*8.1. Heart Failure*

During heart failure, the heart undergoes a metabolic switch favoring ketone metabolism in cardiomyocytes, which are more efficiently used than in the normal heart. Moreover, ketone body oxidation is a more efficient energy substrate than terminal fatty acid oxidation [88]. Significant improvement in the cardiac output of about 24% was observed after ketone infusion in both chronic heart failure patients and animal models with heart failure [84,89]. These cardioprotective properties can be attributed to their increased utilization in the heart or upregulation of crucial oxidative phosphorylation mediators [44]. It has also been demonstrated that ketones improve blood lipid profile in obese adults by lowering LDL (low-density lipoprotein) cholesterol and raising HDL (high-density lipoprotein) cholesterol, reducing adipocyte cell volume, and lowering serum lipolytic products [84]. Ketones' mechanistic action in inhibiting NLRP3 inflammasome and activation of the GPCR109A (G-protein-coupled receptor) has been shown to rescue heart failure by reducing mitochondrial hyperacetylation, resulting in lower inflammation and oxidative stress and preventing atherosclerosis [84]. A study in mice also showed that BHB reduces sympathetic outflow and lowers heart rate and total energy expenditure by antagonizing GPR41, a G-protein−coupled receptor for short-chain fatty acids [88].

### *8.2. Kidneys and Liver Diseases*

During the development of kidney diseases, impaired lipolysis and mTORC1 (mammalian target of rapamycin complex 1) hyperactivation are observed; with this pathological condition, ketone supplementation might be an alternative energy source for mitochondrial respiration. Moreover, ketones' reno-protective roles are mainly via the endogenous inhibition of HDAC (histone deacetylase) and NLRP3, both increased expression of protective genes; consequently, it inhibits mTORC1, inflammation, oxidative stress, and tissue fibrosis [84,89]. Additionally, one mice study involving high-fat liver injury showed that oxidation of the ketone body acetoacetate by liver-resident macrophage-like Kupffer cells lowers fibrosis [89].
