Introduction

Magnetic resonance imaging with hyperpolarized (HP) ¹³C-labeled compounds via dynamic nuclear polarization (DNP) allows for non-invasive human studies of metabolic processes, and has shown great potential for imaging of heart diseases¹. HP ¹³C-pyruvate MRI provides a way to examine substrate selection, for example the relative contribution of glucose metabolism and fatty acid oxidation to energy production in the heart that is associated with ischemia, heart failure, and cardiomyopathies.^2-7 However, cardiac metabolism is also very flexible and can adapt to the available substrates. In this work, we investigated the influence of a fed versus fasted state on human heart metabolism using hyperpolarized [1-¹³C]pyruvate MRI in order to develop protocols for human studies of heart disease.

Methods

Three healthy subjects with no known cardiac disease history were recruited under a UCSF institutional review board approved protocol. MRI scans were performed on a GE 3T scanner following injection of [1-¹³C]pyruvate pre-polarized in a 5T GE SPINlab polarizer. Subjects were fasting for at least four hours before the study. Two scans with identical injections of hyperpolarized [1-¹³C]pyruvate were performed on the same subject. After the first scan, each subject drank a bottle of Gatorade containing 30g total carbohydrates and a second scan started 30 minutes thereafter. ¹³C acquisitions were triggered upon bolus arrival in the right ventricle using an integrated RT-Hawk platform (HeartVista) for real-time frequency and B1 calibration.⁸ Short-axis cardiac images of ¹³C-bicarbonate, [1-¹³C]lactate and [1-¹³C]pyruvate were acquired using a spectral-spatial excitation and 2D multi-slice cardiac-gated spiral gradient-echo sequence8 with a clamshell transmit coil and an 8-channel paddle receive array.⁹ Scan parameters were 6mm in-plane resolution for pyruvate, 12mm in-plane resolution for bicarbonate and lactate, 21mm slice thickness, temporal resolution 3 heartbeats (~3.6s), 5 slices per heartbeat, 90 heartbeats, 20° flip angle for pyruvate and 30° flip angle for lactate and bicarbonate. Images were acquired during free-breathing.

Results and Discussion

Figure 1 shows representative sum-over-time images between the fasted and fed states. The pyruvate distribution was similar, with the largest signals from within the chambers but also signal was observed in the heart wall. The lactate distribution was also similar between fed and fasted states, with similar amounts of lactate observed in the heart wall and within the chambers. Bicarbonate is mostly below the noise level in the fasted state, where as it is observed in the heart wall in the fed state.
Figure 2 shows representative dynamic images of lactate and bicarbonate between fasted and fed states. Lactate first is observed within the right ventricle, then in the left ventricle chamber, after which there is more apparent signal within the heart wall. Bicarbonate appears to be primarily within the heart wall. Interestingly, high lactate and bicarbonate signals are observed at the 7th time-point at the location of the anterior longitudinal sulcus, which could be attributed to the transfer of lactate and bicarbonate in the coronary vasculature.
Figure 3 shows representative dynamic curves of pyruvate, lactate and bicarbonate, measured across ROIs including the chambers and wall of the left and right ventricles. Distinct signal patterns are observed between right ventricle and left ventricle for all metabolites. A small amount of lactate first appears in the right ventricle, which is consistent with the finding in Figure 2. Primary lactate and bicarbonate buildup comes after the pyruvate buildup in the left ventricle, implying that the contraction of left ventricle supplies pyruvate into heart muscles. Both buildup and washout rate of lactate are faster in the left ventricle than in the right ventricle. Comparing the fasted and fed states, the fed states show higher signals for both lactate and bicarbonate. At the fed state, more bicarbonate signals are observed in the left ventricle than in the right ventricle.
Figure 4 summarizes measured metabolite ratios between the fasted and fed states. Both lactate and bicarbonate shows increased signal in the fed state by 40-50%. In the left ventricle, fed-state signal improvement is slightly more in the bicarbonate than in the lactate, whereas it is opposite in the right ventricle. Normalizing lactate and bicarbonate by pyruvate shows a reduced standard deviation relative to the mean, suggesting this can improve the reproducibility.

Conclusion

This work presents the influence of feeding on human hyperpolarized [1-¹³C]pyruvate cardiac image studies. Good image quality was obtained in all volunteers, and approximately 40-50% increases in the lactate and bicarbonate signals were observed in the fed state. This is expected based on prior animal model studies.¹⁰ Distinct metabolite dynamic patterns were observed between the left and right ventricle and warrant further investigation.

Acknowledgements

This work is supported by the National Institute of Biomedical Imaging and Bioengineering (P41EB013598, U01EB026412), Myokardia Myoseeds award and UCSF Resource Allocation Program.

References

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