Croteau Etienne, Richard Gabriel, Prud'Homme Patrick, Rousseau Etienne, Cunnane Stephen C, Dumulon-Perreault Véronique, Sarrhini Otman, Phoenix Serge, Tremblay Sébastien, Guérin Brigitte, Lecomte Roger
Sherbrooke Molecular Imaging Centre (CIMS), CRCHUS, Sherbrooke, QC, Canada.
Department of Medical Imaging and Radiation Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
EJNMMI Res. 2025 Mar 14;15(1):23. doi: 10.1186/s13550-025-01215-9.
In non-insulin-dependent, type 2, diabetes mellitus (T2D), glucose metabolism is compromised, and the heart loses its metabolic flexibility. The Zucker Diabetic Fatty rat (ZDF) model, which replicates the pathophysiology of T2D in patients, shows that as T2D progresses so does heart failure. Heart ketone metabolism seems to play a role in mitigating the heart failure process. This study assesses ketone metabolism in a ZDF heart failure model using cardiac PET imaging.
Six lean ZDF rats (CTRL) and six diabetic obese ZDF rats (T2D) were evaluated for coronary flow reserve (CFR) using [N]ammonia ([N]NH) cardiac PET. In addition, rats were evaluated with [C]acetoacetate ([C]AcAc) PET during rest and stress conditions to assess ketone metabolism, both at baseline and under an acute exogenous ketone ester oral supplementation. Blood chemistry, cardiac function and hemodynamic parameters were also evaluated under these conditions.
CFR was impaired in the T2D model (CTRL: 1.8 ± 0.5; T2D: 1.4 ± 0.2, p < 0.05) suggesting the development of heart failure in the T2D model. Blood ketones increased more than 2-fold after supplementation. The [C]AcAc heart ketone uptake values with and without ketone supplementation were similar for the CTRL group, and these values were higher than for T2D rats. For the T2D group, the uptake decreased by 20% at rest under ketone supplementation vs. no supplementation (p < 0.05) and remained unchanged under stress with and without supplementation. Because of this decrease at rest, the stress/rest ratio after supplementation increases to the level observed in CTRL. [C]AcAc heart ketone metabolism showed a slight decrease under stress for the CTRL group, but not for the T2D. Under ketone supplementation, the metabolism stress/rest ratio increased only in T2D (1.25 ± 0.29, p = 0.03 compared to baseline).
In a rat model of T2D and CFR impairment, we were able to measure changes in ketone metabolism using [C]AcAc PET at rest and under stress with and without acute ketone supplementation. Our findings suggest that the heart ketone metabolism of T2D rats is impaired during the heart failure process. Ketone supplementation may have the potential to restore this cardiac reserve.
在非胰岛素依赖型2型糖尿病（T2D）中，葡萄糖代谢受损，心脏失去代谢灵活性。Zucker糖尿病脂肪大鼠（ZDF）模型可复制患者T2D的病理生理学，表明随着T2D的进展，心力衰竭也会随之发展。心脏酮代谢似乎在减轻心力衰竭过程中发挥作用。本研究使用心脏PET成像评估ZDF心力衰竭模型中的酮代谢。
使用[氮]氨（[N]NH）心脏PET对6只瘦型ZDF大鼠（对照组）和6只糖尿病肥胖ZDF大鼠（T2D）进行冠状动脉血流储备（CFR）评估。此外，在静息和应激条件下，使用[碳]乙酰乙酸（[C]AcAc）PET对大鼠进行评估，以在基线和急性外源性酮酯口服补充的情况下评估酮代谢。在这些条件下还评估了血液化学、心脏功能和血流动力学参数。
T2D模型中的CFR受损（对照组：1.8±0.5；T2D：1.4±0.2，p<0.05），表明T2D模型中出现了心力衰竭。补充后血酮增加了2倍多。对照组在补充和未补充酮的情况下，[C]AcAc心脏酮摄取值相似，且这些值高于T2D大鼠。对于T2D组，补充酮时静息状态下的摄取量比未补充时降低了20%（p<0.05），在应激状态下补充和未补充时摄取量均保持不变。由于静息时的这种降低，补充后应激/静息比增加到对照组观察到的水平。对照组在应激状态下[C]AcAc心脏酮代谢略有下降，但T2D组没有。在补充酮的情况下，仅T2D组的代谢应激/静息比增加（1.25±0.29，与基线相比p=0.03）。
在T2D和CFR受损的大鼠模型中，我们能够使用[C]AcAc PET在静息和应激状态下，以及在补充和未补充急性酮的情况下测量酮代谢的变化。我们的研究结果表明，T2D大鼠的心脏酮代谢在心力衰竭过程中受损。补充酮可能有恢复这种心脏储备的潜力。
