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Cardiorenal ketone metabolism: a positron emission tomography study in healthy humans.

ABSTRACT: Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present double tracer positron emission tomography (PET) study evaluated the organ distribution and basal kinetic rates of the radiolabeled ketone, ¹¹C-acetoacetate (¹¹C-AcAc), in the heart and kidney compared to ¹¹C-acetate (¹¹C-Ac), which is a well-validated metabolic radiotracer. Both tracers were highly metabolized by the left ventricle and the renal cortex. In the heart, kinetic rates were similar for both tracers. But in the renal cortex, uptake of ¹¹C-Ac was higher compared to ¹¹C-AcAc, while the reverse was observed for the clearance. Interestingly, infusion of ¹¹C-AcAc led to a significantly delayed release of radioactivity in the renal medulla and pelvis, a phenomenon not observed with ¹¹C-Ac. This suggests an equilibrium of ¹¹C-AcAc with the other ketone, ¹¹C-D-beta-hydroxybutyrate, and a different clearance profile. Overall, this suggests that in the kidney, the absorption and metabolism of ¹¹C-AcAc is different compared to ¹¹C-Ac. This dual tracer PET protocol provides the opportunity to explore the relative importance of ketone metabolism in cardiac and renal diseases, and to improve our mechanistic understanding of new metabolic interventions targeting these two organs.

SUBMITTER: Cuenoud B

PROVIDER: S-EPMC10587428 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Cardiorenal ketone metabolism: a positron emission tomography study in healthy humans.

Cuenoud Bernard B Croteau Etienne E St-Pierre Valérie V Richard Gabriel G Fortier Mélanie M Vandenberghe Camille C Carpentier André C AC Cunnane Stephen C SC

Frontiers in physiology 20231006

Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present double tracer positron emission tomography (PET) study evaluated the organ distribution and basal kinetic rates of the radiolabeled ketone, 11C-acetoacetate (11C-AcAc), in the heart and kidney compared to 11C-acetate (11C-Ac), which is a well-validated metabolic radiotracer. Both trace ...[more]

PMID: 37869718

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Project description:BackgroundPositron Emission Tomography (PET) is traditionally used to image patients in restrictive positions, with few devices allowing for upright, brain-dedicated imaging. Our team has explored the concept of wearable PET imagers which could provide functional brain imaging of freely moving subjects. To test feasibility and determine future considerations for development, we built a rudimentary proof-of-concept prototype (Helmet_PET) and conducted tests in phantoms and four human volunteers.MethodsTwelve Silicon Photomultiplier-based detectors were assembled in a ring with exterior weight support and an interior mechanism that could be adjustably fitted to the head. We conducted brain phantom tests as well as scanned four patients scheduled for diagnostic F(18-) FDG PET/CT imaging. For human subjects the imager was angled such that field of view included basal ganglia and visual cortex to test for typical resting-state pattern. Imaging in two subjects was performed ~4 hr after PET/CT imaging to simulate lower injected F(18-) FDG dose by taking advantage of the natural radioactive decay of the tracer (F(18) half-life of 110 min), with an estimated imaging dosage of 25% of the standard.ResultsWe found that imaging with a simple lightweight ring of detectors was feasible using a fraction of the standard radioligand dose. Activity levels in the human participants were quantitatively similar to standard PET in a set of anatomical ROIs. Typical resting-state brain pattern activation was demonstrated even in a 1 min scan of active head rotation.ConclusionTo our knowledge, this is the first demonstration of imaging a human subject with a novel wearable PET imager that moves with robust head movements. We discuss potential research and clinical applications that will drive the design of a fully functional device. Designs will need to consider trade-offs between a low weight device with high mobility and a heavier device with greater sensitivity and larger field of view.

Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Dataset Information

Cardiorenal ketone metabolism: a positron emission tomography study in healthy humans.

Publications

Cardiorenal ketone metabolism: a positron emission tomography study in healthy humans.

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