Detection of increased pyruvate dehydrogenase flux in the human heart during adenosine stress test using hyperpolarized [1-13C]pyruvate cardiovascular magnetic resonance imaging

Abstract

Background Hyperpolarized (HP) [1-13C]pyruvate cardiovascular magnetic resonance (CMR) imaging can visualize the uptake and intracellular conversion of [1-13C]pyruvate to either [1-13C]lactate or 13C-bicarbonate depending on the prevailing metabolic state. The aim of the present study was to combine an adenosine stress test with HP [1-13C]pyruvate CMR to detect cardiac metabolism in the healthy human heart at rest and during moderate stress. Methods A prospective descriptive study was performed between October 2019 and August 2020. Healthy human subjects underwent cine CMR and HP [1-13C]pyruvate CMR at rest and during adenosine stress. HP [1-13C]pyruvate CMR images were acquired at the mid-left-ventricle (LV) level. Semi-quantitative assessment of first-pass myocardial [1-13C]pyruvate perfusion and metabolism were assessed. Paired t-tests were used to compare mean values at rest and during stress. Results Six healthy subjects (two female), age 29 ± 7 years were studied and no adverse reactions occurred. Myocardial [1-13C]pyruvate perfusion was significantly increased during stress with a reduction in time-to-peak from 6.2 ± 2.8 to 2.7 ± 1.3 s, p = 0.02. This higher perfusion was accompanied by an overall increased myocardial uptake and metabolism. The conversion rate constant (kPL) for lactate increased from 11 ± 9 *10–3 to 20 ± 10 * 10–3 s−1, p = 0.04. The pyruvate oxidation rate (kPB) increased from 4 ± 4 *10–3 to 12 ± 7 *10–3 s−1, p = 0.008. This increase in carbohydrate metabolism was positively correlated with heart rate (R2 = 0.44, p = 0.02). Conclusions Adenosine stress testing combined with HP [1-13C]pyruvate CMR is feasible and well-tolerated in healthy subjects. We observed an increased pyruvate oxidation during cardiac stress. The present study is an important step in the translation of HP [1-13C]pyruvate CMR into clinical cardiac imaging. Trial registration EUDRACT, 2018-003533-15. Registered 4th of December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-15

Probing Human Heart TCA Cycle Metabolism and Response to Glucose Load using Hyperpolarized [2-13C]Pyruvate MR Spectroscopy

“…The administration of C2-labelled HP pyruvate, the MRI scans and the oral glucose load test were safe and well-tolerated without adverse events in the three volunteers enrolled in this study, each of whom received 2 doses of HP [2- 13 C]pyruvate injection with an approximate 30-minute interval between doses. The safety profile is in good agreement with published HP 13 C studies of cardiac metabolism using C1-labelled pyruvate in patients with ischemic heart disease, diabetes, malignancies, as well as healthy volunteers 19,21–24,45,46 . The six HP dissolutions yielded 198-245mM (median: 229mM) pyruvate with 27.1-31.2% (median:29.3%) polarization, 0.6-2.2µM (median: 1.6µM) residual trityl radical, pH of 7.5-8.2 (median: 7.8), and 30.7-33.7°C (median: 32.8°C) temperature.…”

“…The other tissues present in the slab were the skeletal muscle and subcutaneous fat surrounding the chest, the spine, the rib cage, and part of the arms. Of these tissues, only HP pyruvate and downstream metabolites are expected to be observed in the heart and vasculature based on prior HP [1- 13 C]pyruvate imaging results where little to no signal was observed in skeletal muscle and subcutaneous fat 19,21,23,24 . The placement and sensitivity profile of the receiver coils further improved the localization of HP signals to the heart ( Figure 2B ) and reduced expected major vasculature signal contributions.…”

Regional quantification of cardiac metabolism with hyperpolarized [1 -13C]-pyruvate MRI evaluated in an oral glucose challenge

“…Previous human heart studies with HP 13 C MRI have performed crucial demonstrations of feasibility 8 , improvements to pulse sequence and reconstruction methods 9,10 , the effect of cardiac cycle on metabolic imaging 11 , the effect of adenosine stress tests 12 , the effect of fasting and fed states 14 , and patient studies investigating the effects of chemotherapy in breast cancer 13 , type 2 diabetes mellitus 14 , and post-myocardial infarction 15 . Several prior studies have included imaging acquisitions 8–12,15 , ratiometric methods 11,13,14 and pharmacokinetic modeling 12 . The major unique contribution of this work is to perform regional quantification of metabolism, including comparing ratiometric and pharmacokinetic modeling, with the fed/fasted volunteer studies demonstrating experimental changes in metabolism.…”

“…Several prior studies have included imaging acquisitions [8][9][10][11][12]15 , ratiometric methods 11,13,14 and pharmacokinetic modeling 12 . The major unique contribution of this work is to perform regional quantification of metabolism, including comparing ratiometric and pharmacokinetic modeling, with the fed/fasted volunteer studies demonstrating experimental changes in metabolism.…”

A user independent denoising method for x‐nuclei MRI and MRS

“…One cardiac patient recruited through the cardiology department for another study 36 was used. The local ethics committee approved the study (EudraCT, 2018‐003533‐15).…”