Clinical trial NCT05545501: Ketone Ester and Acute Salt (KEAS) in Young Adults
Official title: Ketone Ester and Acute Salt: Can Ketone Supplementation Prevent the Adverse Negative Effects of High Salt on Blood Vessel Health in Young Adults?
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Salt; Excess
Hypertension
Lead sponsor: Auburn University
Sponsor class: OTHER
Collaborators: name: University of Utah
name: University of Missouri-Columbia
name: Indiana University
First posted: 2022-09-19
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 39
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Placebo-controlled, double-blinded, randomized
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

* Between the ages of 18-39
* Resting blood pressure no higher than 150/90
* BMI below 35 kg/m2 (or otherwise healthy)
* Free of any metabolic disease (diabetes or renal), pulmonary disorders (COPD or cystic fibrosis), cardiovascular disease (peripheral vascular, cardiac, or cerebrovascular), no autoimmune diseases, and no history of cancer
* Do not have any precluding medical conditions (i.e. hemophilia) or medication (Pradaxa, Eliquis, etc.) that prevent participants from giving blood
* Participants must be able to cycle on an exercise bike for up to one hour at a time.

Exclusion Criteria:

* High blood pressure - greater the 150/90 mmHg
* Low blood pressure - less than 90/50 mmHg
* History of cardiovascular disease
* History of cancer
* History of diabetes
* History of kidney disease
* Obesity (BMI \> 30 kg/m2)
* Smoking or tobacco use
* Current pregnancy
* Nursing mothers
* Communication barriers

Primary outcomes:
measure: Flow mediated dilation (FMD)
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
measure: Pulse wave velocity
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
measure: Pulse wave analysis
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
measure: Passive Leg movement
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
measure: Blood pressure reactivity responses
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
Secondary outcomes:
measure: Inflammatory cell responses to Conditions
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
measure: Inflammatory cytokine responses to Conditions
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
measure: Changes in circulating reactive oxygen species
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
measure: Changes in blood biomarkers of nitric oxide bioavailability
timeFrame: Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods)
measure: Objective sleep duration
timeFrame: Pre-intervention (14 days)
measure: Objective sleep efficiency
timeFrame: Pre-intervention (14 days)
measure: Subjective sleep duration
timeFrame: Pre-intervention
measure: Subjective sleep quality
timeFrame: Pre-intervention
measure: Physical activity
timeFrame: Pre-intervention (14 days)
measure: Cardiorespiratory fitness
timeFrame: Pre-intervention
measure: Mental health - social anxiety
timeFrame: Pre-intervention
measure: Mental health - depression
timeFrame: Pre-intervention
measure: Habitual dietary intake
timeFrame: Pre-intervention
Other outcomes:
Locations:
city: Auburn
country: United States
facility: Auburn University
state: Alabama
Study officials:
affiliation: Auburn University
name: Austin T Robinson, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Babcock MC, Robinson AT, Migdal KU, Watso JC, Martens CR, Edwards DG, Pescatello LS, Farquhar WB. High Salt Intake Augments Blood Pressure Responses During Submaximal Aerobic Exercise. J Am Heart Assoc. 2020 May 18;9(10):e015633. doi: 10.1161/JAHA.120.015633. Epub 2020 May 14.
citation: Costa TJ, Linder BA, Hester S, Fontes M, Pernomian L, Wenceslau CF, Robinson AT, McCarthy CG. The janus face of ketone bodies in hypertension. J Hypertens. 2022 Nov 1;40(11):2111-2119. doi: 10.1097/HJH.0000000000003243. Epub 2022 Aug 8.
citation: Barnett AM, Babcock MC, Watso JC, Migdal KU, Gutierrez OM, Farquhar WB, Robinson AT. High dietary salt intake increases urinary NGAL excretion and creatinine clearance in healthy young adults. Am J Physiol Renal Physiol. 2022 Apr 1;322(4):F392-F402. doi: 10.1152/ajprenal.00240.2021. Epub 2022 Feb 14.
citation: Chakraborty S, Galla S, Cheng X, Yeo JY, Mell B, Singh V, Yeoh B, Saha P, Mathew AV, Vijay-Kumar M, Joe B. Salt-Responsive Metabolite, beta-Hydroxybutyrate, Attenuates Hypertension. Cell Rep. 2018 Oct 16;25(3):677-689.e4. doi: 10.1016/j.celrep.2018.09.058.
citation: McCarthy CG, Chakraborty S, Singh G, Yeoh BS, Schreckenberger ZJ, Singh A, Mell B, Bearss NR, Yang T, Cheng X, Vijay-Kumar M, Wenceslau CF, Joe B. Ketone body beta-hydroxybutyrate is an autophagy-dependent vasodilator. JCI Insight. 2021 Oct 22;6(20):e149037. doi: 10.1172/jci.insight.149037.
citation: Wenstedt EF, Verberk SG, Kroon J, Neele AE, Baardman J, Claessen N, Pasaoglu OT, Rademaker E, Schrooten EM, Wouda RD, de Winther MP, Aten J, Vogt L, Van den Bossche J. Salt increases monocyte CCR2 expression and inflammatory responses in humans. JCI Insight. 2019 Nov 1;4(21):e130508. doi: 10.1172/jci.insight.130508.