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.
