Mathew David, Davidson Sean, Yellon Derek
The Hatter Cardiovascular Institute, University College London, London, UK.
Compr Physiol. 2025 Aug;15(4):e70033. doi: 10.1002/cph4.70033.
The 'Cardiovascular-Kidney-Metabolic Syndrome' which is characterized by multi-organ dysfunction ultimately resulting in adverse cardiac outcomes, serves to highlight the importance of organ crosstalk in pathophysiology. The cellular metabolism of fructose, regulated by Ketohexokinase-C with associated inflammatory sequelae, is mechanistically linked with each component of this clinical entity. Fructose metabolism is confined to the Kidney, Liver, and Small Intestine under normal physiological conditions; however, in the context of ischaemia, HIF-1α induces cardiac expression of Ketohexokinase-C with consequent organ hypertrophy and dysfunction. This adverse effect of cardiac HIF-1α accumulation raises concerns over the potential pleiotropic effects of the 'HIF stabilizing' inhibitors of Prolyl Hydroxylase currently entering clinical practice for the treatment of anemia in Chronic Kidney Disease, particularly given the increased cardiovascular mortality observed in this patient group. We suggest that pleiotropic effects of 'HIF stabilization' on cardiac physiology warrant investigation and, furthermore, that pharmacological inhibition of Ketohexokinase-C, and therefore fructose metabolism, represents an opportunity to improve cardiac outcomes in the Cardiovascular-Kidney-Metabolic Syndrome.
“心血管-肾脏-代谢综合征”以多器官功能障碍为特征，最终导致不良心脏结局，这凸显了器官间相互作用在病理生理学中的重要性。果糖的细胞代谢由己酮糖激酶-C调节，并伴有相关的炎症后遗症，在机制上与该临床实体的每个组成部分相关联。在正常生理条件下，果糖代谢局限于肾脏、肝脏和小肠；然而，在缺血情况下，缺氧诱导因子-1α（HIF-1α）会诱导心脏中己酮糖激酶-C的表达，从而导致器官肥大和功能障碍。心脏中HIF-1α积累的这种不良影响引发了人们对目前正进入临床实践用于治疗慢性肾脏病贫血的脯氨酰羟化酶“缺氧诱导因子稳定化”抑制剂潜在多效性作用的担忧，特别是考虑到该患者群体中观察到的心血管死亡率增加。我们认为，“缺氧诱导因子稳定化”对心脏生理学的多效性作用值得研究，此外，对己酮糖激酶-C进行药理学抑制，进而抑制果糖代谢，为改善心血管-肾脏-代谢综合征的心脏结局提供了一个契机。
