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