This document discusses applications of hyperpolarized carbon-13 MRI for studying cardiac metabolism and energetics. It describes how the healthy heart utilizes multiple energy substrates including fatty acids, glucose, lactate, and ketone bodies. Cardiovascular diseases are associated with characteristic changes in substrate selection, such as increased reliance on fatty acids in obesity/diabetes and a shift to glycolysis and ketone bodies in heart failure. Hyperpolarized 13C-pyruvate MRI can provide insights into cardiac metabolism in both animal models and healthy human volunteers. Additional agents under investigation include 13C-labeled acetate, butyrate and urea to probe fatty acid oxidation, substrate competition, and perfusion respectively.

1. Applications of Hyperpolarized
Carbon-13 MR: The Heart
Peder Larson, PhD

2. Outline
 Cardiac metabolism and energetics – substrate utilization
 Metabolism in heart diseases
 Normal variation in cardiac metabolism
 Other agents beyond pyruvate
 Imaging Methods
Cardiac Hyperpolarized 13C MRI2

3. Cardiac Hyperpolarized 13C MRI3
Cardiac Energetics and Metabolism
 Heart uses large amounts of energy, turning over 15
times its weight in ATP every day
 Utilizes multiple energy sources
- Fatty acids are the main source of fuel (~70%)
- Carbohydrates (Glucose, Lactate)
- Ketone bodies
- Amino acids (BCAAs)
 Healthy heart is flexible depending on physiologic
availability
- Fatty acid and glucose oxidation reciprocally regulated
by Randle cycle to modulate fuel choice
- Sensitive to fed/fasted state, which modulates levels of
blood glucose
Lopaschuk and Ussher, Circ Res 2016. DOI:
(10.1161/CIRCRESAHA.116.310078)

4. Cardiac Hyperpolarized 13C MRI4
Metabolism in Heart Disease
 Cardiovascular disease is leading cause of death worldwide,
accounting for 31% of all deaths in 2015
 Characteristic changes in energy substrate selection in disease
 Increased reliance on fatty acids for oxidative energy production in
obese or diabetic heart
 Shift from fatty acid oxidation to glycolysis and increased oxidation
of ketone bodies in heart failure and hypertrophy [Aubert et al.
Circulation 2016, PMID: 26819376]
 Ischemia (e.g. heart attack) leads to increased lactate production

5. Cardiac Hyperpolarized 13C MRI5
Cardiomyocyte metabolism
Timm et al. Progress in NMR Spectroscopy 2018.
https://doi.org/10.1016/j.pnmrs.2018.05.002

6. Cardiac Hyperpolarized 13C MRI6
HP Pyruvate Cardiac Metabolism
Timm et al. Progress in NMR Spectroscopy 2018.
https://doi.org/10.1016/j.pnmrs.2018.05.002

7. Cardiac Hyperpolarized 13C MRI7
Fed versus Fasted state
Have you eaten yet?
 Substantial changes
in cardiac metabolism
between fed and
fasted states
 Fed has increased
blood glucose and
decreased free fatty
acids
 HP 13C-pyruvate:
Increased PDH flux in
fed state
 Healthy heart nimbly
shifts between
substrates for ATP
production
 Often studies performed with fasting, then oral glucose 1 hour before HP study
for standardization
 Tougaard et al: access to carbohydrate‐rich food before examinations may be
an alternative to increase metabolite signal without introducing variance
Schroeder et al. PNAS 2008
doi: 10.1073/pnas.0805953105
Tougaard, MRM 2019.
10.1002/mrm.27560

8. Cardiac Hyperpolarized 13C MRI8
Ischemia-Reperfusion
 Ischemia created via
coronary artery occlusion
 Increased lactate,
decreased bicarbonate
after occlusion
 Return to baseline
metabolic state 1 week
after ischemia-reperfusion
O h-Ici et al, Radiology 2016.
https://doi.org/10.1148/radiol.2015151332

9. Cardiac Hyperpolarized 13C MRI9
Dilated Cardiomyopathy
 Reduced [5-
13C]glutamate
produced from [2-
13C]pyruvate
 [Schroeder et al. Eur J
Hear Fail 2013]

10. Cardiac Hyperpolarized 13C MRI10
Human Hyperpolarized Cardiac Results
 Healthy Volunteers
Cunningham et al. Circ Res 2016 doi:
10.1161/CIRCRESAHA.116.309769

11. Cardiac Hyperpolarized 13C MRI11
Other Agents - Acetate
 Fatty acid oxidation –
extremely attractive since
this is primary energy
source for the heart
 Acetate
- short chain fatty acid
- 10-20% polarization
- T1 ~ 40-50 s in liquid
state, ~20s in vivo
- Observe production of
acetylcarnitine
Flori et al. Contrast Media & Molecular Imaging, 2014, DOI: (10.1002/cmmi.1618)
Koellisch et al. MRM 2014, DOI: (10.1002/mrm.25485)
Dobutamine (induces stress,
increases cardiac workload) only
increased acetyl-carnitine in
skeletal muscle

12. Cardiac Hyperpolarized 13C MRI12
Other Agents - Butyrate
 Fatty acid oxidation –
extremely attractive since
this is primary energy source
for the heart
 Butyrate
- short chain fatty acid (4-
carbon)
- T1 ~ 20 s
- 13% polarization
- Monocarboxylate
transporter (MCT) uptake –
same as pyruvate
Ball et al, MRM 2013, DOI: (10.1002/mrm.24849)

13. Cardiac Hyperpolarized 13C MRI13
Co-polarized Pyruvate and Butyrate
 Direct measurement of substrate
competition between fatty acid
(Butyrate) and carbohydrate
(pyruvate) metabolism
Bastiaansen et al, Scientific Reports 2016, doi: 10.1038/srep25573

14. Cardiac Hyperpolarized 13C MRI14
Other Agents - Urea
 Urea for perfusion
 Flow sensitizing gradients for quantification
Lau et al, MRM. Doi:(10.1002/mrm.25713)

15. Cardiac Hyperpolarized 13C MRI15
Cardiac pH imaging
 Pyruvate for intracellular pH [Schroeder et al, 2009 Card Res,
Lau et al MRM 2017]
 Pyruvate uptake, then only 13C-Bicarbonate and 13CO2 only
created intracellularly

16. Cardiac Hyperpolarized 13C MRI16
Imaging Methods
 Robust to motion – spirals are
preferred for imaging
 Resolve myocardium from the lumen
in the heart
 Cardiac triggering
 Respiratory triggering or breatholds
maybe required
 Pulse Sequences
- Metabolite Spectral-spatial + Spiral
- Acetate: Spiral IDEAL CSI + SpSp
Lau et al, MRM 2010. Doi:(10.1002/mrm.22525)
Koellisch et al. MRM 2014, DOI: (10.1002/mrm.25485)