This talk will provide an overview of the current status of clinical cardiac hyperpolarized 13C imaging studies and ideas for potential future directions.
TARGET AUDIENCE – MR scientists, MR technologists, clinicians, and scientists interested in performing cardiac hyperpolarized 13C studies clinically.
OUTCOME/OBJECTIVES – Explain the current progress of cardiac hyperpolarized 13C imaging in clinical research and identify the requirements of implementing cardiac hyperpolarized 13C imaging studies clinically.
OVERVIEW – The heart requires a vast amount of energy, in the form of ATP, to maintain the constant output needed by the body to supply oxygenated blood. As such, most diseases that affect the heart have a metabolic component. This can be structural in origin, e.g. in ischemic heart disease where the obstruction of blood flow limits the supply of fuel and oxygen to myocardial tissue driving anaerobic metabolism. Alternatively, this can be metabolic in origin, e.g. in diabetic cardiomyopathy where there is a functional consequence to the altered metabolism that is inherent in the diabetic heart. As such, the ability to directly assess metabolic derangements offers the potential for improved diagnosis, prognosis and monitoring of disease progression and treatment response. Metabolic assessment can also yield improved understanding of the mechanisms underlying cardiovascular diseases and aid the development of novel therapeutics through basic and clinical research.
Many different approaches have been proposed, and indeed are routinely used, to assess metabolic changes in cardiovascular diseases, however, they generally rely on indirect measurements of metabolism (i.e. inferring anaerobic metabolism from reduced perfusion) or they subject the patient to ionising radiation (e.g. 18FDG studies with PET), which limits their repeated use in the same subject and their use in clinical research studies. Further, such methods are unable to differentiate between the injected tracer and its downstream metabolic products, providing an incomplete picture of metabolic changes. An ideal solution would enable the direct, rapid and repeated measurement of multiple metabolic pathways without subjecting the patient to ionising radiation, whilst simultaneously providing structural and functional readouts with which to support the metabolic information acquired.
Towards this goal, magnetic resonance imaging (MRI) is routinely used to monitor cardiac structure and function at repeated times and progressive stages of disease, whilst the associated technique of magnetic resonance spectroscopy (MRS) could ideally be used to study metabolism due to the extensive range of compounds it can detect, using nuclei such as carbon (13C) and phosphorus (31P). However, the application of MRS in the measurement of metabolism has been limited by an intrinsically low sensitivity. To overcome this fundamental limitation, the use of a novel technique called hyperpolarized magnetic resonance (HP-MRI) can increase the in vivo sensitivity of MRS to detect 13C-enriched tracers by more than 10,000-fold [1]. In this way, HP-MRI enables unprecedented visualization of normal and abnormal metabolism, allowing real-time measurement of instantaneous substrate uptake and enzymatic transformation in vivo [2]. When coupled with the exquisite structural and functional information provided by standard MRI, this provides a unique imaging approach to understand the “chicken and egg” nature of changes in metabolism and function in the diseased heart.
Work undertaken over the last 10 years has demonstrated the ability of HP-MRI to detect changes in cardiac metabolism in a wide range of animal models of cardiovascular disease [3-4] and has led to the first demonstration of the HP-MRI approach in humans [5-7]. This talk will provide an overview of the current status of clinical cardiac hyperpolarized 13C imaging studies and ideas for potential future directions.
The session will start with a summary of the particular challenges that clinical hyperpolarized 13C MRI can help to address in the field of cardiology before giving an update of the latest data emerging from the different sites currently undertaking clinical cardiac 13C studies in healthy volunteers, diabetic patients and patients with hypertrophic cardiomyopathy (HCM). It will then continue with a discussion of the technical challenges specific to undertaking cardiovascular HP-MRI studies with a focus on the development of rapid imaging approaches. Finally, emerging pre-clinical studies with a high degree of clinical translatability will be discussed, exploring new potential applications (e.g. imaging myocardial inflammation [8], assessment of myocardial perfusion [9]) and the development of novel probes of myocardial metabolism (e.g. the use of hyperpolarized fumarate as a marker of cellular necrosis [10]).
Following the talk, attendees should be able to understand how hyperpolarized 13C MRI can be used to directly investigate metabolic changes in the human heart, opening up new insight into the mechanisms that underlie a range of cardiovascular diseases.
1) Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR.Ardenkjaer-Larsen JH, Fridlund B, Gram A, Hansson G, Hansson L, Lerche MH, Servin R, Thaning M, Golman K.Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10158-63. Epub 2003 Aug 20.PMID: 12930897
2) Molecular imaging with endogenous substances.Golman K, Ardenkjaer-Larsen JH, Petersson JS, Mansson S, Leunbach I.Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10435-9. Epub 2003 Aug 20.PMID: 12930896
3) Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI.Golman K, Petersson JS, Magnusson P, Johansson E, Akeson P, Chai CM, Hansson G, Månsson S.Magn Reson Med. 2008 May;59(5):1005-13. doi: 10.1002/mrm.21460.PMID: 184290387)
4) In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance.Schroeder MA, Cochlin LE, Heather LC, Clarke K, Radda GK, Tyler DJ.Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12051-6. doi: 10.1073/pnas.0805953105. Epub 2008 Aug 8.PMID: 18689683
5) Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate.Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PE, Harzstark AL, Ferrone M, van Criekinge M, Chang JW, Bok R, Park I, Reed G, Carvajal L, Small EJ, Munster P, Weinberg VK, Ardenkjaer-LarsenJH, Chen AP, Hurd RE, Odegardstuen LI, Robb FJ, Tropp J, Murray JA.Sci Transl Med. 2013 Aug 14;5(198):198ra108. doi: 10.1126/scitranslmed.3006070.PMID: 23946197
6) Dynamic nuclear polarization polarizer for sterile use intent.Ardenkjaer-Larsen JH, Leach AM, Clarke N, Urbahn J, Anderson D, Skloss TW.NMR Biomed. 2011 Oct;24(8):927-32. doi: 10.1002/nbm.1682. Epub 2011 Mar 18.PMID: 21416540
7) Hyperpolarized 13C Metabolic MRI of the Human Heart: Initial Experience.Cunningham CH, Lau JY, Chen AP, Geraghty BJ, Perks WJ, Roifman I, Wright GA, Connelly KA.Circ Res. 2016 Nov 11;119(11):1177-1182. doi: 10.1161/CIRCRESAHA.116.309769. Epub 2016 Sep 15.PMID: 27635086
8) Noninvasive Immunometabolic Cardiac Inflammation Imaging Using Hyperpolarized Magnetic Resonance.Lewis AJM, Miller JJ, Lau AZ, Curtis MK, Rider OJ, Choudhury RP, Neubauer S, Cunningham CH, Carr CA, Tyler DJ.Circ Res. 2018 Apr 13;122(8):1084-1093. doi: 10.1161/CIRCRESAHA.117.312535. Epub 2018 Feb 12.PMID: 29440071
9) Hyperpolarized [1,4-13C2]Fumarate Enables Magnetic Resonance-Based Imaging of Myocardial Necrosis.Miller JJ, Lau AZ, Nielsen PM, McMullen-Klein G, Lewis AJ, Jespersen NR, Ball V, Gallagher FA, Carr CA, Laustsen C, Bøtker HE, Tyler DJ, Schroeder MA.JACC Cardiovasc Imaging. 2018 Nov;11(11):1594-1606. doi: 10.1016/j.jcmg.2017.09.020. Epub 2017 Dec 13.PMID: 29248653
10) Simultaneous assessment of cardiac metabolism and perfusion using copolarized [1-13 C]pyruvate and 13 C-urea.Lau AZ, Miller JJ, Robson MD, Tyler DJ.Magn Reson Med. 2017 Jan;77(1):151-158. doi: 10.1002/mrm.26106. Epub 2016 Jan 7.PMID: 26743440