Metabolic imaging of acute and chronic infarction in the perfused rat heart using hyperpolarised [1‐<sup>13</sup>C]pyruvate

Ball, Daniel R.; Cruickshank, Rachel; Carr, Carolyn A.; Stuckey, Daniel J.; Lee, Philip; Clarke, Kieran; Tyler, Damian J.

doi:10.1002/nbm.2972

Cited by 40 publications

(40 citation statements)

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“…We found that the 13 C Bic/Lac ratio in the IRI kidneys was approximately 51% lower at day 7 when compared with baseline, and the 13 C Bic/Lac ratio was significantly lower in the IRI kidneys when compared with that in the contralateral sham‐operated kidneys at day 7. The Bic/Lac ratio has been suggested to serve as a sensitive metric for the opposing changes in the conversion of Pyr to Bic and Lac . In addition, as both Bic and Lac are produced from Pyr, the Bic/Lac ratio can be used to account for changes in perfusion between baseline and following IRI .…”

Section: Discussionmentioning

confidence: 99%

Hyperpolarized ¹³C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model

et al. 2017

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Acute kidney injury (AKI) is a major risk factor for the development of chronic kidney disease (CKD). Persistent oxidative stress and mitochondrial dysfunction are implicated across diverse forms of AKI and in the transition to CKD. In this study, we applied hyperpolarized (HP) 13C dehydroascorbate (DHA) and 13C pyruvate MR spectroscopy to investigate the renal redox capacity and mitochondrial pyruvate dehydrogenase (PDH) activity, respectively, in a murine model of AKI at baseline, and 7 days after unilateral ischemia reperfusion injury (IRI). Compared to the contralateral sham-operated kidneys, the kidneys subjected to IRI showed a significant decrease in the HP 13C Vitamin C/(Vitamin C+DHA) ratio, consistent with a decrease in redox capacity. The kidneys subjected to IRI also showed a significant decrease in the HP 13C bicarbonate/pyruvate ratio, consistent with impaired PDH activity. The IRI kidneys showed a significantly higher HP 13C lactate/pyruvate ratio at day 7 compared to baseline, although the 13C lactate/pyruvate ratio was not significantly different between the IRI and the contralateral sham-operated kidneys at day 7. Arterial spin labeling MRI demonstrated significantly reduced perfusion in the IRI kidneys. Renal tissue analysis showed corresponding increased reactive oxygen species (ROS), and reduced PDH activity in the IRI kidneys. Our results show the feasibility of HP 13C MR for the noninvasive assessment of oxidative stress and mitochondrial PDH activity following renal ischemia reperfusion injury.

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Section: Discussionmentioning

confidence: 99%

Hyperpolarized ¹³C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model

et al. 2017

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“…This generated a KH buffer with a final substrate concentration of 10mM glucose and 4mM hyperpolarized [1‐ 13 C]acetoacetate or [1‐ 13 C]β‐hydroxybutyrate. The supply to the perfused heart was subsequently switched to the hyperpolarized solution and a 13 C pulse–acquire experiment was immediately started (TR = 1 s; hard pulse; sweep width, 180 ppm; 4096 complex points) with a 30° flip angle chosen as a compromise between the signal‐to‐noise ratio (SNR), intracellular metabolite signals and magnetization depletion, as discussed elsewhere …”

Section: Methodsmentioning

confidence: 99%

Hyperpolarized ketone body metabolism in the rat heart

et al. 2018

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The aim of this work was to investigate the use of 13C‐labelled acetoacetate and β‐hydroxybutyrate as novel hyperpolarized substrates in the study of cardiac metabolism. [1‐13C]Acetoacetate was synthesized by catalysed hydrolysis, and both it and [1‐13C]β‐hydroxybutyrate were hyperpolarized by dissolution dynamic nuclear polarization (DNP). Their metabolism was studied in isolated, perfused rat hearts. Hyperpolarized [1‐13C]acetoacetate metabolism was also studied in the in vivo rat heart in the fed and fasted states. Hyperpolarization of [1‐13C]acetoacetate and [1‐13C]β‐hydroxybutyrate provided liquid state polarizations of 8 ± 2% and 3 ± 1%, respectively. The hyperpolarized T 1 values for the two substrates were 28 ± 3 s (acetoacetate) and 20 ± 1 s (β‐hydroxybutyrate). Multiple downstream metabolites were observed within the perfused heart, including acetylcarnitine, citrate and glutamate. In the in vivo heart, an increase in acetylcarnitine production from acetoacetate was observed in the fed state, as well as a potential reduction in glutamate. In this work, methods for the generation of hyperpolarized [1‐13C]acetoacetate and [1‐13C]β‐hydroxybutyrate were investigated, and their metabolism was assessed in both isolated, perfused rat hearts and in the in vivo rat heart. These preliminary investigations show that DNP can be used as an effective in vivo probe of ketone body metabolism in the heart.

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“…Furthermore, cardiac conditions, such as ischemic disease, may have regional myocardial involvement, which will only be adequately assessed by generating 2D or 3D metabolic maps of 13 C-MRS imaging in pigs. Ball et al 14 demonstrated the feasibility of 13 C-MRS imaging in the isolated rat heart, but the technological requirements are a long way from allowing translation to in vivo rat studies. An important aspect is the translational value of the technological improvements of 13 C-MRS (in pigs studies), particularly in coil design, radiofrequency sequence optimization, and 13 C-kinetic modeling.…”

Section: Aquaro and Menichetti Hyperpolarized 13c-magnetic Resonance mentioning

confidence: 99%

Hyperpolarized 13C-Magnetic Resonance Spectroscopy

Aquaro

Menichetti

2014

Circ: Cardiovascular Imaging

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M yocardial metabolic abnormalities have been demonstrated widely in diverse cardiac diseases. Metabolic impairment may be secondary to the underlying pathophysiological mechanism; however, in most conditions, it could be considered a direct cause, or at least a cofactor, in the functional abnormalities of the heart. Article see p 895A more complete understanding of the myocardial metabolic changes associated with cardiac diseases may lead to pharmacological studies and potentially new metabolic-targeted drugs. In heart failure, agents that act through the optimization of cardiac metabolism may be particularly attractive as they could potentially work without exerting negative hemodynamic effects; this would allow for their addition to current therapies.1 It has been demonstrated that shifting the metabolic substrate of the heart from fatty acids to carbohydrate oxidation can improve pump function and delay the progression of heart failure.2 That said, in spite of the initial enthusiasm over drugs that showed promising metabolic effects in vitro, few clinical benefits have been unequivocally demonstrated. A robust imaging technique, which would allow the direct assessment of metabolism in vivo, is essential to understanding the metabolic changes and the effectiveness of pharmacological drugs. Unfortunately, nuclear medicine techniques, such as positron emission tomography and single photon emission computed tomography, are unable to detect the metabolized tracers and distinguish between different downstream metabolites. Magnetic resonance spectroscopy (MRS) with hyperpolarized 13 C-enriched substrates is a promising imaging technique for the evaluation of cardiac metabolism in vivo. Because the natural amount of 13 C in biological tissue is low, a sufficient signal:noise ratio for 13 C-MRS is obtained by increasing the polarization level (hyperpolarization) of these compounds. Currently, dynamic nuclear polarization is the most widely used hyperpolarization technique for 13 C-enriched molecules and this enables an increased signal:noise ratio of ≈10 000-fold.4 13 C-MRS allows for a semiquantitative assessment of substrate changes in a target tissue and real-time measurements of metabolic fluxes. 5,6 An understanding of the metabolic pathways involved helps to inform the potential use of the 13 C-enriched techniques. Pyruvate, which contains 3 carbon atoms, is the most used 13 C-enriched molecule. Pyruvate is a key metabolic substrate that is involved in different metabolic pathways; depending on the position of the In this issue of Circulation: Cardiovascular Imaging, the elegant study by Dodd et al 8 demonstrates an example of the application of hyperpolarized 13 C-MRS when studying the interaction between metabolic and cardiac functional impairment. In this study, the authors assessed the metabolic changes that occur in the cardiac mitochondrial function using hyperpolarized [1-13 C] and [2-13 C]-pyruvate; the experiment used surgically induced myocardial infarction in rats. Remarkably, this study links the ch...

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Metabolic imaging of acute and chronic infarction in the perfused rat heart using hyperpolarised [1‐¹³C]pyruvate

Cited by 40 publications

References 50 publications

Hyperpolarized ¹³C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model

Hyperpolarized ¹³C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model

Hyperpolarized ketone body metabolism in the rat heart

Hyperpolarized 13C-Magnetic Resonance Spectroscopy

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Metabolic imaging of acute and chronic infarction in the perfused rat heart using hyperpolarised [1‐13C]pyruvate

Cited by 40 publications

References 50 publications

Hyperpolarized 13C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model

Hyperpolarized 13C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model

Hyperpolarized ketone body metabolism in the rat heart

Hyperpolarized 13C-Magnetic Resonance Spectroscopy

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Product

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Metabolic imaging of acute and chronic infarction in the perfused rat heart using hyperpolarised [1‐¹³C]pyruvate

Hyperpolarized ¹³C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model

Hyperpolarized ¹³C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model