The janus face of ketone bodies in hypertension

Abstract

Hypertension is the most important risk factor for the development of terminal cardiovascular diseases, such as heart failure, chronic kidney disease, and atherosclerosis. Lifestyle interventions to lower blood pressure are generally desirable prior to initiating pharmaceutical drug treatments, which may have undesirable side effects. Ketogenic interventions are popular but the scientific literature supporting their efficacy is specific to certain interventions and outcomes in animal models and patient populations. For example, although caloric restriction has its own inherent difficulties (e.g. it requires high levels of motivation and adherence is difficult), it has unequivocally been associated with lowering blood pressure in hypertensive patients. On the other hand, the antihypertensive efficacy of ketogenic diets is inconclusive, and this is surprising, given that these diets have been largely helpful in mitigating metabolic syndrome and promoting longevity. It is possible that side effects associated with ketogenic diets (e.g. dyslipidemia) aggravate the hypertensive phenotype. However, given the recent data from our group, and others, reporting that the most abundant ketone body, β-hydroxybutyrate, can have positive effects on endothelial and vascular health, there is hope that ketone bodies can be harnessed as a therapeutic strategy to combat hypertension. Therefore, we conclude this review with a summary of the type and efficacy of ketone supplements. We propose that ketone supplements warrant investigation as low-dose antihypertensive therapy that decreases total peripheral resistance with minimal adverse side effects.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Figures

FIGURE 1

The biochemistry of ketogenesis and ketone utilization. Although ketone bodies are predominantly produced in the liver, their biosynthesis can be divided into hepatic and extrahepatic metabolism. Fatty acids are brought into the mitochondria via carnitine CPT-1 and broken down into acetyl CoA via beta-oxidation. Two acetyl-CoA molecules are converted into acetoacetyl-CoA via the enzyme ACAT. Afterward, acetoacetyl-CoA is converted to HMG-CoA via the enzyme HMG-CoA synthase 2. HMG-CoA lyase then converts HMG-CoA to AcAc. The AcAc can be converted to either acetone through nonenzymatic decarboxylation or to βOHB via BDH. Once they reach extrahepatic tissues, βOHB is converted to AcAc via the enzyme BDH, and AcAc is converted back to acetoacetyl-CoA via the enzyme SCOT1, and acetoacetyl-CoA is converted into two acetyl-CoA molecules via ACAT. Acetyl-CoA goes through the citric acid cycle, and after oxidative phosphorylation, produces ATP. AcAc, acetoacetate; ACAT, acetyl-coenzyme A acetyltransferases; βOHB, β-hydroxybutyrate; BDH, βOHB-dehydrogenase; CPT-1, carnitine palmitoyltransferase; HMGCL, HMG-CoA lyase; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HMGCS2, 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase 2; NADH, nicotinamide adenine dinucleotide; SCOT1, succinyl-CoA:3-ketoacid CoA transferase 1. Figure created by Biorender.com under license.

FIGURE 2

Low-dose ketone supplementation could be a novel antihypertensive therapy by promoting endothelium-dependent vasodilation and proliferation. Exogenous supplementation is a means of bypassing endogenous ketogenesis, as interventions such as caloric restriction, ketogenic diets, and 1,3-butanediol all have concerns regarding their long-term utilization and/or efficacy at lowering blood pressure. Figure created by Biorender.com under license.