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

Figures

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  FIGURE 1. Metabolism of acetoacetate and acetate leading to the production of mitochondrial acetyl-CoA. Fatty acids and glucose are the main precursors of acetyl-CoA via acyl-CoA and pyruvate, respectively. AcAc: acetoacetate; ACAT: acetyl-CoA acetyltransferase; ACSS: acyl-CoA short-chain synthetase; AMP: Adenosine monophosphate; ATP: Adenosine triphosphate; BDH: 3-hydroxybutyrate dehydrogenase; CoA: Coenzyme A; D-BHB: D-beta-hydroxybutyrate; NAD: Nicotinamide adenine dinucleotide; PP: pyrophosphate; Ox Phos: oxidative phosphorylation; SCOT: succinyl-CoA:3-ketoacid CoA transferase; TCA: tricarboxylic acid cycle (or Krebs’s cycle).

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  FIGURE 2. Typical PET images. (A) Dynamic time frames after tracer administration for the heart and kidney within the 26-cm axial field of view of the PET scanner superimposed on a low-dose computerized tomography. Summed images for the heart (5–30 min) (B) and kidney (5–15 min) (C) in the short, vertical, and horizontal long axis for the two radiotracers, 11C-AcAc (acetoacetate) and 11C-Ac (acetate).

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  FIGURE 3. (A) 11C-AcAc (acetoacetate) and 11C-Ac (acetate) time activity curves. Each point is the average ± standard deviation (n = 10). (B) Compartmental models were used to derive the pharmacokinetic parameters. 1TC: one-tissue compartment model; 2 TC: two-tissue compartment model; SUV—standardized uptake value.

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  FIGURE 4. Uptake rate (K 1) of 11C-AcAc (acetoacetate) and 11C-Ac (acetate) in the myocardium (n = 10). (A) Individual K 1 values. Points are paired for both tracers for each participant. (B) Correlation of 11C-AcAc and 11C-Ac K 1 without (upper panel) and with (lower panel) scaling with the individual rate-pressure product (RPP). (C) Correlation between 11C-Ac derived myocardial blood flow (MBF) and 11C-AcAc K 1 for the 17 myocardial segments in all 10 participants. Paired two-tailed Student’s t-test for 11C-AcAc and 11C-Ac. r2: coefficient of determination.

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  FIGURE 5. Clearance rate (k 2) of 11C-AcAc (acetoacetate) and 11C-Ac (acetate) in the myocardium (n = 10). (A) Paired data for individual k 2 of 11C-AcAc and 11C-Ac in each participant. (B) Correlation of 11C-AcAc and 11C-Ac k 2 in each participant. Paired two-tailed Student’s t-test for 11C-AcAc and 11C-Ac. r2: coefficient of determination.

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  FIGURE 6. Uptake rate (K 1) and clearance rate (k 2) of 11C-AcAc (acetoacetate) and 11C-Ac (acetate) in the renal cortex (n = 10) using a one-tissue model. (A) Individual K 1 values for 11C-AcAc and 11C-Ac. Points are paired across both tracers for each participant. (B) Correlation of 11C-AcAc and 11C-Ac K 1 values with one point for each participant. (C) Individual k 2 values for 11C-AcAc and 11C-Ac. Points are paired across both tracers for each participant. (D) Correlation of 11C-AcAc and 11C-Ac k 2 values with one point for each participant. Paired two-tailed Student’s t-test for 11C-AcAc and 11C-Ac. r2: coefficient of determination.

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  FIGURE 7. Comparison of 11C-AcAc (acetoacetate) and 11C-Ac (acetate) kinetic rates in the heart and kidney cortex (n = 10): (A) Uptake rate (K 1 ), (B) Clearance rate (k 2 ), (C) Kinetic ratio K 1 /k 2.