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Translational Microstructural and Metabolic Magnetic Resonance Imaging for Cardiac Regeneration Therapy

English title Translational Microstructural and Metabolic Magnetic Resonance Imaging for Cardiac Regeneration Therapy
Applicant Kozerke Sebastian
Number 153014
Funding scheme Project funding
Research institution Institut für Biomedizinische Technik Universität Zürich und ETHZ
Institution of higher education University of Zurich - ZH
Main discipline Biomedical Engineering
Start/End 01.05.2014 - 30.04.2018
Approved amount 429'000.00
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All Disciplines (3)

Discipline
Biomedical Engineering
Electrical Engineering
Clinical Cardiovascular Research

Keywords (8)

Magnetic Resonance Imaging; Stem Cells; Cardiac Regeneration; Dynamic Nuclear Polarization; Tissue Engineering; Heart Failure; Cardiovascular Magnetic Resonance; Magnetic Resonance Spectroscopy

Lay Summary (German)

Lead
Die Herzinsuffizienz betrifft weltweit 22 Mio. Patienten mit einer Prävalenz, die mit dem Alter zunimmt. Trotz vielfältiger Bemühungen und entsprechender Erfolge bei der Behandlung der Herzinsuffizienz, sterben weiterhin 50% der Patienten innerhalb der ersten 5 Jahre nach erfolgter Diagnose.Im Rahmen des vorliegenden Projektes werden diagnostische Verfahren, basiered auf der Magnetresonanzbildgebung, für eine bessere Charakterisierung der Gewebeveränderungen und des Stoffwechsels in der Herzinsuffizienz entwickelt und getestet. Die Entwicklungen erfolgen insbesondere in Hinblick auf mögliche stammzellenbasierte Interventionen, mit deren Hilfe mechanisch inaktive Gebiete des Herzmuskels "reaktiviert" werden können.
Lay summary

Magnetic Resonance Imaging (MRI) has become a prime diagnostic modality. MRI is considered the gold standard for assessing cardiac function in the clinic.

Beyond morphological imaging, MRI offers the unique feature of non-invasively probing tissue properties at a microscopic scale. While Diffusion Weighted Imaging and Diffusion Tensor Imaging have been well established for stationary organs including the brain, its application to the in-vivo heart is very challenging as cardiac and respiratory motion of the heart is orders of magnitude greater than the diffusion processes.

In addition to structural information about the heart as measured by MRI, Magnetic Resonance Spectroscopy (MRS) allows to assess tissue metabolism. To this end, however, the sensitivity of the experiment needs to be enhancedby order of magnitude. This is achieved by a technique called Dynamic Nuclear Polarization (DNP). In DNP an endogenous, metabolically active substrate which is taken up by the heart, is magnetized in a DNP polarizer and subsequently injected back into the blood stream in-vivo. Following this, metabolic reactions can be observed using MRS during a short time window, giving unique insights into the use of the "fuels" consumed by the heart.

It is the aim of the present project  to develop, validate and translate MRI and MRS methodology to map microstructural and metabolic information alongside with functional indices of the in-vivo heart for monitoring and guiding cardiac regeneration therapy.

Direct link to Lay Summary Last update: 01.05.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Direct comparison of in vivo versus postmortem second-order motion-compensated cardiac diffusion tensor imagingDirect Comparison of In Vivo Versus Postmortem Cardiac DTI
Stoeck Christian T., von Deuster Constantin, Fleischmann Thea, Lipiski Miriam, Cesarovic Nikola, Kozerke Sebastian (2018), Direct comparison of in vivo versus postmortem second-order motion-compensated cardiac diffusion tensor imagingDirect Comparison of In Vivo Versus Postmortem Cardiac DTI, in Magnetic Resonance in Medicine, 79(4), 2265-2276.
Overestimation of cardiac lactate production caused by liver metabolism of hyperpolarized [1- 13 C]pyruvate
Wespi Patrick, Steinhauser Jonas, Kwiatkowski Grzegorz, Kozerke Sebastian (2018), Overestimation of cardiac lactate production caused by liver metabolism of hyperpolarized [1- 13 C]pyruvate, in Magnetic Resonance in Medicine, 1.
High-resolution hyperpolarized metabolic imaging of the rat heart using k - t PCA and k - t SPARSE
Wespi Patrick, Steinhauser Jonas, Kwiatkowski Grzegorz, Kozerke Sebastian (2018), High-resolution hyperpolarized metabolic imaging of the rat heart using k - t PCA and k - t SPARSE, in NMR in Biomedicine, 31(2), e3876-e3876.
Assessing the influence of isoflurane anesthesia on cardiac metabolism using hyperpolarized [1- 13 C]pyruvate
Steinhauser Jonas, Wespi Patrick, Kwiatkowski Grzegorz, Kozerke Sebastian (2018), Assessing the influence of isoflurane anesthesia on cardiac metabolism using hyperpolarized [1- 13 C]pyruvate, in NMR in Biomedicine, 31(2), e3856-e3856.
Myocardial Scar Delineation Using Diffusion Tensor Magnetic Resonance Tractography
Mekkaoui Choukri, Jackowski Marcel P., Kostis William J., Stoeck Christian T., Thiagalingam Aravinda, Reese Timothy G., Reddy Vivek Y., Ruskin Jeremy N., Kozerke Sebastian, Sosnovik David E. (2018), Myocardial Scar Delineation Using Diffusion Tensor Magnetic Resonance Tractography, in Journal of the American Heart Association, 7(3), e007834-e007834.
Hyperpolarized 13C urea myocardial first-pass perfusion imaging using velocity-selective excitation
Fuetterer Maximilian, Busch Julia, Peereboom Sophie M., von Deuster Constantin, Wissmann Lukas, Lipiski Miriam, Fleischmann Thea, Cesarovic Nikola, Stoeck Christian T., Kozerke Sebastian (2017), Hyperpolarized 13C urea myocardial first-pass perfusion imaging using velocity-selective excitation, in Journal of Cardiovascular Magnetic Resonance, 19(1), 46-46.
A multisample dissolution dynamic nuclear polarization system for serial injections in small animalsMultisample Dissolution DNP Polarizer for Small Animals
Krajewski Marcin, Wespi Patrick, Busch Julia, Wissmann Lukas, Kwiatkowski Grzegorz, Steinhauser Jonas, Batel Michael, Ernst Matthias, Kozerke Sebastian (2017), A multisample dissolution dynamic nuclear polarization system for serial injections in small animalsMultisample Dissolution DNP Polarizer for Small Animals, in Magnetic Resonance in Medicine, 77(2), 904-910.
Second-order motion-compensated spin echo diffusion tensor imaging of the human heartMotion-Compensated Cardiac DTI
Stoeck Christian T., von Deuster Constantin, Genet Martin, Atkinson David, Kozerke Sebastian (2016), Second-order motion-compensated spin echo diffusion tensor imaging of the human heartMotion-Compensated Cardiac DTI, in Magnetic Resonance in Medicine, 75(4), 1669-1676.

Collaboration

Group / person Country
Types of collaboration
Prof. David Sosnovik - Harvard Medical School, Boston, USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. Thomas Eykyn - Imgaging Science and Biomedical Engineering, King's College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Age, gender and heart rate dependency of spin-echo based diffusion tensor imaging measurements in healthy hearts 16.06.2018 Paris, France Kozerke Sebastian; Manka Robert;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Second-order motion-compensated in-vivo cardiac diffusion tensor imaging in diastole - impact of ventricular flow, strain and trigger delay 16.06.2018 Paris, France Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Extended signal modelling and regularization for multi-echo hyperpolarized metabolic image reconstruction 16.06.2018 Paris, France Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Talk given at a conference Overestimation of cardiac lactate production due to liver metabolism of hyperpolarized [1-13C] pyruvate 16.06.2018 Paris, France Steinhauser Jonas; Kozerke Sebastian; Wespi Patrick;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Analysis of cardiac motion induced error for in-vivo cardiac DTI in different heart phases - a comparison of second-order motion compensated SE versus STEAM 16.06.2018 Paris, France Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster The effect of mixing time on diffusion spectrum imaging of the ex-vivo porcine heart 22.04.2017 Honolulu, United States of America Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Dynamic shimming for multi-slice hyperpolarized metabolic imaging of the rat heart at 9.4T 22.04.2017 Honolulu, United States of America Steinhauser Jonas; Wespi Patrick; Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Free-breathing Black-blood Prepared Cardiac Diffusion Tensor Imaging 22.04.2017 Honolulu, United States of America Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Production of Highly Polarized Acetate by Rapid Decarboxylation of Pyruvate – Application to Hyperpolarized Cardiac Spectroscopy 22.04.2017 Honolulu, United States of America Steinhauser Jonas; Kozerke Sebastian; Wespi Patrick;
Annual Meeting of International Society for Magnetic Resonance in Medicine Talk given at a conference Impact of eddy-currents and cardiac motion in DTI of the in-vivo heart - a comparison of second-order motion compensated SE versus STEAM 22.04.2017 Honolulu, United States of America Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Talk given at a conference Towards Quantitative Cardiac First-Pass Perfusion Imaging using Hyperpolarized [13]-Urea 22.04.2017 Honolulu, United States of America Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Influence of Isoflurane Anesthesia on Assessment of Cardiac Metabolism Using Hyperpolarized [1-13C] Pyruvate 22.04.2017 Honolulu, United States of America Steinhauser Jonas; Wespi Patrick; Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Effect of B0 inhomogeneity on the quantification of hyperpolarized metabolic data of the heart at 9.4T 22.04.2017 Honolulu, United States of America Steinhauser Jonas; Kozerke Sebastian; Wespi Patrick;
Annual Meeting of International Society for Magnetic Resonance in Medicine Talk given at a conference Velocity-selective tip-back excitation for hyperpolarized [13C] urea cardiac perfusion imaging 07.05.2016 Singapore, Singapore Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Talk given at a conference Accelerating hyperpolarized metabolic imaging of the rat heart using k-t PCA and k-t SPARSE 07.05.2016 Singapore, Singapore Kozerke Sebastian; Steinhauser Jonas; Wespi Patrick;
Annual Meeting of European Society for Magnetic Resonance in Medicine in Biology Talk given at a conference Hyperpolarized [1-13C]pyruvate metabolic magnetic resonance imaging in pigs 01.10.2015 Edinburgh, Great Britain and Northern Ireland Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Talk given at a conference First and second order motion compensated spin-echo diffusion tensor imaging of the human heart 30.05.2015 Toronto, Canada Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Talk given at a conference 3D myofiber reconstruction from in vivo cardiac DTI data through extraction of low rank modes 30.05.2015 Toronto, Canada Kozerke Sebastian;
Annual Meeting of International Society for Magnetic Resonance in Medicine Poster Second order motion compensated cardiac DTI: direct comparison in-vivo and post-mortem 30.05.2015 Toronto, Canada Kozerke Sebastian;


Awards

Title Year
Fellow of the Society of Cardiovascular Magnetic Resonance 2018
Fellow of the International Society for Magnetic Resonance in Medicine 2017

Associated projects

Number Title Start Funding scheme
145007 Hyperpolarized Magnetic Resonance Metabolic Imaging - From Bench to Bedside 01.08.2013 R'EQUIP
132671 Development of Highly Accelerated Magnetic Resonance Methods for Quantitative Analysis of Perfusion, Metabolism and Function in Cardiac Ischemia 01.02.2011 Interdisciplinary projects
166485 Magnetic Resonance Imaging-Guided Computational Mechanics of Growth and Remodeling of the Failing Heart 01.07.2016 Interdisciplinary projects

Abstract

Heart failure (HF) affects 22 million patients worldwide with an incidence that is steadily increasing with age. While survival after HF diagnosis has improved, 50% of HF patients die within five years. According to the guidelines of the European Society of Cardiology, HF is defined as an “abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues”. Causes leading to HF include hypertension, chemotherapy, viral infection, valvular and congenital heart diseases. However, 60% of all HF cases are associated with coronary artery disease, which is the most common type of heart disease. Treatment options of HF depend on many factors, but for end-stage HF, heart transplantation is often the only choice. The general shortage of donor organs and contraindications have, however, limited the number and success of heart transplantations for end-stage HF. To this end, alternative treatment options using regenerative medicine approaches are pursued. Intracoronary administration of stem cells has shown varying success in recovering cardiac function with an ongoing debate about the efficacy of stem cell strategies. Measures of success in-vivo have primarily been based on global indices including ejection fraction in human trials, while studies in animals have allowed additional validation against histology. In light of the limited clinical measures in in-vivo studies, there is an urgent need to enable non-invasive imaging of microstructural and metabolic changes of cardiac tissue during and upon stem cell therapy in addition to standard measures of cardiac function.Magnetic Resonance imaging (MRI) has become a prime diagnostic modality. It is regarded the gold standard for assessing cardiac mass and ejection fraction. Beyond morphological imaging, MRI offers the unique feature of non-invasively probing tissue properties at a microscopic scale. While Diffusion Weighted Imaging and Diffusion Tensor Imaging have been well established for stationary organs including the brain, its application to the in-vivo heart is very challenging as cardiac and respiratory motion of the heart is orders of magnitude greater than water self-diffusion. Break-through advances in dissolution Dynamic Nuclear Polarization (DNP) technology now also allow for real-time MR imaging of key metabolic substrates in the in-vivo heart with sufficient spatial resolution. Thereby a number of important enzymatically catalyzed reactions can be imaged non-invasively upon injection of hyperpolarized endogenous compounds. While most studies thus far have been restricted to small animal research, the recent advent of sterile DNP equipment now also opens up a route towards application of the technology in large animals and humans with particular potential to monitoring metabolic fingerprints of the in-vivo heart.It is the objective of the present proposal to develop, validate and translate MRI methodology to map microstructural and metabolic information alongside with functional indices of the in-vivo heart for monitoring and guiding cardiac regeneration therapy. The research draws upon considerable expertise of the applicants in in-vivo cardiac diffusion and hyperpolarized metabolic MR imaging methodology on one side (Institute for Biomedical Engineering, University and ETH Zurich) and leading research in tissue engineering and transplantation of stem-cell based micro tissues on the other (Department of Regenerative Medicine, University and University Hospital Zurich). The project envisages a bench-to-bedside approach encompassing four main work packages as follows:1.Development and Implementation of High-Resolution Cardiac Diffusion Imaging Methodologya.Optimization of pulse sequence design for multi-slice spin-echo based cardiac diffusion imagingb.Derivation of diffusion tensor based metrics to reflect myocyte aggregate architecture c.Experimental validation of microstructural metrics against histology 2.Development and Implementation of Hyperpolarized Cardiac Metabolic Imaging Methodologya.Set up of carbon functionality including coils and pulse sequences on clinical MR systemb.Implementation of highly accelerated 3D multi-echo based imaging to map metabolic activity c.Pilot study to simultaneously record proton and carbon based perfusion and metabolic turnover3.Integration of Microstructural and Metabolic Imaging into Comprehensive Cardiac Imaging Protocol a.Standard imaging for determining myocardial mass, ejection fraction, perfusion, tissue relaxivity, scarb.Advanced imaging of myocardial motion and strain using 3D tissue taggingc.Development of scoring matrix to correlate global and local structural and metabolic indices4.Longitudinal Experimental Study of Cardiac Regeneration Therapy in Pigs a.Pig model with induction of myocardial infarction b.Harvesting of stem cells, generation of stem-cell based 3D microtissues and implantation in pigsc.Longitudinal follow-up of treatment versus control group using comprehensive imaging protocolThe project proposed herein aims to provide non-invasive MRI based diagnostic tools permitting to monitor and ultimately guide cardiac regeneration therapy of the in-vivo heart. It deploys cutting-edge imaging technology for mapping microstructural and metabolic information along with global and local anatomical and mechanical indices of cardiac tissue integrity and overall metabolic and mechanical performance. Thereby the efficacy of novel stem-cell based interventions in the in-vivo heart can be assessed longitudinally and hence will provide important information of the success of regeneration therapy in view of its translation into patients.
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