Introduction

Heart failure is accompanied by a myriad of metabolic changes in the heart ¹. Poor mitochondrial oxidation reserve is thought to be associated with the decreased contractile function in heart failure ². Therefore, means of assessing the myocardial metabolic reserve in-vivo are needed. We hypothesized that hyperpolarized [1-¹³C]pyruvate magnetic resonance spectroscopy (MRS) at rest and under stress can be used to assess the metabolic reserve in a porcine model of right ventricular volume overload.

Methods

Danish domestic pigs underwent surgery to induce pulmonary insufficiency, leading to chronic volume overload of the right ventricle. After 19 weeks of overload, we assessed contractile function and metabolic reserve of the heart using conventional MRI and hyperpolarized [1-¹³C]pyruvate MRS under rest and dobutamine-induced stress (10 µg/kg/min IV). All scans were performed on a 3T system (GE Discovery MR750, GE Healthcare) equipped with a 32-channel body array coil for proton imaging and an oyster transmit coil with a 16 channel receive coil (Rapid Biomedical, Rimpar, Germany) for 13C spectroscopy. The pyruvate was hyperpolarized in a commercially available polarizer (SpinLab, GE Healthcare). At start of injection, 128 spectra centered at the pyruvate frequency were acquired using pulse-acquire spectroscopy (slice thickness = 8 cm, TR = 1 s, excitation flip angle = 12°, spectral width = 5000 Hz, acquired points = 2048). The spectroscopy was planned over the ventricles under care to avoid the liver. MRS data were processed using a local adaptation of a validated MATLAB script 3 and analyzed using a model-free approach. To understand the pathophysiological role of decreased metabolic reserve, one third of the pigs were fed dichloroacetate (DCA, 50 mg/kg/day orally) from the 12^th week and onwards. DCA increases pyruvate oxidation capacity through pyruvate dehydrogenase kinase inhibition. In-vivo data were supported by in-vitro analysis of mitochondrial function.

Results

Overload of the right ventricle resulted in increased right ventricular end-diastolic volume and compression of the left ventricle. Resting right ventricular ejection fraction was 71.3 ± 4.1 % in the non-treated group versus 63.3 ± 6 % in the DCA group, P = 0.042, which was similar to the 58.7 ± 5 % of the control group, P = 0.176. Metabolically (Figures 1+2), right ventricular overload decreased resting pyruvate oxidation to 55 % of the controls, P = 0.044. Under stress, pyruvate oxidation in the overloaded group was 44 % of the controls, P = 0.024. At rest, DCA normalized pyruvate oxidation to control levels. Under stress, the animals fed DCA showed increased pyruvate oxidation compared to both control and non-treated animals. The in-vitro mitochondrial pyruvate respiration was 1058 ± 128 nmol/mg/h in the overloaded group versus 1509 ± 131 nmol/mg/h in the control group, P = 0.0012. In the DCA group, mitochondrial oxygen consumption was 1888 ± 208 nmol/mg/h, P = 0.0028 vs controls. Improved contractile reserve and reduced hypertrophy was observed in the DCA group. Right ventricular mass was 27.8 ± 4.5 in the overloaded group and 20.9 ± 2.3 in the DCA-group, P = 0.0095 (Figure 3a+b). Right ventricular ejection fraction increased 1.4 ± 1.6 points from rest to stress in the overloaded group, and 15.0 ± 3 points in the DCA group, P < 0.001 (Figure 3c). Similarly, left ventricular ejection fraction increased 4.1 ± 3.6 points in the overloaded group vs 14.0 ± 5.2 points in the DCA-treated animals, P = 0.003.

Discussion

Our results suggest that hyperpolarized MRS assessment of the myocardial metabolic reserve is feasible under pharmacological stress. This approach may improve our capabilities for detection of mitochondrial dysfunction and impaired metabolism in early cardiac dysfunction. In addition, our results underline that inhibition of the pyruvate dehydrogenase kinase is an intriguing approach in metabolic heart failure therapy ^4,5.

Conclusion

In future preclinical and clinical work, hyperpolarized MRS under stress may be considered a viable option for sensitive assessment of impaired myocardial metabolism.

Acknowledgements

No acknowledgement found.

References

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