Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, C30
In vivo assessment of cardiac metabolism and functional derangement in the spontaneously hypertensive rat heart using hyperpolarized magnetic resonance spectroscopy and CINE-MR imaging
M. S. Dodd1,2, D. Ball1, M. Schroeder1, H. Atherton1, L. Le Page1, H. Ashrafian2, H. Watkins2, G. Radda1, K. Clarke1, D. Tyler1
1. Physiology, Anatomy and Genetics, Oxford University, Oxford, United Kingdom. 2. Cardiovascular Medicine, Oxford University, Oxford, United Kingdom.
Spontaneously hypertensive rats (SHRs) are a model of hypertension and develop pressure-overload concentric hypertrophy after 15 weeks . One of the cellular responses to hypertrophy is a reduction in β-oxidation. It is hypothesised that in response the SHR heart switches to a glycolytic phenotype. The aim of this work was to assess in vivo metabolism in the hypertensive rat heart by performing magnetic resonance (MR) spectroscopy, using hyperpolarized [1-13C] and [2-13C]pyruvate. Cardiac functional and left ventricular mass (LVM) were assessed using CINE-MR. SHRs (n=13) were compared to control Wistar rats (n=11). Student two-tailed t-test were used to compare groups. On two separate days cardiac metabolism was assessed following a bolus injection of either hyperpolarized [1-13C] or [2-13C]pyruvate . 1ml of 80mM hyperpolarized pyruvate was injected over 10s via a tail vein catheter into an anaesthetised rat positioned in a 7T MR scanner (2% isofluorane in O2 and N2O (4:1), 2l/min). On a third day cardiac function and hypertrophy were assessed using CINE-MR imaging. SHRs had a significant 63% increase in LVM compared to control (p<0.001). Cardiac function was altered in the SHR heart, with an increase in stroke volume and diastolic dysfunction in the atrial filling phase. A significant 85% increase in pyruvate dehydrogenase (PDH) flux (assessed using the sum of the 13CO2 and [1-13C]bicarbonate resonances detected following injection of [1-13C]pyruvate) was detected in the SHR hearts compared with controls (p<0.01). No difference in 13C label incorporation into lactate and alanine was observed between groups. [2-13C]pyruvate was used to assess 13C-label incorporation into downstream TCA cycle metabolites. Incorporation into acetylcarnitine (p<0.001), glutamate (p<0.01) and citrate (p<0.05) pools was significantly increased within SHR hearts. However when these data were normalized to account for the increased PDH flux, no change in normalized label incorporation was observed. This implies the increase in acetylcarnitine, glutamate and citrate resonances was derived from increased production of [2-13C]acetyl-CoA and represents normal flux through the TCA cycle. This study shows an increase in PDH flux in the in vivo hypertensive heart. There is normal flux of metabolites within the TCA cycle, indicating no deficiency in energy production in the SHR heart. Cardiac functional data shows hallmarks of adaption to hypertension and hypertrophy. This study has not shown a switch to a glycolytic phenotype, as label incorporation into lactate remained unchanged between groups. However it does suggest a switch to increased glucose oxidation through PDH and the TCA cycle.
Where applicable, experiments conform with Society ethical requirements