imaging, Institute of Molecular Cardiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (P.K.); (P.B.); (S.P.); (U.F.)
| | - Juliana Görges
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (Z.-B.T.); (A.Z.); (W.D.); (J.G.)
| | - Ulrich Flögel
- Experimental Cardiovascular Imaging, Institute of Molecular Cardiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (P.K.); (P.B.); (S.P.); (U.F.)
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Kakaei N, Amirian R, Azadi M, Mohammadi G, Izadi Z. Perfluorocarbons: A perspective of theranostic applications and challenges. Front Bioeng Biotechnol 2023; 11:1115254. [PMID: 37600314 PMCID: PMC10436007 DOI: 10.3389/fbioe.2023.1115254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 03/15/2023] [Indexed: 08/22/2023] Open
Abstract
Perfluorocarbon (PFC) are biocompatible compounds, chemically and biologically inert, and lacks toxicity as oxygen carriers. PFCs nanoemulsions and nanoparticles (NPs) are highly used in diagnostic imaging and enable novel imaging technology in clinical imaging modalities to notice and image pathological and physiological alterations. Therapeutics with PFCs such as the innovative approach to preventing thrombus formation, PFC nanodroplets utilized in ultrasonic medication delivery in arthritis, or PFC-based NPs such as Perfluortributylamine (PFTBA), Pentafluorophenyl (PFP), Perfluorohexan (PFH), Perfluorooctyl bromide (PFOB), and others, recently become renowned for oxygenating tumors and enhancing the effects of anticancer treatments as oxygen carriers for tumor hypoxia. In this review, we will discuss the recent advancements that have been made in PFC's applications in theranostic (therapeutics and diagnostics) as well as assess the benefits and drawbacks of these applications.
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Affiliation(s)
- Nasrin Kakaei
- Student Research Committee, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Roshanak Amirian
- Student Research Committee, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mehdi Azadi
- Student Research Committee, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ghobad Mohammadi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zhila Izadi
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Multimodal characterization of Yucatan minipig behavior and physiology through maturation. Sci Rep 2021; 11:22688. [PMID: 34811385 PMCID: PMC8608884 DOI: 10.1038/s41598-021-00782-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 10/13/2021] [Indexed: 01/11/2023] Open
Abstract
Brain injuries induced by external forces are particularly challenging to model experimentally. In recent decades, the domestic pig has been gaining popularity as a highly relevant animal model to address the pathophysiological mechanisms and the biomechanics associated with head injuries. Understanding cognitive, motor, and sensory aspects of pig behavior throughout development is crucial for evaluating cognitive and motor deficits after injury. We have developed a comprehensive battery of tests to characterize the behavior and physiological function of the Yucatan minipig throughout maturation. Behavioral testing included assessments of learning and memory, executive functions, circadian rhythms, gait analysis, and level of motor activity. We applied traditional behavioral apparatus and analysis methods, as well as state-of-the-art sensor technologies to report on motion and activity, and artificial intelligent approaches to analyze behavior. We studied pigs from 16 weeks old through sexual maturity at 35 weeks old. The results show multidimensional characterization of minipig behavior, and how it develops and changes with age. This animal model may capitulate the biomechanical consideration and phenotype of head injuries in the developing brain and can drive forward the field of understanding pathophysiological mechanisms and developing new therapies to accelerate recovery in children who have suffered head trauma.
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Flögel U, Temme S, Jacoby C, Oerther T, Keul P, Flocke V, Wang X, Bönner F, Nienhaus F, Peter K, Schrader J, Grandoch M, Kelm M, Levkau B. Multi-targeted 1H/ 19F MRI unmasks specific danger patterns for emerging cardiovascular disorders. Nat Commun 2021; 12:5847. [PMID: 34615876 PMCID: PMC8494909 DOI: 10.1038/s41467-021-26146-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 09/20/2021] [Indexed: 12/28/2022] Open
Abstract
Prediction of the transition from stable to acute coronary syndromes driven by vascular inflammation, thrombosis with subsequent microembolization, and vessel occlusion leading to irreversible myocardial damage is still an unsolved problem. Here, we introduce a multi-targeted and multi-color nanotracer platform technology that simultaneously visualizes evolving danger patterns in the development of progressive coronary inflammation and atherothrombosis prior to spontaneous myocardial infarction in mice. Individual ligand-equipped perfluorocarbon nanoemulsions are used as targeting agents and are differentiated by their specific spectral signatures via implementation of multi chemical shift selective 19F MRI. Thereby, we are able to identify areas at high risk of and predictive for consecutive development of myocardial infarction, at a time when no conventional parameter indicates any imminent danger. The principle of this multi-targeted approach can easily be adapted to monitor also a variety of other disease entities and constitutes a technology with disease-predictive potential.
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Affiliation(s)
- Ulrich Flögel
- Experimental Cardiovascular Imaging, Institute for Molecular Cardiology, Heinrich Heine University, Düsseldorf, Germany.
- Cardiovascular Research Institute Düsseldorf (CARID), Heinrich Heine University, Düsseldorf, Germany.
- Department of Cardiology, Pneumology and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany.
| | - Sebastian Temme
- Experimental Cardiovascular Imaging, Institute for Molecular Cardiology, Heinrich Heine University, Düsseldorf, Germany
- Cardiovascular Research Institute Düsseldorf (CARID), Heinrich Heine University, Düsseldorf, Germany
- Department of Cardiology, Pneumology and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany
- Department of Anesthesiology, Heinrich Heine University, Düsseldorf, Germany
| | - Christoph Jacoby
- Experimental Cardiovascular Imaging, Institute for Molecular Cardiology, Heinrich Heine University, Düsseldorf, Germany
- Department of Cardiology, Pneumology and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany
| | | | - Petra Keul
- Institute of Molecular Medicine III, Heinrich Heine University, Düsseldorf, Germany
| | - Vera Flocke
- Experimental Cardiovascular Imaging, Institute for Molecular Cardiology, Heinrich Heine University, Düsseldorf, Germany
| | - Xiaowei Wang
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Florian Bönner
- Department of Cardiology, Pneumology and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Fabian Nienhaus
- Department of Cardiology, Pneumology and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany
| | | | - Jürgen Schrader
- Cardiovascular Research Institute Düsseldorf (CARID), Heinrich Heine University, Düsseldorf, Germany
- Department of Cardiology, Pneumology and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Maria Grandoch
- Department of Pharmacology and Clinical Pharmacology, Heinrich Heine University, Düsseldorf, Germany
| | - Malte Kelm
- Cardiovascular Research Institute Düsseldorf (CARID), Heinrich Heine University, Düsseldorf, Germany
- Department of Cardiology, Pneumology and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Bodo Levkau
- Institute of Molecular Medicine III, Heinrich Heine University, Düsseldorf, Germany
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Wang X, Ziegler M, McFadyen JD, Peter K. Molecular Imaging of Arterial and Venous Thrombosis. Br J Pharmacol 2021; 178:4246-4269. [PMID: 34296431 DOI: 10.1111/bph.15635] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/14/2020] [Accepted: 09/23/2020] [Indexed: 11/30/2022] Open
Abstract
Thrombosis contributes to one in four deaths worldwide and is the cause of a large proportion of mortality and morbidity. A reliable and rapid diagnosis of thrombosis will allow for immediate therapy, thereby providing significant benefits to patients. Molecular imaging is a fast-growing and captivating area of research, in both preclinical and clinical applications. Major advances have been achieved by improvements in three central areas of molecular imaging: 1) Better markers for diseases, with increased sensitivity and selectivity; 2) Optimised contrast agents with improved signal to noise ratio; 3) Progress in scanner technologies with higher sensitivity and resolution. Clinically available imaging modalities used for molecular imaging include, magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound, as well as nuclear imaging, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT). In the preclinical imaging field, optical (fluorescence and bioluminescent) molecular imaging has provided new mechanistic insights in the pathology of thromboembolic diseases. Overall, the advances in molecular imaging, driven by the collaboration of various scientific disciplines, have substantially contributed to an improved understanding of thrombotic disease, and raises the exciting prospect of earlier diagnosis and individualised therapy for cardiovascular diseases. As such, these advances hold significant promise to be translated to clinical practice and ultimately to reduce mortality and morbidity in patients with thromboembolic diseases.
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Affiliation(s)
- Xiaowei Wang
- Molecular Imaging and Theranostics Laboratory.,Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute.,Department of Medicine, Monash University.,Department of Cardiometabolic Health, University of Melbourne
| | - Melanie Ziegler
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute
| | - James D McFadyen
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute.,Department of Cardiometabolic Health, University of Melbourne.,Clinical Hematology Department, Alfred Hospital
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute.,Department of Medicine, Monash University.,Department of Cardiometabolic Health, University of Melbourne.,Department of Cardiology, Alfred Hospital, Melbourne, Australia
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6
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Molecular MR-Imaging in Thromboembolic Stroke Using a Fibrin-Specific Contrast Agent in Patients at 3 Tesla. Clin Neuroradiol 2021; 31:925-931. [PMID: 34236442 DOI: 10.1007/s00062-021-01052-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 06/05/2021] [Indexed: 10/20/2022]
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Hajhosseiny R, Prieto C, Qi H, Phinikaridou A, Botnar RM. Thrombosis and Embolism. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00072-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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8
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Kimura Y, Okumura T, Kazama S, Shibata N, Oishi H, Arao Y, Kuwayama T, Kato H, Yamaguchi S, Hiraiwa H, Kondo T, Morimoto R, Mutsuga M, Fujimoto K, Usui A, Murohara T. Predictors of residual mitral regurgitation after left ventricular assist device implantation. Int J Artif Organs 2020; 44:101-109. [PMID: 32677853 DOI: 10.1177/0391398820942526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Patients with advanced heart failure often have functional mitral regurgitation. Left ventricular assist device implantation improves functional mitral regurgitation through left ventricular unloading. However, residual mitral regurgitation after left ventricular assist device implantation leads to adverse outcomes, and whether patients need concomitant mitral valve surgery is not fully elucidated. Therefore, this study aimed to elucidate the predictors of residual mitral regurgitation and to describe the temporal changes in residual mitral regurgitation. We retrospectively enrolled 15 patients with implantable continuous-flow left ventricular assist device, who had significant mitral regurgitation on echocardiography before left ventricular assist device implantation. Three patients had residual mitral regurgitation (mitral regurgitation color jet area/left atrial area >0.2) 1 month after left ventricular assist device implantation. We investigated factors associated with residual mitral regurgitation and compared patients with or without residual mitral regurgitation. On univariate analysis, mitral valve tethering area and mitral regurgitation vena contracta before left ventricular assist device implantation were significantly associated with residual mitral regurgitation (odds ratio, 1.03; p = 0.036 and odds ratio, 10.45; p = 0.0087). One month after left ventricular assist device implantation, the mean pulmonary capillary wedge pressure and pulmonary artery pressure were higher in patients with residual mitral regurgitation (pulmonary capillary wedge pressure: 11.3 ± 3.5 vs 6.4 ± 3.4 mmHg, p = 0.029 and pulmonary artery pressure: 21.3 ± 4.0 vs 15.9 ± 3.3 mmHg, p = 0.023). However, the mitral regurgitation grading and hemodynamics were not significantly different 6 months after left ventricular assist device implantation. The hospitalization-free survival was not significantly different between the two groups. Mitral valve tethering area and mitral regurgitation vena contracta were predictors of residual mitral regurgitation. Residual mitral regurgitation improved until 6 months after left ventricular assist device implantation and might not affect the prognosis.
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Affiliation(s)
- Yuki Kimura
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahiro Okumura
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shingo Kazama
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naoki Shibata
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideo Oishi
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihito Arao
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tasuku Kuwayama
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroo Kato
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shogo Yamaguchi
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Hiraiwa
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toru Kondo
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ryota Morimoto
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Mutsuga
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuro Fujimoto
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akihiko Usui
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Meijerink F, Wijdh-den Hamer IJ, Bouma W, Pouch AM, Aly AH, Lai EK, Eperjesi TJ, Acker MA, Yushkevich PA, Hung J, Mariani MA, Khabbaz KR, Gleason TG, Mahmood F, Gorman JH, Gorman RC. Intraoperative post-annuloplasty three-dimensional valve analysis does not predict recurrent ischemic mitral regurgitation. J Cardiothorac Surg 2020; 15:161. [PMID: 32616001 PMCID: PMC7333337 DOI: 10.1186/s13019-020-01138-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 05/04/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND High ischemic mitral regurgitation (IMR) recurrence rates continue to plague IMR repair with undersized ring annuloplasty. We have previously shown that pre-repair three-dimensional echocardiography (3DE) analysis is highly predictive of IMR recurrence. The objective of this study was to determine the quantitative change in 3DE annular and leaflet tethering parameters immediately after repair and to determine if intraoperative post-repair 3DE parameters would be able to predict IMR recurrence 6 months after repair. METHODS Intraoperative pre- and post-repair transesophageal real-time 3DE was performed in 35 patients undergoing undersized ring annuloplasty for IMR. An advanced modeling algorhythm was used to assess 3D annular geometry and regional leaflet tethering. IMR recurrence (≥ grade 2) was assessed with transthoracic echocardiography 6 months after repair. RESULTS Annuloplasty significantly reduced septolateral diameter, commissural width, annular area, and tethering volume and significantly increased all segmental tethering angles (except A2). Intraoperative post-repair annular geometry and leaflet tethering did not differ significantly between patients with recurrent IMR (n = 9) and patients with non-recurrent IMR (n = 26). No intraoperative post-repair predictors of IMR recurrence could be identified. CONCLUSIONS Undersized ring annuloplasty changes mitral geometry acutely, exacerbates leaflet tethering, and generally fixes IMR acutely, but it does not always fix the delicate underlying chronic problem of continued left ventricular dilatation and remodeling. This may explain why pre-repair 3D valve geometry (which reflects chronic left ventricular remodeling) is highly predictive of recurrent IMR, whereas immediate post-repair 3D valve geometry (which does not completely reflect chronic left ventricular remodeling anymore) is not.
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Affiliation(s)
- Frank Meijerink
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
| | - Inez J Wijdh-den Hamer
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Wobbe Bouma
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Alison M Pouch
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA
| | - Ahmed H Aly
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA
| | - Eric K Lai
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA
| | - Thomas J Eperjesi
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael A Acker
- Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Paul A Yushkevich
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Judy Hung
- Department of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Massimo A Mariani
- Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Kamal R Khabbaz
- Department of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Thomas G Gleason
- Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Feroze Mahmood
- Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Joseph H Gorman
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA
- Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Robert C Gorman
- Gorman Cardiovascular Research Group, University of Pennsylvania, Philadelphia, PA, USA
- Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA
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10
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Bouvain P, Temme S, Flögel U. Hot spot 19 F magnetic resonance imaging of inflammation. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1639. [PMID: 32380579 DOI: 10.1002/wnan.1639] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/20/2020] [Accepted: 04/01/2020] [Indexed: 12/11/2022]
Abstract
Among the preclinical molecular imaging approaches, lately fluorine (19 F) magnetic resonance imaging (MRI) has garnered significant scientific interest in the biomedical research community, due to the unique properties of fluorinated materials and the 19 F nucleus. Fluorine is an intrinsically sensitive nucleus for MRI-there is negligible endogenous 19 F in the body and, thus, no background signal which allows the detection of fluorinated materials as "hot spots" by combined 1 H/19 F MRI and renders fluorine-containing molecules as ideal tracers with high specificity. In addition, perfluorocarbons are a family of compounds that exhibit a very high fluorine payload and are biochemically as well as physiologically inert. Perfluorocarbon nanoemulsions (PFCs) are well known to be readily taken up by immunocompetent cells, which can be exploited for the unequivocal identification of inflammatory foci by tracking the recruitment of PFC-loaded immune cells to affected tissues using 1 H/19 F MRI. The required 19 F labeling of immune cells can be accomplished either ex vivo by PFC incubation of isolated endogenous immune cells followed by their re-injection or by intravenous application of PFCs for in situ uptake by circulating immune cells. With both approaches, inflamed tissues can unambiguously be detected via background-free 19 F signals due to trafficking of PFC-loaded immune cells to affected organs. To extend 19 F MRI tracking beyond cells with phagocytic properties, the PFC surface can further be equipped with distinct ligands to generate specificity against epitopes and/or types of immune cells independent of phagocytosis. Recent developments also allow for concurrent detection of different PFCs with distinct spectral signatures allowing the simultaneous visualization of several targets, such as various immune cell subtypes labeled with these PFCs. Since ligands and targets can easily be adapted to a variety of problems, this approach provides a general and versatile platform for inflammation imaging which will strongly extend the frontiers of molecular MRI. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease.
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Affiliation(s)
- Pascal Bouvain
- Experimental Cardiovascular Imaging, Molecular Cardiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sebastian Temme
- Experimental Cardiovascular Imaging, Molecular Cardiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ulrich Flögel
- Experimental Cardiovascular Imaging, Molecular Cardiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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11
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Salarian M, Ibhagui OY, Yang JJ. Molecular imaging of extracellular matrix proteins with targeted probes using magnetic resonance imaging. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1622. [PMID: 32126587 DOI: 10.1002/wnan.1622] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 01/04/2020] [Accepted: 02/04/2020] [Indexed: 12/14/2022]
Abstract
The extracellular matrix (ECM) consists of proteins and carbohydrates that supports different biological structures and processes such as tissue development, elasticity, and preservation of organ structure. Diseases involving inflammation, fibrosis, tumor invasion, and injury are all attributed to the transition of the ECM from homeostasis to remodeling, which can significantly change the biochemical and biomechanical features of ECM components. While contrast agents have played an indispensable role in facilitating clinical diagnosis of diseases using magnetic resonance imaging (MRI), there is a strong need to develop novel biomarker-targeted imaging probes for in vivo visualization of biological processes and pathological alterations at a cellular and molecular level, for both early diagnosis and monitoring drug treatment. Herein, we will first review the pathological accumulation and characterization of ECM proteins recognized as important molecular features of diseases. Developments in MRI probes targeting ECM proteins such as collagen, fibronectin, and elastin via conjugation of existing contrast agents to targeting moieties and their applications to various diseases, are also reviewed. We have also reviewed our progress in the development of collagen-targeted protein MRI contrast agent with significant improvement in relaxivity and metal binding specificity, and their applications in early detection of fibrosis and metastatic cancer. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Biology-Inspired Nanomaterials > Peptide-Based Structures Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.
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Affiliation(s)
- Mani Salarian
- Department of Chemistry, Georgia State University, Atlanta, Georgia
| | | | - Jenny J Yang
- Department of Chemistry, Georgia State University, Atlanta, Georgia.,Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia
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12
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Zhang B, Pang Z, Hu Y. Targeting hemostasis-related moieties for tumor treatment. Thromb Res 2020; 187:186-196. [PMID: 32032807 DOI: 10.1016/j.thromres.2020.01.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 12/23/2019] [Accepted: 01/14/2020] [Indexed: 12/12/2022]
Abstract
Under normal conditions, the hemostatic system, that includes the involvement of the coagulation response and platelets, is anatomically and functionally inseparable from the vasculature. However, the hemostatic response always occurs in a wide range of tumors because of the high expression of coagulation initiator tissue factor (TF) in many tumor tissues, and due to the leakage of coagulation factors and platelets from the circulation system into the tumor interstitium through abnormal tumor vessels. Therefore, in addition to TF, these coagulation factors, platelets, the central moiety thrombin, the final product fibrin, and fibronectin, which is capable of stabilizing coagulation clots, are also abundant in tumors. These hemostasis-related moieties (HRMs), including TF, thrombin, fibrin, fibronectin, and platelets, are also closely associated with tumor progression, e.g., primary tumor growth and distal metastasis. The hemostatic response only occurs under pathological conditions, such as tumors, thrombosis, and atherosclerosis other than in normal tissues. The HRMs within tumors are also highly specific, establishing functional and therapeutic targets for tumor treatment. Therefore, strategies including active targeting to these moieties, modulation of HRMs deposited in the tumor microenvironment to improve tumor drug delivery, activation of prodrug by the coagulation complex formed during coagulation response, and direct inhibition of the tumor-promoting activity of HRMs could be designed for tumor therapy. In this review, we summarize various strategies that target HRMs for tumor treatment.
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Affiliation(s)
- Bo Zhang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China
| | - Zhiqing Pang
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China.
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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13
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Lanza GM, Cui G, Schmieder AH, Zhang H, Allen JS, Scott MJ, Williams T, Yang X. An unmet clinical need: The history of thrombus imaging. J Nucl Cardiol 2019; 26:986-997. [PMID: 28608182 PMCID: PMC5741521 DOI: 10.1007/s12350-017-0942-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 05/24/2017] [Indexed: 11/24/2022]
Abstract
Robust thrombus imaging is an unresolved clinical unmet need dating back to the mid 1970s. While early molecular imaging approaches began with nuclear SPECT imaging, contrast agents for virtually all biomedical imaging modalities have been demonstrated in vivo with unique strengths and common weaknesses. Two primary molecular imaging targets have been pursued for thrombus imaging: platelets and fibrin. Some common issues noted over 40 years ago persist today. Acute thrombus is readily imaged with all probes and modalities, but aged thrombus remains a challenge. Similarly, anti-coagulation continues to interfere with and often negate thrombus imaging efficacy, but heparin is clinically required in patients suspected of pulmonary embolism, deep venous thrombosis or coronary ruptured plaque prior to confirmatory diagnostic studies have been executed and interpreted. These fundamental issues can be overcome, but an innovative departure from the prior approaches will be needed.
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Affiliation(s)
- Gregory M Lanza
- Department of Medicine, Division of Cardiology, Washington University Medical School, St. Louis, MO, 63108, USA.
| | - Grace Cui
- Department of Medicine, Division of Cardiology, Washington University Medical School, St. Louis, MO, 63108, USA
| | - Anne H Schmieder
- Department of Medicine, Division of Cardiology, Washington University Medical School, St. Louis, MO, 63108, USA
| | - Huiying Zhang
- Department of Medicine, Division of Cardiology, Washington University Medical School, St. Louis, MO, 63108, USA
| | - John S Allen
- Department of Medicine, Division of Cardiology, Washington University Medical School, St. Louis, MO, 63108, USA
| | - Michael J Scott
- Department of Medicine, Division of Cardiology, Washington University Medical School, St. Louis, MO, 63108, USA
| | - Todd Williams
- Department of Medicine, Division of Cardiology, Washington University Medical School, St. Louis, MO, 63108, USA
| | - Xiaoxia Yang
- Department of Medicine, Division of Cardiology, Washington University Medical School, St. Louis, MO, 63108, USA
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14
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Boutagy NE, Feher A, Alkhalil I, Umoh N, Sinusas AJ. Molecular Imaging of the Heart. Compr Physiol 2019; 9:477-533. [PMID: 30873600 DOI: 10.1002/cphy.c180007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Multimodality cardiovascular imaging is routinely used to assess cardiac function, structure, and physiological parameters to facilitate the diagnosis, characterization, and phenotyping of numerous cardiovascular diseases (CVD), as well as allows for risk stratification and guidance in medical therapy decision-making. Although useful, these imaging strategies are unable to assess the underlying cellular and molecular processes that modulate pathophysiological changes. Over the last decade, there have been great advancements in imaging instrumentation and technology that have been paralleled by breakthroughs in probe development and image analysis. These advancements have been merged with discoveries in cellular/molecular cardiovascular biology to burgeon the field of cardiovascular molecular imaging. Cardiovascular molecular imaging aims to noninvasively detect and characterize underlying disease processes to facilitate early diagnosis, improve prognostication, and guide targeted therapy across the continuum of CVD. The most-widely used approaches for preclinical and clinical molecular imaging include radiotracers that allow for high-sensitivity in vivo detection and quantification of molecular processes with single photon emission computed tomography and positron emission tomography. This review will describe multimodality molecular imaging instrumentation along with established and novel molecular imaging targets and probes. We will highlight how molecular imaging has provided valuable insights in determining the underlying fundamental biology of a wide variety of CVDs, including: myocardial infarction, cardiac arrhythmias, and nonischemic and ischemic heart failure with reduced and preserved ejection fraction. In addition, the potential of molecular imaging to assist in the characterization and risk stratification of systemic diseases, such as amyloidosis and sarcoidosis will be discussed. © 2019 American Physiological Society. Compr Physiol 9:477-533, 2019.
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Affiliation(s)
- Nabil E Boutagy
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA
| | - Attila Feher
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA
| | - Imran Alkhalil
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA
| | - Nsini Umoh
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA
| | - Albert J Sinusas
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA.,Yale University School of Medicine, Department of Radiology and Biomedical Imaging, New Haven, Connecticut, USA
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15
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Kim KS, Song CG, Kang PM. Targeting Oxidative Stress Using Nanoparticles as a Theranostic Strategy for Cardiovascular Diseases. Antioxid Redox Signal 2019; 30:733-746. [PMID: 29228781 PMCID: PMC6350062 DOI: 10.1089/ars.2017.7428] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE Nanomedicine is an application of nanotechnology that provides solutions to unmet medical challenges. The unique features of nanoparticles, such as their small size, modifiable components, and diverse functionality, make them attractive and suitable materials for novel diagnostic, therapeutic, or theranostic applications. Cardiovascular diseases (CVDs) are the major cause of noncommunicable illness in both developing and developed countries. Nanomedicine offers novel theranostic options for the treatment of CVDs. Recent Advances: Many innovative nanoparticles to target reactive oxygen species (ROS) have been developed. In this article, we review the characteristics of nanoparticles that are responsive to ROS, their limitations, and their potential clinical uses. Significant advances made in diagnosis of atherosclerosis and treatment of acute coronary syndrome using nanoparticles are discussed. CRITICAL ISSUES Although there is a tremendous potential for the nanoparticle applications in medicine, their safety should be considered while using in humans. We discuss the challenges that may be encountered with some of the innovative nanoparticles used in CVDs. FUTURE DIRECTIONS The unique properties of nanoparticles offer novel diagnostic tool and potential therapeutic strategies. However, nanomedicine is still in its infancy, and further in-depth studies are needed before wide clinical application is achieved.
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Affiliation(s)
- Kye S Kim
- 1 Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts.,2 Harvard Medical School, Boston, Massachusetts
| | - Chul Gyu Song
- 3 Department of Electronic Engineering, Chonbuk National University, Jeonju, South Korea
| | - Peter M Kang
- 1 Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts.,2 Harvard Medical School, Boston, Massachusetts
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16
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Ta HT, Arndt N, Wu Y, Lim HJ, Landeen S, Zhang R, Kamato D, Little PJ, Whittaker AK, Xu ZP. Activatable magnetic resonance nanosensor as a potential imaging agent for detecting and discriminating thrombosis. NANOSCALE 2018; 10:15103-15115. [PMID: 30059122 DOI: 10.1039/c8nr05095c] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The early detection and accurate characterization of life-threatening diseases such as cardiovascular disease and cancer are critical to the design of treatment. Knowing whether or not a thrombus in a blood vessel is new (fresh) or old (constituted) is very important for physicians to decide a treatment protocol. We have designed smart MRI nano-sensors that can detect, sense and report the stage or progression of cardiovascular diseases such as thrombosis. The nanosensors were functionalized with fibrin-binding peptide to specifically target thrombus and were also labelled with fluorescent dye to enable optical imaging. We have demonstrated that our nanosensors were able to switch between the T1 and T2 signal depending on thrombus age or the presence or absence of thrombin at the thrombus site. The developed nanosensors appeared to be non-toxic when tested with Chinese Hamster Ovarian cells within the tested concentrations. The working principle demonstrated in this study can be applied to many other diseases such as cancer.
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Affiliation(s)
- Hang T Ta
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland, Australia. and School of Pharmacy, the University of Queensland, Brisbane, Queensland, Australia
| | - Nina Arndt
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland, Australia. and Department of Biotechnology, Technische Universität Berlin, Berlin, Germany
| | - Yuao Wu
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland, Australia. and School of Pharmacy, the University of Queensland, Brisbane, Queensland, Australia
| | - Hui Jean Lim
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland, Australia.
| | - Shea Landeen
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland, Australia. and Department of Biological Engineering, Massachusetts Institute of Technology, Boston, USA
| | - Run Zhang
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland, Australia.
| | - Danielle Kamato
- School of Pharmacy, the University of Queensland, Brisbane, Queensland, Australia
| | - Peter J Little
- School of Pharmacy, the University of Queensland, Brisbane, Queensland, Australia
| | - Andrew K Whittaker
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland, Australia. and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Brisbane, Queensland, Australia and Centre of Advanced Imaging, the University of Queensland, Brisbane, Queensland, Australia
| | - Zhi Ping Xu
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland, Australia.
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17
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Botnar RM, Brangsch J, Reimann C, Janssen CHP, Razavi R, Hamm B, Makowski MR. In Vivo Molecular Characterization of Abdominal Aortic Aneurysms Using Fibrin-Specific Magnetic Resonance Imaging. J Am Heart Assoc 2018; 7:e007909. [PMID: 29848500 PMCID: PMC6015382 DOI: 10.1161/jaha.117.007909] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 01/24/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND The incidence of abdominal aortic aneurysms (AAAs) will significantly increase during the next decade. Novel biomarkers, besides diameter, are needed for a better characterization of aneurysms and the estimation of the risk of rupture. Fibrin is a key protein in the formation of focal hematoma associated with the dissection of the aortic wall and the development of larger thrombi during the progression of AAAs. This study evaluated the potential of a fibrin-specific magnetic resonance (MR) probe for the in vivo characterization of the different stages of AAAs. METHODS AND RESULTS AAAs spontaneously developed in ApoE-/- mice following the infusion of angiotensin-II (Ang-II, 1 μg/kg-1·per minute). An established fibrin-specific molecular MR probe (EP2104R, 10 μmol/kg-1) was administered after 1 to 4 weeks following Ang-II infusion (n=8 per group). All imaging experiments were performed on a clinical 3T Achieva MR system with a microscopy coil (Philips Healthcare, Netherlands). The development of AAA-associated fibrin-rich hematoma and thrombi was assessed. The high signal generated by the fibrin probe enabled high-resolution MR imaging for an accurate assessment and quantification of the relative fibrin composition of focal hematoma and thrombi. Contrast-to-noise-ratios (CNRs) and R1-relaxation rates following the administration of the fibrin probe were in good agreement with ex vivo immunohistomorphometry (R2=0.83 and 0.85) and gadolinium concentrations determined by inductively coupled plasma mass spectroscopy (R2=0.78 and 0.72). CONCLUSIONS The fibrin-specific molecular MR probe allowed the delineation and quantification of changes in fibrin content in early and advanced AAAs. Fibrin MRI could provide a novel in vivo biomarker to improve the risk stratification of patients with aortic aneurysms.
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MESH Headings
- Angiotensin II
- Animals
- Aorta, Abdominal/diagnostic imaging
- Aorta, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/chemically induced
- Aortic Aneurysm, Abdominal/diagnostic imaging
- Aortic Aneurysm, Abdominal/genetics
- Aortic Aneurysm, Abdominal/metabolism
- Disease Models, Animal
- Fibrin/metabolism
- Magnetic Resonance Imaging
- Male
- Mice, Inbred C57BL
- Mice, Knockout, ApoE
- Molecular Imaging/methods
- Predictive Value of Tests
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Affiliation(s)
- René M Botnar
- Division of Imaging Sciences, King's College London, London, United Kingdom
- BHF Centre of Excellence, King's College London, London, United Kingdom
- Wellcome Trust and EPSRC Medical Engineering Center, King's College London, London, United Kingdom
- NIHR Biomedical Research Centre, King's College London, London, United Kingdom
| | | | | | | | - Reza Razavi
- Division of Imaging Sciences, King's College London, London, United Kingdom
- BHF Centre of Excellence, King's College London, London, United Kingdom
- Wellcome Trust and EPSRC Medical Engineering Center, King's College London, London, United Kingdom
- NIHR Biomedical Research Centre, King's College London, London, United Kingdom
| | - Bernd Hamm
- Department of Radiology, Charite, Berlin, Germany
| | - Marcus R Makowski
- Division of Imaging Sciences, King's College London, London, United Kingdom
- Department of Radiology, Charite, Berlin, Germany
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18
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Abstract
The development of new methods to image the onset and progression of thrombosis is an unmet need. Non-invasive molecular imaging techniques targeting specific key structures involved in the formation of thrombosis have demonstrated the ability to detect thrombus in different disease state models and in patients. Due to its high concentration in the thrombus and its essential role in thrombus formation, the detection of fibrin is an attractive strategy for identification of thrombosis. Herein we provide an overview of recent and selected fibrin-targeted probes for molecular imaging of thrombosis by magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical techniques. Emphasis is placed on work that our lab has explored over the last 15 years that has resulted in the progression of the fibrin-binding PET probe [64Cu]FBP8 from preclinical studies into human trials.
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Affiliation(s)
- Bruno L Oliveira
- Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
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19
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van Mourik TR, Claesener M, Nicolay K, Grüll H. Development of a novel, fibrin-specific PET tracer. J Labelled Comp Radiopharm 2017; 60:286-293. [DOI: 10.1002/jlcr.3501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 02/02/2017] [Accepted: 03/15/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Tiemen R. van Mourik
- Department of Biomedical Engineering; Eindhoven University of Technology; Eindhoven The Netherlands
| | - Michael Claesener
- Department of Nuclear Medicine; University of Münster; Münster Germany
| | - Klaas Nicolay
- Department of Biomedical Engineering; Eindhoven University of Technology; Eindhoven The Netherlands
| | - Holger Grüll
- Department of Biomedical Engineering; Eindhoven University of Technology; Eindhoven The Netherlands
- Department of Oncology Solutions; Philips Research; Eindhoven The Netherlands
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20
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Wang X, Peter K. Molecular Imaging of Atherothrombotic Diseases: Seeing Is Believing. Arterioscler Thromb Vasc Biol 2017; 37:1029-1040. [PMID: 28450298 DOI: 10.1161/atvbaha.116.306483] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/11/2017] [Indexed: 12/13/2022]
Abstract
Molecular imaging, with major advances in the development of both innovative targeted contrast agents/particles and radiotracers, as well as various imaging technologies, is a fascinating, rapidly growing field with many preclinical and clinical applications, particularly for personalized medicine. Thrombosis in either the venous or the arterial system, the latter typically caused by rupture of unstable atherosclerotic plaques, is a major determinant of mortality and morbidity in patients. However, imaging of the various thrombotic complications and the identification of plaques that are prone to rupture are at best indirect, mostly unreliable, or not available at all. The development of molecular imaging toward diagnosis and prevention of thrombotic disease holds promise for major advance in this clinically important field. Here, we review the medical need and clinical importance of direct molecular imaging of thrombi and unstable atherosclerotic plaques that are prone to rupture, thereby causing thrombotic complications such as myocardial infarction and ischemic stroke. We systematically compare the advantages/disadvantages of the various molecular imaging modalities, including X-ray computed tomography, magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, fluorescence imaging, and ultrasound. We further systematically discuss molecular targets specific for thrombi and those characterizing unstable, potentially thrombogenic atherosclerotic plaques. Finally, we provide examples for first theranostic approaches in thrombosis, combining diagnosis, targeted therapy, and monitoring of therapeutic success or failure. Overall, molecular imaging is a rapidly advancing field that holds promise of major benefits to many patients with atherothrombotic diseases.
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Affiliation(s)
- Xiaowei Wang
- From the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute (X.W., K.P.), Departments of Medicine (X.W., K.P.), and Immunology (K.P.), Monash University, Melbourne, Victoria, Australia
| | - Karlheinz Peter
- From the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute (X.W., K.P.), Departments of Medicine (X.W., K.P.), and Immunology (K.P.), Monash University, Melbourne, Victoria, Australia.
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21
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Salmasi MY, Acharya M, Humayun N, Baskaran D, Hubbard S, Vohra H. Is valve repair preferable to valve replacement in ischaemic mitral regurgitation? A systematic review and meta-analysis. Eur J Cardiothorac Surg 2016; 50:17-28. [PMID: 27009102 DOI: 10.1093/ejcts/ezw053] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 12/29/2015] [Indexed: 11/13/2022] Open
Abstract
Ischaemic mitral regurgitation (MR) is associated with poor survival. The favoured surgical option remains debatable. Our aim was to perform a meta-analysis to compare the outcomes of mitral valve repair (MVRp) with replacement (MVR). A literature search was conducted in PubMed, Medline and Ovid using the terms 'ischaemic mitral regurgitation', 'repair' and 'replacement'. The primary outcome measure was 30-day survival. The secondary outcome measures were MR recurrence and reoperation. Out of 310 articles, 18 fulfilled the inclusion criteria. A total of 3978 patients were included: 2563 (64%) MVRp cases and 1415 (36%) MVR cases. Operative techniques included annuloplasty for MVRp and subvalvular apparatus-sparing MVR techniques. Thirty-day mortality was lower after MVRp compared with MVR [OR 0.42; (95% CI 0.33-0.54; P = 0.0001)]. There was no difference in long-term survival ranging 1-5 years (HR 0.85, 95% CI 0.65-1.12). Recurrence of MR was significantly higher in the MVRp group (OR 4.26, 95% CI 2.52-7.22), as was the rate of reoperation (OR 2.03, 95% CI 1.49-2.77). Although MVR for ischaemic MR has a higher 30-day mortality rate compared with MVRp, MVRp is associated with the higher rate of MR recurrence and the need for reoperation. MVR remains an attractive option for ischaemic MR.
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Affiliation(s)
| | - Metesh Acharya
- Department of Cardiac Surgery, Harefield Hospital, London, UK
| | - Nada Humayun
- Department of Cardiothoracic Surgery, University Hospitals of Leicester, Leicester, UK
| | | | - Stephanie Hubbard
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Hunaid Vohra
- Bristol Heart Institute, Bristol Royal Infirmary, Bristol, UK
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22
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Goldstein D, Moskowitz AJ, Gelijns AC, Ailawadi G, Parides MK, Perrault LP, Hung JW, Voisine P, Dagenais F, Gillinov AM, Thourani V, Argenziano M, Gammie JS, Mack M, Demers P, Atluri P, Rose EA, O'Sullivan K, Williams DL, Bagiella E, Michler RE, Weisel RD, Miller MA, Geller NL, Taddei-Peters WC, Smith PK, Moquete E, Overbey JR, Kron IL, O'Gara PT, Acker MA. Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation. N Engl J Med 2016; 374:344-53. [PMID: 26550689 PMCID: PMC4908819 DOI: 10.1056/nejmoa1512913] [Citation(s) in RCA: 618] [Impact Index Per Article: 68.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND In a randomized trial comparing mitral-valve repair with mitral-valve replacement in patients with severe ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI), survival, or adverse events at 1 year after surgery. However, patients in the repair group had significantly more recurrences of moderate or severe mitral regurgitation. We now report the 2-year outcomes of this trial. METHODS We randomly assigned 251 patients to mitral-valve repair or replacement. Patients were followed for 2 years, and clinical and echocardiographic outcomes were assessed. RESULTS Among surviving patients, the mean (±SD) 2-year LVESVI was 52.6±27.7 ml per square meter of body-surface area with mitral-valve repair and 60.6±39.0 ml per square meter with mitral-valve replacement (mean changes from baseline, -9.0 ml per square meter and -6.5 ml per square meter, respectively). Two-year mortality was 19.0% in the repair group and 23.2% in the replacement group (hazard ratio in the repair group, 0.79; 95% confidence interval, 0.46 to 1.35; P=0.39). The rank-based assessment of LVESVI at 2 years (incorporating deaths) showed no significant between-group difference (z score=-1.32, P=0.19). The rate of recurrence of moderate or severe mitral regurgitation over 2 years was higher in the repair group than in the replacement group (58.8% vs. 3.8%, P<0.001). There were no significant between-group differences in rates of serious adverse events and overall readmissions, but patients in the repair group had more serious adverse events related to heart failure (P=0.05) and cardiovascular readmissions (P=0.01). On the Minnesota Living with Heart Failure questionnaire, there was a trend toward greater improvement in the replacement group (P=0.07). CONCLUSIONS In patients undergoing mitral-valve repair or replacement for severe ischemic mitral regurgitation, we observed no significant between-group difference in left ventricular reverse remodeling or survival at 2 years. Mitral regurgitation recurred more frequently in the repair group, resulting in more heart-failure-related adverse events and cardiovascular admissions. (Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00807040.).
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Affiliation(s)
- Daniel Goldstein
- From the Department of Cardiothoracic Surgery, Montefiore Medical Center-Albert Einstein College of Medicine (D.G., R.E.M.), International Center for Health Outcomes and Innovation Research, Department of Population Health Science and Policy (A.J.M., A.C.G., M.K.P., K.O., D.L.W., E.B., E.M., J.R.O.) and Cardiovascular Institute (E.A.R.), Icahn School of Medicine at Mount Sinai, and Division of Cardiothoracic Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University (M.A.) - all in New York; the Division of Thoracic and Cardiovascular Surgery, University of Virginia School of Medicine, Charlottesville (G.A., I.L.K.); Montreal Heart Institute, University of Montreal, Montreal (L.P.P., P.D.), Institut Universitaire de Cardiologie de Québec, Hôpital Laval, Quebec, QC (P.V., F.D.), and Peter Munk Cardiac Centre and Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network and the Division of Cardiac Surgery, University of Toronto, Toronto (R.D.W.) - all in Canada; the Echocardiography Core Lab, Massachusetts General Hospital (J.W.H.), and the Cardiovascular Division, Brigham and Women's Hospital (P.T.O.) - both in Boston; the Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland (A.M.G.); the Clinical Research Unit, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta (V.T.); the University of Maryland, Baltimore (J.S.G.), and the Division of Cardiovascular Sciences (M.A.M., W.C.T-.P.) and Office of Biostatistics Research (N.L.G.), National Heart, Lung, and Blood Institute, Bethesda - both in Maryland; Baylor Research Institute, Dallas (M.M.); the Department of Surgery, Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia (P.A., M.A.A.); and the Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC (P.K.S.)
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23
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Nappi F, Spadaccio C, Chello M, Lusini M, Acar C. Double row of overlapping sutures for downsizing annuloplasty decreases the risk of residual regurgitation in ischaemic mitral valve repair. Eur J Cardiothorac Surg 2015; 49:1182-7. [PMID: 26351400 DOI: 10.1093/ejcts/ezv291] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 07/22/2015] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES The aim of this study was to evaluate a novel insertion technique of the prosthetic ring that would further magnify the degree of annulus narrowing, thereby reducing the potential for a residual leak in ischaemic mitral valve repair. METHODS Thirty-six patients with ischaemic mitral regurgitation (MR) were randomly assigned into two groups. In 18 patients, the prosthetic ring was inserted in the conventional manner with a single row of sutures (control group). In the remaining 18 patients, the ring was attached using a double row of sutures tied both on the inner and on the outer part of the sewing cuff. Both groups had similar preoperative clinical and echocardiographic characteristics with severe leaflet tethering: mean tenting area >2.5 cm(2), mean anterior leaflet angle >25° and posterior leaflet angle >45°. The mean prosthetic ring sizes inserted in both groups were identical (mean: 27.3 mm). RESULTS At 12 months, there was no clinical event except for 1 rehospitalization in the control group. The mean mitral regurgitation grade was higher in the control group than in the group with the double row of sutures at 1.6 ± 0.9 vs 0.7 ± 0.3 (P = 0.0003). Annulus diameter reduction was less pronounced in the control group when compared with the group with the double row of sutures, both in the parasternal long-axis: 29.3 ± 3 vs 26.3 ± 3 mm (P = 0.0003) and in apical four-chamber views: 31 ± 3 vs 28 ± 2 mm (P = 0.003). Leaflet tethering indices were greater in the control group than in the group with the double row of sutures: tenting area: 1.42 ± 0.3 vs 1.1 ± 0.5 cm(2) (P = 0.002), anterior leaflet angle: 33 ± 3° vs 28 ± 5° (P = 0.0009) and posterior leaflet angle: 110 ± 13° vs 80 ± 11° (P = 0.0001). Left ventricular function parameters were not statistically different among the two groups. CONCLUSION A double row of overlapping sutures for attaching the prosthetic ring in downsizing annuloplasty is more efficient in narrowing the mitral annulus than the conventional technique in ischaemic mitral repair. Even in high-risk patients whose leaflets were severely tethered on echocardiography, it almost eliminated the risk of MR recurrence in this study.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiovascular Surgery, University Campus Bio-Medico, Rome, Italy Department of Cardiac Surgery, Centre Cardiologique du Nord, Saint Denis, France
| | - Cristiano Spadaccio
- Department of Cardiovascular Surgery, University Campus Bio-Medico, Rome, Italy
| | - Massimo Chello
- Department of Cardiovascular Surgery, University Campus Bio-Medico, Rome, Italy
| | - Mario Lusini
- Department of Cardiovascular Surgery, University Campus Bio-Medico, Rome, Italy
| | - Christophe Acar
- Department of Cardiothoracic Surgery, Hôpital Pitié-Salpétrière, Paris, France
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Noninvasive Imaging of Early Venous Thrombosis by
19
F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions. Circulation 2015; 131:1405-14. [DOI: 10.1161/circulationaha.114.010962] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Accepted: 02/13/2015] [Indexed: 11/16/2022]
Abstract
Background—
Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques.
Methods and Results—
Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free
19
F magnetic resonance imaging, together with α2-antiplasmin peptide (α2
AP
)–targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter <0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching
1
H and
19
F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, α2
AP
-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of α2
AP
-PFCs >60 minutes after thrombus induction no longer resulted in detectable
19
F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2
AP
-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention.
Conclusions—
Our results demonstrate that
1
H/
19
F magnetic resonance imaging, together with α2
AP
-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo
19
F magnetic resonance imaging.
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Abstract
This perspective outlines strategies towards the development of MR imaging probes that our lab has explored over the last 15 years. Namely, we discuss methods to enhance the signal generating capacity of MR probes and how to achieve tissue specificity through protein targeting or probe activation within the tissue microenvironment.
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Affiliation(s)
- Eszter Boros
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Eric M Gale
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Peter Caravan
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
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Affiliation(s)
- Hans J de Haas
- From the Icahn School of Medicine at Mount Sinai, New York, NY (H.J.d.H., J.N., V.F.); University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (H.J.d.H.); and Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain (V.F.)
| | - Jagat Narula
- From the Icahn School of Medicine at Mount Sinai, New York, NY (H.J.d.H., J.N., V.F.); University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (H.J.d.H.); and Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain (V.F.)
| | - Valentin Fuster
- From the Icahn School of Medicine at Mount Sinai, New York, NY (H.J.d.H., J.N., V.F.); University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (H.J.d.H.); and Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain (V.F.).
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Suzuki M, Bachelet-Violette L, Rouzet F, Beilvert A, Autret G, Maire M, Menager C, Louedec L, Choqueux C, Saboural P, Haddad O, Chauvierre C, Chaubet F, Michel JB, Serfaty JM, Letourneur D. Ultrasmall superparamagnetic iron oxide nanoparticles coated with fucoidan for molecular MRI of intraluminal thrombus. Nanomedicine (Lond) 2014; 10:73-87. [PMID: 24960075 DOI: 10.2217/nnm.14.51] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
AIM We have designed ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles associated with fucoidan (USPOI-FUCO), a natural sulfated polysaccharide with high affinity for activated platelets, to visualize by MRI arterial thrombi. MATERIALS & METHODS USPIOs were prepared and sizes, zeta-potentials and relaxivities were measured. Elastase perfusion in the infrarenal aorta of Wistar rats induced intraluminal thrombus. They were scanned on 4.7 T MRI before and after injection of USPIO-FUCO or USPIO coated with anionic dextran. RESULTS Surface plasmon resonance evidenced that fucoidan and USPIO-FUCO bind in vitro to immobilized P-selectin. All intraluminal hyposignals detected by MRI after injection of USPIO-FUCO on animals (13 out of 13) were correlated by histology with thrombi, whereas none could be identified with control USPIOs (0 out of 7). No signal was seen in absence of thrombus. Thrombi by MRI were correlated with P-selectin immunostaining and USPIO detection by electron microscopy. CONCLUSION In vivo thrombi can thus be evidenced by MRI with USPIO-FUCO.
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Affiliation(s)
- Michimasa Suzuki
- French Institute of Health & Medical Research (Inserm) U1148, Laboratory for Vascular Translational Science, CHU X Bichat, University Paris 7, 46 rue H Huchard, F-75877, France
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Ay I, Blasi F, Rietz TA, Rotile NJ, Kura S, Brownell AL, Day H, Oliveira BL, Looby RJ, Caravan P. In vivo molecular imaging of thrombosis and thrombolysis using a fibrin-binding positron emission tomographic probe. Circ Cardiovasc Imaging 2014; 7:697-705. [PMID: 24777937 DOI: 10.1161/circimaging.113.001806] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Fibrin is a major component of arterial and venous thrombi and represents an ideal candidate for molecular imaging of thrombosis. Here, we describe imaging properties and target uptake of a new fibrin-specific positron emission tomographic probe for thrombus detection and therapy monitoring in 2 rat thrombosis models. METHODS AND RESULTS The fibrin-binding probe FBP7 was synthesized by conjugation of a known short cyclic peptide to a cross-bridged chelator (CB-TE2A), followed by labeling with copper-64. Adult male Wistar rats (n=26) underwent either carotid crush injury (mural thrombosis model) or embolic stroke (occlusive thrombosis model) followed by recombinant tissue-type plasminogen activator treatment (10 mg/kg, IV). FBP7 detected thrombus location in both animal models with a high positron emission tomographic target-to-background ratio that increased over time (>5-fold at 30-90 minutes, >15-fold at 240-285 minutes). In the carotid crush injury animals, biodistribution analysis confirmed high probe uptake in the thrombotic artery (≈0.5%ID/g; >5-fold greater than blood and other tissues of the head and thorax). Similar results were obtained from ex vivo autoradiography of the ipsilateral versus contralateral carotid arteries. In embolic stroke animals, positron emission tomographic-computed tomographic imaging localized the clot in the internal carotid/middle cerebral artery segment of all rats. Time-dependent reduction of activity at the level of the thrombus was detected in recombinant tissue-type plasminogen activator-treated rats but not in vehicle-injected animals. Brain autoradiography confirmed clot dissolution in recombinant tissue-type plasminogen activator-treated animals, but enduring high thrombus activity in control rats. CONCLUSIONS We demonstrated that FBP7 is suitable for molecular imaging of thrombosis and thrombolysis in vivo and represents a promising candidate for bench-to-bedside translation.
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Affiliation(s)
- Ilknur Ay
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Francesco Blasi
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Tyson A Rietz
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Nicholas J Rotile
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Sreekanth Kura
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Anna Liisa Brownell
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Helen Day
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Bruno L Oliveira
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Richard J Looby
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Peter Caravan
- From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
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Singh P, Kaur R, Kaur A. Clot composition and treatment approach to acute ischemic stroke: The road so far. Ann Indian Acad Neurol 2014; 16:494-7. [PMID: 24339566 PMCID: PMC3841587 DOI: 10.4103/0972-2327.120433] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 02/11/2013] [Accepted: 03/11/2013] [Indexed: 11/10/2022] Open
Abstract
Recent histological studies of thrombi retrieved from patients with an acute ischemic stroke using the endovascular thrombectomy devices and correlation with early vessel computed tomography (CT) and magnetic resonance imaging (MRI) characteristics have given relevant insights into the pathophysiology of thrombotic lesions and may facilitate the development of improved reperfusion treatment approaches. We present a review of recent studies on the histopathologic analysis of thrombi, studies of MRI, and CT imaging correlation with thrombus histology, and detailed structural analysis of thromboemboli retrieved by thrombectomy devices during an acute ischemic stroke.
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Affiliation(s)
- Paramdeep Singh
- Department of Radiology, Guru Gobind Singh Medical College and Hospital, Baba Farid University of Health Sciences, Faridkot, Punjab, India
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Paparella D, Malvindi PG, Romito R, Fiore G, Tupputi Schinosa LDL. Ischemic mitral regurgitation: pathophysiology, diagnosis and surgical treatment. Expert Rev Cardiovasc Ther 2014; 4:827-38. [PMID: 17173499 DOI: 10.1586/14779072.4.6.827] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Ischemic mitral valve regurgitation often complicates acute myocardial infarction and also represents a negative prognostic factor for long-term survival in patients undergoing surgical myocardial revascularization. While severe mitral regurgitation should always be corrected during a coronary artery bypass operation, the decision making is more difficult in patients with a mild-to-moderate degree of regurgitation. Recent studies and experimental protocols have elucidated the pathophysiological mechanisms leading to mitral regurgitation with great interest in annular modifications and subvalvular alterations. These data suggest that new and integrated surgical approaches that address annuloplasty ring sizing, ring type selection and tethering phenomenon (i.e., chordal cutting, 'edge-to-edge' technique and left-ventricular plasty techniques) are required for a safer and durable valve repair. Transthoracic and transesophageal echocardiography are useful in determining the etiology and the degree of mitral regurgitation, to assess mitral deformation and to measure indexes of global and regional left-ventricular remodeling. Stress echocardiography may unmask higher degrees of mitral regurgitation. More data are needed in order to confirm the promising and interesting preliminary experimental findings of magnetic resonance imaging in diagnosis and clinical evaluation of ischemic mitral regurgitation.
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Affiliation(s)
- Domenico Paparella
- University of Bari, Division of Cardiac Surgery, Piazza Giulio Cesare 11, 70100 Bari, Italy.
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Murphy MO, Ahmed K, Athanasiou T. Surgery for chronic ischemic mitral regurgitation – which mitral intervention? Expert Rev Cardiovasc Ther 2014; 9:587-97. [DOI: 10.1586/erc.11.50] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Wildgruber M, Swirski FK, Zernecke A. Molecular imaging of inflammation in atherosclerosis. Am J Cancer Res 2013; 3:865-84. [PMID: 24312156 PMCID: PMC3841337 DOI: 10.7150/thno.5771] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 04/29/2013] [Indexed: 01/13/2023] Open
Abstract
Acute rupture of vulnerable plaques frequently leads to myocardial infarction and stroke. Within the last decades, several cellular and molecular players have been identified that promote atherosclerotic lesion formation, maturation and plaque rupture. It is now widely recognized that inflammation of the vessel wall and distinct leukocyte subsets are involved throughout all phases of atherosclerotic lesion development. The mechanisms that render a stable plaque unstable and prone to rupture, however, remain unknown and the identification of the vulnerable plaque remains a major challenge in cardiovascular medicine. Imaging technologies used in the clinic offer minimal information about the underlying biology and potential risk for rupture. New imaging technologies are therefore being developed, and in the preclinical setting have enabled new and dynamic insights into the vessel wall for a better understanding of this complex disease. Molecular imaging has the potential to track biological processes, such as the activity of cellular and molecular biomarkers in vivo and over time. Similarly, novel imaging technologies specifically detect effects of therapies that aim to stabilize vulnerable plaques and silence vascular inflammation. Here we will review the potential of established and new molecular imaging technologies in the setting of atherosclerosis, and discuss the cumbersome steps required for translating molecular imaging approaches into the clinic.
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Zhao Q, Hu X. Postoperative pulmonary hypertensive crisis caused by inverted left atrial appendage after cardiopulmonary bypass surgery for congenital heart disease in a neonate. Heart Lung Circ 2013; 22:781-3. [PMID: 24054493 DOI: 10.1016/j.hlc.2013.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 02/21/2013] [Accepted: 03/07/2013] [Indexed: 10/26/2022]
Abstract
Postoperative pulmonary hypertensive crisis (PHC) caused by an inverted left atrial appendage (ILAA) is a rare complication following cardiac surgery. We present a case of 23 day-old male infant who developed postoperative PHC attacks after undergoing cardiopulmonary bypass (CPB) surgery for repair of the coactation of aorta. A hyperechogenic left atrial mass was detected via bedside transthoracic echocardiography (TTE), which was identified as an ILAA and corrected following repeat surgery. In this case, both the negative pressure in vent catheter and the long left atrial appendage (LAA) with a narrow base led to an irreversible ILAA. As in this neonate, ILAA had significant influence on the left atrial volume and caused PHC since the ILAA was located on the mitral valve orifice and interfered with the blood flow through the valve. Therefore, we recommend that the vent catheter should be turned off before removing to avoid this potential complication. Additionally, LAA should be carefully inspected after CPB surgery, and intra-operative and post-operative transoesophageal echocardiography (TEE) should be performed to detect ILAA intraoperatively so as to avoid the reoperation. When an ILAA is diagnosed postoperatively, whether conservative treatment or surgery will depend on the balance of benefit and risk for a particular patient.
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Affiliation(s)
- Qifeng Zhao
- Department of Cardiovascular and Thoracic Surgery, The 2nd Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical College, Wenzhou, China.
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Transapical Valve-in-Valve-in-Ring for Stenotic Mitral Valve Repair. INNOVATIONS-TECHNOLOGY AND TECHNIQUES IN CARDIOTHORACIC AND VASCULAR SURGERY 2013; 8:376-80. [DOI: 10.1097/imi.0b013e3182a6940b] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A 53-year-old woman, previously treated with irradiation and chemotherapy for Hodgkin lymphoma, was referred for redovalve surgery. She had had a pacemaker implantation and undergone coronary bypass surgery, mitral valve repair with a Carpentier-Edwards 28-mm Physio-annuloplasty ring, as well as a mechanical tricuspid valve replacement and a transfemoral CoreValve 26-mm implantation. She had cardiac cachexia, pleura effusion, and a failed mitral valve repair with stenosis. She was judged inoperable for open surgery but suitable for a transapical valve-in-valve implantation on partial femorofemoral bypass. A 26-mm Edwards SAPIEN XT aortic valve inversely mounted on the Ascendra + delivery catheter was balloon expanded into the Physio ring. During expansion, the introducer sheath remained too deep into the left ventricle and rotated the SAPIEN valve upward to the left atrium, creating the onset of a new mitral regurgitation and retaining the stenosis. Another Edwards SAPIEN XT 26-mm valve was then positioned into the first valve in a “valve-in-valve-in-ring” tandem configuration. Both valves were supported by the Physio ring. The stenosis and the regurgitation were thereafter eliminated.
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Dahle G, Rein KA, Jönsson AL. Transapical Valve-in-Valve-in-Ring for Stenotic Mitral Valve Repair. INNOVATIONS-TECHNOLOGY AND TECHNIQUES IN CARDIOTHORACIC AND VASCULAR SURGERY 2013. [DOI: 10.1177/155698451300800510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Gry Dahle
- Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway
| | - Kjell-Arne Rein
- Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway
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Abstract
RATIONALE AND OBJECTIVES Fibrin deposition has been indicated within the stroma of a majority of solid tumors. Here we assess the feasibility of using the established fibrin-specific probe EP-2104R for noninvasive imaging of fibrin in the context of breast cancer. METHODS EP-2104R, untargeted gadopentetate dimeglumine (Gd-DTPA), and a newly synthesized nonfibrin binding control linear peptide (CLP) were compared using steady-state and dynamic contrast-enhanced magnetic resonance imaging in a breast cancer xenograft mouse model at 9.4 T. RESULTS EP-2104R transiently enhanced both tumor core and tumor periphery, but only the enhancement in the tumor periphery persisted even 90 minutes after EP-2104R administration. However, untargeted Gd-DTPA and CLP are not retained in the tumor periphery. The half-life of EP-2104R in the tumor periphery (103 ± 18 minutes) is significantly longer (P < 0.05) than that of either Gd-DTPA (29.6 ± 2.4 minutes) or CLP (42.4 ± 1.5 minutes), but the rate of clearance is similar for all the 3 probes from the tumor core. The presence of high concentrations of fibrin in the tumor periphery was corroborated using immunohistochemistry with a fibrin-specific antibody. CONCLUSIONS The persistent enhancement observed in the tumor periphery with EP-2104R is likely a result of its fibrin-specific binding rather than its size and demonstrates the feasibility of EP-2104R for molecular imaging of fibrin in tumor stroma.
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Transapical 29-mm Edwards SAPIEN-XT aortic valve in a 34-mm mitral annuloplasty ring. INNOVATIONS-TECHNOLOGY AND TECHNIQUES IN CARDIOTHORACIC AND VASCULAR SURGERY 2012; 7:290-4. [PMID: 23123997 DOI: 10.1097/imi.0b013e31826d5cd0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A 71-year-old woman with severe congestive heart failure and failed mitral valve repair was referred for surgery. Because of her low ejection fraction, a valve-in-ring procedure was suggested. There was a great difference in the given size for the 34-mm Carpentier-Edwards-Physio-Ring and the biggest available transcatheter valve of 29 mm from Edwards. Therefore, we did a "bench test." We expanded a 29-mm Edwards SAPIEN-XT aortic valve in a 34-mm Carpentier-Edwards-Physio-Ring. It fitted well and turned out circular with good coaptation of the leaflets. Thereafter, a successful transapical mitral valve-in-ring implantation on cardiopulmonary bypass was performed, and additional leads for cardiac resynchronization was placed.
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Phinikaridou A, Andia ME, Shah AM, Botnar RM. Advances in molecular imaging of atherosclerosis and myocardial infarction: shedding new light on in vivo cardiovascular biology. Am J Physiol Heart Circ Physiol 2012; 303:H1397-410. [PMID: 23064836 DOI: 10.1152/ajpheart.00583.2012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Molecular imaging of the cardiovascular system heavily relies on the development of new imaging probes and technologies to facilitate visualization of biological processes underlying or preceding disease. Molecular imaging is a highly active research discipline that has seen tremendous growth over the past decade. It has broadened our understanding of oncologic, neurologic, and cardiovascular diseases by providing new insights into the in vivo biology of disease progression and therapeutic interventions. As it allows for the longitudinal evaluation of biological processes, it is ideally suited for monitoring treatment response. In this review, we will concentrate on the major accomplishments and advances in the field of molecular imaging of atherosclerosis and myocardial infarction with a special focus on magnetic resonance imaging.
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Affiliation(s)
- Alkystis Phinikaridou
- Division of Imaging Science and Biomedical Engineering, King's College London, United Kingdom.
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Dahle G, Fiane AE, Rein KA. Transapical 29-mm Edwards SAPIEN-XT Aortic Valve in a 34-mm Mitral Annuloplasty Ring. INNOVATIONS-TECHNOLOGY AND TECHNIQUES IN CARDIOTHORACIC AND VASCULAR SURGERY 2012. [DOI: 10.1177/155698451200700410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Gry Dahle
- Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway
| | - Arnt E. Fiane
- Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kjell-Arne Rein
- Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway
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Unger P, Magne J, Dedobbeleer C, Lancellotti P. Ischemic mitral regurgitation: not only a bystander. Curr Cardiol Rep 2012; 14:180-9. [PMID: 22203438 DOI: 10.1007/s11886-011-0241-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ischemic mitral regurgitation (MR) is a common complication of left ventricular (LV) dysfunction related to chronic coronary artery disease. This complex multifactorial disease involves global and regional LV remodeling, as well as dysfunction and distortion of the components of the mitral valve including the chordae, the annulus, and the leaflets. Its occurrence is associated with a poor prognosis. The suboptimal results obtained with the most commonly used surgical strategy, involving mitral valve annuloplasty with coronary bypass grafting, emphasize the need to develop alternative surgical techniques targeting the causal mechanisms of the disease. A comprehensive preoperative assessment of mitral valve configuration and LV geometry and function and an accurate quantification of MR severity at rest and during exercise may contribute to improve risk stratification and to tailor the surgical strategy according to the individual characteristics of the patient.
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Affiliation(s)
- Philippe Unger
- Cardiology Department, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
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Clofent-Sanchez G, Jacobin-Valat MJ, Laroche-Traineau J. The growing interest of fibrin imaging in atherosclerosis. Atherosclerosis 2012; 222:22-5. [DOI: 10.1016/j.atherosclerosis.2012.01.041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 01/23/2012] [Indexed: 12/19/2022]
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Caravan P, Zhang Z. Structure - relaxivity relationships among targeted MR contrast agents. Eur J Inorg Chem 2012; 2012:1916-1923. [PMID: 22745568 PMCID: PMC3381435 DOI: 10.1002/ejic.201101364] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Indexed: 01/22/2025]
Abstract
Paramagnetic gadolinium(III) complexes are widely used to increase contrast in magnetic resonance (MR) images. Contrast enhancement depends on the concentration of the gadolinium complex and on its relaxivity, an inherent property of the complex. Increased relaxivity results in greater image contrast or the ability to detect the contrast agent at a lower concentration. Increasing relaxivity enables imaging of abundant molecular targets.Relaxivity depends on the structure of the complex, kinetics of inner-sphere and second sphere water exchange, and on the rotational dynamics of the molecule. The latter, and in some cases the former, properties of the complex change when it is bound to its target. All of these properties can be rationally tuned to enhance relaxivitry. In this Microreview we summarize our efforts in understanding and optimizing the relaxivity of contrast agents targeted to serum albumin and to fibrin.
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Affiliation(s)
- Peter Caravan
- A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth St, Suite 2301, Charlestown, MA 02129, USA
| | - Zhaoda Zhang
- A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth St, Suite 2301, Charlestown, MA 02129, USA
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Kolodziej AF, Nair SA, Graham P, McMurry TJ, Ladner RC, Wescott C, Sexton DJ, Caravan P. Fibrin specific peptides derived by phage display: characterization of peptides and conjugates for imaging. Bioconjug Chem 2012; 23:548-56. [PMID: 22263840 DOI: 10.1021/bc200613e] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Peptides that bind to fibrin but not to fibrinogen or serum albumin were selected from phage display libraries as targeting moieties for thrombus molecular imaging probes. Three classes of cyclic peptides (cyclized via disulfide bond between two Cys) were identified with consensus sequences XArXCPY(G/D)LCArIX (Ar = aromatic, Tn6), X(2)CXYYGTCLX (Tn7), and NHGCYNSYGVPYCDYS (Tn10). These peptides bound to fibrin at ∼2 sites with K(d) = 4.1 μM, 4.0 μM, and 8.7 μM, respectively, whereas binding to fibrinogen was at least 100-fold weaker. The peptides also bind to the fibrin degradation product DD(E) with similar affinity to that measured for fibrin. The Tn7 and Tn10 peptides bind to the same site on fibrin, while the Tn6 peptides bind to a unique site. Alanine scanning identified the N- and C-terminal ends of the Tn6 and Tn7 peptides as most tolerant to modification. Peptide conjugates with either fluorescein or diethylenetriaminepentaaceto gadolinium(III) (GdDTPA) at the N-terminus were prepared for potential imaging applications, and these retained fibrin binding affinity and specificity in plasma. Relaxivity and binding studies on the GdDTPA derivatives revealed that an N-terminal glycyl linker had a modest effect on fibrin affinity but resulted in lower fibrin-bound relaxivity.
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Winter PM, Taylor MD. Magnetic Resonance Molecular Imaging of Plaque Angiogenesis. CURRENT CARDIOVASCULAR IMAGING REPORTS 2012. [DOI: 10.1007/s12410-011-9121-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Sharif F, Lohan DG, Wijns W. Non-invasive detection of vulnerable coronary plaque. World J Cardiol 2011; 3:219-29. [PMID: 21860703 PMCID: PMC3158870 DOI: 10.4330/wjc.v3.i7.219] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Revised: 06/16/2011] [Accepted: 06/23/2011] [Indexed: 02/06/2023] Open
Abstract
Critical coronary stenoses have been shown to contribute to only a minority of acute coronary syndromes and sudden cardiac death. Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis. Consequently, a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease. Recent advances in invasive and non-invasive imaging techniques have shown the potential to identify these high-risk plaques. Non-invasive imaging with magnetic resonance imaging, computed tomography and positron emission tomography holds the potential to differentiate between low- and high-risk plaques. There have been significant technological advances in non-invasive imaging modalities, and the aim is to achieve a diagnostic sensitivity for these technologies similar to that of the invasive modalities. Molecular imaging with the use of novel targeted nanoparticles may help in detecting high-risk plaques that will ultimately cause acute myocardial infarction. Moreover, nanoparticle-based imaging may even provide non-invasive treatments for these plaques. However, at present none of these imaging modalities are able to detect vulnerable plaque nor have they been shown to definitively predict outcome. Further trials are needed to provide more information regarding the natural history of high-risk but non-flow-limiting plaque to establish patient specific targeted therapy and to refine plaque stabilizing strategies in the future.
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Affiliation(s)
- Faisal Sharif
- Faisal Sharif, Department of Cardiology, Regional Hospital Galway, and Regenerative Medicine Institute, National University of Ireland Galway, County Galway, Ireland
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Affiliation(s)
- Ian Y Chen
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5111, USA
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Uppal R, Catana C, Ay I, Benner T, Sorensen AG, Caravan P. Bimodal thrombus imaging: simultaneous PET/MR imaging with a fibrin-targeted dual PET/MR probe--feasibility study in rat model. Radiology 2010; 258:812-20. [PMID: 21177389 DOI: 10.1148/radiol.10100881] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To image thrombus by using magnetic resonance (MR) imaging and positron emission tomography (PET) simultaneously in a rat arterial thrombus model with a dual PET/MR probe. MATERIALS AND METHODS Animal studies were approved by the institutional animal use committee. A dual PET/MR probe was synthesized by means of partial exchange of gadolinium for copper 64 ((64)Cu) in the fibrin-targeted MR probe EP-2104R. A preformed 25-mm thrombus was injected into the right internal carotid artery of a rat. Imaging was performed with a clinical 3.0-T MR imager with an MR-compatible human PET imager. Rats (n = 5) were imaged prior to and after systemic administration of the dual probe by using simultaneous PET/MR. The organ distribution of (64)Cu and gadolinium was determined ex vivo (n = 8), 2 hours after injection by using well counting and inductively coupled plasma mass spectrometry, respectively. Signal intensity ratios (SIRs) between the thrombus-containing and contralateral vessel were computed from PET images and MR data before and after probe administration. RESULTS The dual probe was synthesized with greater than 98% radiochemical purity. Thrombus enhancement was observed in all five animals at both MR (SIR([postprobe])/SIR([preprobe]) = 1.71 ± 0.35, P = .0053) and PET (SIR = 1.85 ± 0.48, P = .0087) after injection of the dual PET/MR probe. Ex vivo analysis at 2 hours after injection showed the highest (64)Cu and gadolinium concentrations, after the excretory organs (kidney and liver), to be in the thrombus. CONCLUSION A fibrin-targeted dual PET/MR probe enables simultaneous, direct MR and PET imaging of thrombus.
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Affiliation(s)
- Ritika Uppal
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, MA 02129, USA
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Winter PM, Caruthers SD, Lanza GM, Wickline SA. Quantitative cardiovascular magnetic resonance for molecular imaging. J Cardiovasc Magn Reson 2010; 12:62. [PMID: 21047411 PMCID: PMC2987770 DOI: 10.1186/1532-429x-12-62] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2010] [Accepted: 11/03/2010] [Indexed: 12/14/2022] Open
Abstract
Cardiovascular magnetic resonance (CMR) molecular imaging aims to identify and map the expression of important biomarkers on a cellular scale utilizing contrast agents that are specifically targeted to the biochemical signatures of disease and are capable of generating sufficient image contrast. In some cases, the contrast agents may be designed to carry a drug payload or to be sensitive to important physiological factors, such as pH, temperature or oxygenation. In this review, examples will be presented that utilize a number of different molecular imaging quantification techniques, including measuring signal changes, calculating the area of contrast enhancement, mapping relaxation time changes or direct detection of contrast agents through multi-nuclear imaging or spectroscopy. The clinical application of CMR molecular imaging could offer far reaching benefits to patient populations, including early detection of therapeutic response, localizing ruptured atherosclerotic plaques, stratifying patients based on biochemical disease markers, tissue-specific drug delivery, confirmation and quantification of end-organ drug uptake, and noninvasive monitoring of disease recurrence. Eventually, such agents may play a leading role in reducing the human burden of cardiovascular disease, by providing early diagnosis, noninvasive monitoring and effective therapy with reduced side effects.
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Affiliation(s)
- Patrick M Winter
- Cincinnati Children's Hospital, Department of Radiology, 3333 Burnet Ave., ML 5033, Cincinnati, OH, 45229, USA
| | - Shelton D Caruthers
- Washington University, C-TRAIN Labs, 660 S. Euclid Ave., Campus Box 8215, St. Louis, MO, 63110, USA
| | - Gregory M Lanza
- Washington University, C-TRAIN Labs, 660 S. Euclid Ave., Campus Box 8215, St. Louis, MO, 63110, USA
| | - Samuel A Wickline
- Washington University, C-TRAIN Labs, 660 S. Euclid Ave., Campus Box 8215, St. Louis, MO, 63110, USA
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Shudo Y, Matsumiya G, Sakaguchi T, Miyagawa S, Yoshikawa Y, Yamauchi T, Takeda K, Saito S, Nakatani S, Taniguchi K, Izutani H, Sawa Y. Assessment of changes in mitral valve configuration with multidetector computed tomography: impact of papillary muscle imbrication and ring annuloplasty. Circulation 2010; 122:S29-36. [PMID: 20837921 DOI: 10.1161/circulationaha.109.928002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND The optimal surgical procedures in functional mitral regurgitation remain controversial. We applied papillary muscle imbrication (PMI) combined with undersized mitral annuloplasty (UMAP). Multidetector computed tomography (MDCT) provides images of different phases of the cardiac cycle, allowing an assessment of the geometry. In the present study, we evaluated the mitral valve configuration and subvalvular apparatus before and after UMAP and/or PMI using MDCT imaging. METHODS AND RESULTS We studied 26 patients with functional mitral regurgitation (3+ to 4+) with an ejection fraction ≥35% who underwent diagnostic MDCT examinations before and early after the operation. Of these, 15 underwent UMAP and PMI (UMAP+PMI group) and 11 underwent UMAP (UMAP group). The annular anteroposterior diameter, tenting height, tenting area, and interpapillary muscle distance at end-systole were quantified. The annular anteroposterior diameter, tenting height, and tenting area were significantly decreased after the operation in both groups. Whereas the average change in annular anteroposterior diameter, tenting area, and interpapillary muscle distance did not differ between the 2 groups, the average change in tenting height was greater in the UMAP+PMI group than in the UMAP group (5.1±1.3 versus 3.8±2.3 mm, P=0.036). There was a significant correlation between the change in interpapillary muscle distance and the change in tenting height in the UMAP+PMI group (r=0.788, P=0.0005). CONCLUSIONS Our results examined with MDCT indicated that UMAP combined with PMI improved leaflet tethering compared with UMAP, reflecting differences in the effects of the surgical procedures used, and suggested that concomitant PMI might be beneficial in some cases.
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Affiliation(s)
- Yasuhiro Shudo
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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