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Assessing cardiac metabolic pathways and inflammatory responses in the ischemic-reperfused myocardium using hyperpolarized 13C metabolic MR spectroscopy and 19F-MR macrophage imaging

English title Assessing cardiac metabolic pathways and inflammatory responses in the ischemic-reperfused myocardium using hyperpolarized 13C metabolic MR spectroscopy and 19F-MR macrophage imaging
Applicant Schwitter Jürg
Number 163050
Funding scheme Project funding (Div. I-III)
Research institution Service de Cardiologie Département de Médecine CHUV
Institution of higher education University of Lausanne - LA
Main discipline Cardiovascular Research
Start/End 01.05.2016 - 30.04.2019
Approved amount 429'000.00
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All Disciplines (4)

Discipline
Cardiovascular Research
Pathophysiology
Cellular Biology, Cytology
Biochemistry

Keywords (8)

Cardiac inflammation; Hyperpolarization; Cardiac metabolism; Radical oxygen species; MR spectroscopy; Ischemia / Reperfusion; 19F-fluorine Magnetic Resonance Imaging; Macrophages

Lay Summary (French)

Lead
Les alterations métaboliques et inflammatoires dans le muscle du coeur après un infarctus, i.e. après le rétablissement de la circulation sanguine, seront investigués par la Résonance Magnétique du carbon-13 hyperpolarisé et le fluor-19 dans un modèle établi chez le rat.
Lay summary
Les maladies cardiovasculaires restent la cause principale de décès dans les pays développés. L’ischémie et l’infarction myocardique peuvent entraîner les lésions et les troubles de la fonction cardiaque, même après le rétablissement de la circulation sanguine. Il est bien établi que les radicaux libres produits au moment du rétablissement de la circulation causent paradoxalement un grand parti des lésons des tissus.  En plus, des réactions inflammatoires dans le tissu reperfusé contribuent au dégât du myocarde. Donc par mieux comprendre les changements métaboliques et inflammatoires qui entraînent la lésion d'ischémie-reperfusion cardiaque, on pourrait développer des traitements plus efficaces. 
Nous proposons de l’étudier utilisant un modèle d’ischémie réversible établi chez le rat. L’imagerie et la spectroscopie à résonance magnétique (RM) du carbone-13 hyperpolarisé, grâce à sa haute sensibilité de manière minimalement invasive, sont bien adaptées à suivre les changements métaboliques juste après le rétablissement de la circulation. En plus nous utiliserons la RM du fluor-19 basée sur des produits de contraste de type per-fluoro-carbon. Ces produits sont incorporés dans les cellules inflammatoires qui seront visualisés par la RM du fluor-19. L'état d'oxydoréduction ainsi que les niveaux des métabolites énergétiques qui sont impliqués dans la production des dérivés réactifs de l'oxygène seront examinées avec des précurseurs hyperpolarisés. Avec les conditions de base établies, les effets des traitements expérimentaux conçus pour réduire la production des dérivés réactifs de l'oxygène ainsi que la réponse inflammatoire seront testés. Cette étude fait progresser nos connaissances sur la lésion d'ischémie-reperfusion cardiaque et comment on pourrait la mieux traiter.
Direct link to Lay Summary Last update: 08.08.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
From Lab to Life
Schwitter Juerg (2018), From Lab to Life, in JACC: Cardiovascular Imaging, 11(11), 1607-1610.
Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicals
Bastiaansen Jessica A. M., Yoshihara Hikari A. I., Capozzi Andrea, Schwitter Juerg, Gruetter Rolf, Merritt Matthew E., Comment Arnaud (2018), Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo-induced nonpersistent radicals, in Magnetic Resonance in Medicine, 79(5), 2451-2459.

Collaboration

Group / person Country
Types of collaboration
Albeda Research Aps Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
HYP18 Hyperpolarized Magnetic Resonance Southampton, UK, 2018 Sept 2-5 Poster Renal metabolism of hyperpolarized [1-13C]aspartate 02.09.2018 Southampton, Great Britain and Northern Ireland Yoshihara Hikari; Schwitter Jürg;
Annual Meeting ISMRM, Singapore, 2016 May 9-13 Poster The formulation of hyperpolarized 13C-pyruvate solutions influences the labeling of myocardial metabolites in vivo 09.05.2016 Singapore, Singapore Schwitter Jürg; Comment Arnaud; Yoshihara Hikari;


Associated projects

Number Title Start Funding scheme
144077 19F-Fluorine MRI as a novel imaging approach for detection and tracking of specific cell populations in-vivo 01.11.2012 Project funding (Div. I-III)
138146 Assessing cardiac metabolic pathways in the post-ischemic heart and in progressive heart failure using hyperpolarized 13C MR 01.05.2012 Project funding (Div. I-III)
173129 A Paradigm Shift in Magnetic Resonance Imaging of the Heart: 5D Imaging - Sample Now and Ask Questions Later 01.06.2017 Project funding (Div. I-III)
157547 Hyperpolarization techniques for biomedical applications 01.04.2015 SNSF Professorships

Abstract

1. SUMMARY OF PROJECT Background: Cardiovascular diseases are still the single most important cause of death in industrialized countries killing over 2 million people per year in Europe and causing costs of 196 billion € in 2009. Acute myocardial infarction, and consequently heart failure are the main contributors to cardiovascular morbidity and mortality world-wide. Novel MR-based imaging techniques are now available for a non-invasive real-time assessment of intracellular energy metabolism. These techniques are based on the hyperpolarization of carbon compounds such as 13C-pyruvate and others that deliver signals up to 10‘000 times higher than in conventional MR. This MR technique yields spectra of intracellular energy metabolites every 1-5 sec that allow studying non-invasively the fate of injected substrates with high temporal and chemical resolution. In the current SNF grant period, we were able to establish an intact rat model of ischemia-reperfusion (I/R) to measure PDH activity (lactate/bicarbonate production by 13C-pyruvate) and to assess ß-oxidation by 13C-octanoate (submitted to Circulation-CVI). In addition, novel 19F-based MR techniques emerged over the past years, which allow to monitoring specific cell types in-vivo over hours and days when labeled with perfluorocarbons (PFC). In the current SNF grant period, we could establish the 19F-MRI technique to monitor macrophages non-invasively in a mouse model of autoimmune experimental myocarditis (Circ-CVI, Pfizer-Prize Cardiac Basic Research). Aim: To combine metabolic 13C-spectroscopy and 19F-MRI to investigate the interplay between metabolic alterations and the inflammatory response in the I/R injury in the intact rat model. 13C-aspartate-labeling will be established to monitor intramitochondrial succinate accumulation during ischemia, a crucial step for radical oxygen species (ROS) formation upon reperfusion. ROS formation will be studied non-invasively by 13C-dehydroascorbate. The importance of ß-oxidation for energy production during I/R and the carnitine pool size fed by ß-oxidation products will be explored by 13C-octanoate. In the second part, these metabolic studies will be complemented by the assessment of the inflammatory response by 19F-MRI to test the hypothesis that the metabolic milieu (in particular ROS formation) is crucial for macrophage attraction and differentiation. In the third part we will test the effect of 2 treatment strategies to mitigate succinate accumulation/ROS formation (by MitoSNO-1) and the excessive inflammatory response (by the anti-inflammatory peptide thymosin-ß4). Methods: Preparations of hyperpolarized 13C-pyruvate (established), 13C-aspartate (to develop), 13C-octanoate (to modify), and 13C-dehydroascorbate (to develop) will be used to probe the metabolic/redox milieu during I/R in the intact rat model by spectroscopy at 9.4T. The studies will be combined with 19F-MRI (established) to quantify the inflammatory response. Immunofluorescence histology and flow cytometry will be used to correlate macrophage influx and polarization with the MR spectroscopic and imaging results. Myocardial necrosis, scarring, function and cardiac remodeling over time will be measured by conventional 1H-MRI. Timelines: 1. year: Establishment of succinate labeling via 13C-aspartate, probing ß-oxidation with multiply-13C-labelled octanoate and assessing ROS formation by ascorbate labeling via 13C-dehydroascorbate. 2. year: Combined assessment of the metabolic state and the inflammatory response by 19F-MRI in I/R, 3. year: Assessment of two treatment strategies in I/R targeting ROS formation (by MitoSNO-1) and the inflammatory response (by thymosin-ß4). Assessment of treatment effects acutely and on cardiac remodeling. Outlook: These studies will allow us to better understand the mechanisms leading to ROS formation during I/R and how they might influence the inflammatory response. Techniques established during the current SNF grant period will be refined and new techniques will be added to yield a platform for unique non-invasive studies linking metabolism and inflammation. These techniques are in principle applicable to man, thus, allowing in the future for translation into patients. Finally, this knowledge should set the basis for the development of novel treatment strategies targeted to reduce I/R injury.
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