Ketone Ester and Salt (KEAS) in Young Adults

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

35 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-03-24

Study Completion Date

2026-09-30

Brief Summary

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Most Americans consume excess dietary salt based on the recommendations set by the American Heart Association and Dietary Guidelines for Americans. High dietary salt impairs the ability of systemic blood vessels and the kidneys to control blood pressure, which contributes to excess salt consumption being associated with increased risk for chronic kidney disease and cardiovascular disease, the leading cause of death in America. There is a critical need for strategies to counteract the effects of high dietary salt as consumption is likely not going to decrease. One promising option is ketones, metabolites that are produced in the liver during prolonged exercise and very low-calorie diets. While exercise and low-calorie diets are beneficial, not many people engage in these activities. However, limited evidence indicates that ketone supplements improve cardiovascular health in humans. Additionally published rodent data indicates that ketone supplements prevent high salt-induced increases in blood pressure, blood vessel dysfunction, and kidney injury. Our human pilot data also indicates that high dietary salt reduces intrinsic ketone production, but it is unclear whether ketone supplementation confers humans protection against high salt similar to rodents. Therefore, the investigators seek to conduct a short-term high dietary salt study to determine whether ketone supplementation prevents high dietary salt from eliciting increased blood pressure, blood vessel dysfunction, and kidney injury/impaired blood flow. The investigators will also measure inflammatory markers in blood samples and isolate immune cells that control inflammation. Lastly, the investigators will also measure blood ketone concentration and other circulating metabolites that may be altered by high salt, which could allow us to determine novel therapeutic targets to combat high salt.

Detailed Description

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Excessive salt consumption is widespread across the United States and remains a leading risk factor for developing hypertension and cardiovascular disease (CVD). What has been less appreciated until recently is that high salt (HS) plays a large role in the development of chronic inflammation, which importantly, plays a critical role in the development of CVD. The well-documented relation between HS, hypertension, and CVD risk along with the ubiquitous HS intake in the United States demonstrate a critical need for investigation into mechanisms of salt-induced CVD; and the development of therapeutic strategies to combat the consequences of HS, particularly in at-risk populations. The investigators have identified the liver-derived ketone body β-hydroxybutyrate (β-OHB) as a potential target to combat the negative cardiovascular health effects of HS. Circulating β-OHB concentration typically increases in response to endurance exercise or calorie restriction, both of which also reduce blood pressure (BP) and lower CVD risk. Further, recent data suggest that increasing circulating β-OHB concentrations, using short-term exogenous ketone supplements, also improves resting BP and vascular function in humans. Interestingly, chronic HS consumption suppressed endogenous hepatic β-OHB production in rats, but nutritionally upregulated hepatic β-OHB production attenuated the adverse effects of HS in the rats. Specifically, using 1,3-butanediol to increase β-OHB counteracts the adverse effects of HS on resting BP, in part by acting as a vasodilator, and attenuating inflammation. Our human pilot data also indicates that HS suppresses circulating β-OHB concentration in healthy young adults. However, there is a knowledge gap regarding whether increasing β-OHB during HS intake can counteract the negative effects of HS on BP and cardiovascular function in humans. Therefore, the investigators will measure resting blood pressure, endothelial function, kidney blood flow, BP responses during and after submaximal aerobic exercise and inflammatory markers in blood and isolated immune cells (i.e., monocytes). Recognizing that HS does not increase BP in everyone, several studies consistently indicate that short-term HS ingestion (days to weeks) leads to endothelial dysfunction and exaggerated BP reactivity during submaximal exercise in rodents and humans. Importantly, endothelial dysfunction contributes to atherosclerotic cardiovascular disease. Additionally, exaggerated BP responses during aerobic exercise (i.e., BP reactivity) have prognostic value for future hypertension, coronary disease risk, and cardiovascular mortality. Apart from leading to exaggerated exercise BP reactivity, the investigators have found that HS also reduces the magnitude of post-exercise hypotension (PEH) after an acute bout of submaximal aerobic exercise in healthy adults. Importantly, the reductions in BP observed after a single bout of exercise are associated with longer-term exercise reductions in BP, suggesting that some of the benefits of aerobic exercise on BP status are the result of transient reductions in BP resulting from an acute bout of exercise. Regarding the effects of HS on the immune system and inflammation, microenvironments with elevated concentrations of sodium increase the prevalence of proinflammatory phenotypes within specific immune cell subsets. For example, HS conditions activate monocytes to produce pro-inflammatory cytokines. Thus, HS-induced immune system dysregulation may further amplify BP dysregulation and CVD risk. The investigators hypothesize that increasing circulating β-OHB concentration via ketone supplementation will counteract the negative effects of HS on these measures of cardiovascular health. Interestingly, elevating β-OHB leads to greater sodium excretion under HS conditions (indicative of restoration of plasma volume homeostasis) and restores nitric oxide-dependent vasodilation in rodents. Thus, the investigators hypothesize that ketone supplementation will improve endothelial function and BP regulation during and after exercise. Though exploratory, the investigators hypothesize that β-OHB supplementation blunts the HS-induced proinflammatory alterations in monocytes and blood samples using parallel in vitro and applied approaches.

Participants will report to the laboratory for four visits. At the first visit, consent for study participation will be obtained and participants will be screened for eligibility. Participants will then be randomly assigned to a crossover schedule for exposure to salt and ketone supplementation. Supplementation conditions include \[A\] Placebo capsules and Placebo beverage, \[B\] Salt capsules and Placebo beverage, and \[C\] Salt capsules and Ketone beverage. Each participant will be exposed to all three conditions, however, the order of exposure will be randomly assigned. Participants will consume their placebo/salt capsules three times per day and their placebo/ketone beverage three times per day.

Participants will consume the first assigned supplement combination for nine days prior to their first scheduled experiment visit (i.e., first experimental visit is day 10 of supplement combination#1). After a washout period, participants will consume the next randomly assigned supplement combination for nine days prior to the second scheduled experiment visit (i.e., day 10 of supplement combination #2). After another washout period, participants will consume the final randomly assigned supplement combination for nine days prior to the third scheduled experiment visit (i.e., day 10 of supplement combination #3). Participation will end after the third experimental visit has been completed.

Conditions

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Salt; Excess Hypertension

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Placebo-controlled, double-blinded, randomized

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

DOUBLE

Participants Investigators

Participants will be randomized to a condition order. A single lab member, not involved in data collection or analysis, will know condition order and contents and distribute them to participants.

Study Groups

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Placebo/Placebo, then Salt/Placebo, then Salt/Ketone

Participants will consume each of the supplement combinations for 10 days (in this assigned order). On Day 10 of each interventional condition, participants will arrive at the laboratory where the investigators will assess resting blood pressure, arterial stiffness, endothelial function, renal blood flow, and submaximal exercise blood pressure reactivity. Blood will be collected to investigate inflammatory and immune responses to the dietary conditions. A washout period will be required prior to starting each of the next two supplement combination assignments.

Group Type ACTIVE_COMPARATOR