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Hyperpolarised 13C MR Spectroscopy Demonstrates Impaired PDH flux In the Diabetic Human Heart, Correlating with Impaired Energetics, Relaxation and Increased Myocardial Lipid Content: A Multi–Nuclear Spectroscopy Study.
Andrew Apps1, Justin Lau1,2, Jack Miller1,2, Mark Peterzan1, Andrew Lewis1, Michael Dodd3, Angus Lau4, Ferenc Mozes1, Oliver Rider1, Stefan Neubauer1, and Damian J Tyler1,2

1Oxford Centre for Magnetic Resonance Research, Oxford, United Kingdom, 2Department of Physiology, Anatomy and Genetics., University of Oxford, Oxford, United Kingdom, 3School of Life Sciences, Coventry University, Coventry, United Kingdom, 4Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada

Synopsis

Hyperpolarised 13C MRS offers unparalleled opportunities for studying in-vivo, real time metabolism. In our current study we demonstrate how the technique easily demonstrates early pathological changes in PDH flux in the diabetic heart, and is complementary to other spectroscopic and imaging techniques, in defining the metabolic and structural changes characterising the disease.

Introduction

The development of type 2 diabetes is associated with a panoply of myocardial structural and metabolic aberrations. Such changes include impaired myocardial energetics (PCr/ATP), the onset of diastolic dysfunction and increased myocardial fat content.1 Such changes often precede development of the overt systolic dysfunction characteristic of diabetic cardiomyopathy. The transition from the fasted to fed state is characterised by a shift in energy substrate utilisation towards glucose and away from fatty acids, mediated in part by the activation of Pyruvate Dehydrogenase (PDH). Flexibility of substrate usage is lost in diabetes, which is characterised by blunted flux through PDH.2 We aimed to investigate the ability of human hyperpolarised 13C MRS to characterise such changes in an early type 2 diabetic phenotype and to correlate this to alterations in myocardial energetics, resting diastolic function and myocardial lipid content.

Method

Five people with type two diabetes (age 53±4years, HbA1c 6.8±0.7%, Left Ventricular Ejection Fraction (LVEF) 58±5%) and four controls (age 50±12, LVEF 59±3%) received 1H CINE imaging for functional assessment, [1-13C]pyruvate hyperpolarized MRS, 31P MRS, and 1H MRS 3,4 for assessment of PDH flux, myocardial energetics and myocardial lipid content (proton density fat fraction (PDFF)) respectively, and echocardiographic assessment of diastolic function in the fasted state. Five participants (3 Control, 2 Diabetic) then went on to receive successful repeat 13C imaging 45 minutes after a 70g oral glucose load (Rapilose®). Hyperpolarized [1-13C]pyruvate (SpinLab, GE healthcare, 0.4ml/kg) was injected via a Medrad syringe, following which an ECG gated, 13C slice selective spectroscopy sequence was initiated for four minutes (FA=100, BW5kHz, minimum TR 500 ms).

Results

60 seconds of hyperpolarized spectra were summed, beginning from the first appearance of pyruvate within the LV. Baseline cardiac, demographic, 13C, 31P, 1H, and echocardiographic data are shown in table 1. H13CO3-/Pyr for all successful injections are shown in figure 2, alongside the time course of H13CO3- production for a control and diabetic participant. Diabetes significantly reduced PDH flux (2-way ANOVA paired datasets, df =1, p<0.05). In our fasted participants (controls vs diabetes) trends toward impaired myocardial energetics (PCr/ATP 1.89+/-.14 vs 1.71+/-.36 p=.38), increased lipid content (PDFF (%) 1.5+/-.5 vs 3.0+/-1.9 p=.17), and impaired diastolic function (E/e’ (sep) 5.1+/-1.4 vs 7.8+/-1.4) were seen in diabetes. Across all participants fasting PDH flux was mildly correlated with PCr/ATP (positively) and fat fraction (inversely, figure 3).

Discussion

In a mildly insulin resistant diabetic cohort, using a multi-nuclear spectroscopic approach, we have successfully characterised multiple pathological metabolic alterations that may collectively drive progression toward the diabetic cardiomyopathy phenotype.

Conclusion

Using 13C MRS, for the first time in human participants, we have demonstrated impaired cardiac PDH flux in diabetes, and shown how the signal generated via this technique gives huge power over other techniques (such as those used in this study) to detect pathological change.

Acknowledgements

This work was supported by the British Heart Foundation under grant number HSR00620

References

1. Chong, C.-R., K. Clarke, and E. Levelt, Metabolic remodelling in diabetic cardiomyopathy. Cardiovascular research, 2017. 113(4): p. 422-430.

2. Schroeder, M.A., et al., In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc Natl Acad Sci U S A, 2008. 105(33): p. 12051-6.

3.Levelt, E., et al., Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus. European heart journal, 2015. 37(46): p. 3461-3469.

4 .Rial, B., et al., Rapid quantification of myocardial lipid content in humans using single breath‐hold 1H MRS at 3 Tesla. Magnetic resonance in medicine, 2011. 66(3): p. 619-624.

Figures

Baseline line patient demographics, structural cardiac, and enzymatic flux data.

Time course of H13CO3- production after spectral [1-13C]Pyruvate appearance for a control and diabetic participant in both the fasted and fed states (left). PDH flux as demonstrated by the Bic/Pyr ratio of all successful [1-13C]Pyruvate injections.

Fasting data from all participants (red denotes diabetes) demonstrating relationships between PDH flux and myocardial fat fraction and energetics.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
0407