Hypertension Clinical Trial
— KEASOfficial title:
Ketone Ester and Acute Salt: Can Ketone Supplementation Prevent the Adverse Negative Effects of High Salt on Blood Vessel Health in Young Adults?
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.
Status | Recruiting |
Enrollment | 35 |
Est. completion date | September 30, 2026 |
Est. primary completion date | September 30, 2025 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 18 Years to 39 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
United States | Auburn University | Auburn | Alabama |
Lead Sponsor | Collaborator |
---|---|
Auburn University | University of Missouri-Columbia, University of Utah |
United States,
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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Flow mediated dilation (FMD) | Flow-mediated vasodilation will be assessed using continuous measures of brachial artery diameter and velocity via duplex Doppler ultrasound (Hitachi Arietta 70). The brachial artery will be imaged in the longitudinal plane proximal to the medial epicondyle using a high-frequency (10-12 MHz) linear-array probe. The ultrasound probe will be stabilized using a custom-built clamp. Shear rate (sec-1) will be calculated as [(blood flow velocity (cm*s-1) *4)/blood vessel diameter (mm)] The image will be recorded throughout a 60-s baseline, a 300-s ischemic stimulus (250 mmHg), and 180 seconds post deflation. FMD will be expressed as % dilation (final diameter-baseline diameter/baseline diameter x 100) and also normalized to the shear stimulus. Allometric scaling will be used if appropriate, including if there are baseline differences in artery diameter by race or condition. | Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Primary | Pulse wave velocity | The investigators will use the SphygmoCor XCEL system to assess pulse wave velocity (PWV). A high-fidelity transducer is used to obtain the pressure waveform at the carotid pulse. Distances from the carotid artery sampling site to the femoral artery (upper leg instrumented with a thigh cuff for oscillometric sphygmomanometry), and from the carotid artery to the suprasternal notch will be recorded. PWV will be expressed as cm/s | Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Primary | Pulse wave analysis | The investigators will use the SphygmoCor XCEL system to assess pulse wave analysis (PWA) The sampling site is the brachial artery (upper alarm instrumented with a cuff for oscillometric sphygmomanometer). PWA will be expressed as % (calculated as augmentation pressure divided by the pulse pressure). | Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Primary | Passive Leg movement | Passive leg movement will be used assessed blood flow responses to movement. The investigators will usie continuous measures of femoral artery diameter and velocity via duplex Doppler ultrasound (Hitachi Arietta 70) to calculate blood flow at rest and with the passive lelg movement. The femoral artery will be imaged in the longitudinal plane distal to the inguinal crease using a high-frequency (10-12 MHz) linear-array probe.
Participants will be in a seated, reclined position with the lower leg free hanging. The ultrasound probe will be positioned by a lab member and the image will be recorded throughout triplicate 60-s measurements. Another lab member will independently move the lower leg through 90º range of motion at a rate of 1 Hz. |
Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Primary | Blood pressure reactivity responses | The investigators will measure systolic and diastolic pressure using photoplethysmography at the finger and manually measure brachial pressures. Systolic and diastolic blood pressure will be assessed at rest and during submaximal cycling exercise. Blood pressure reactivity will be expressed as a change in pressure (mmHg) from baseline to a predetermined time during the stressor. | Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Secondary | Inflammatory cell responses to Conditions | Participants' blood will be used to isolate peripheral blood mononuclear cells (PBMCs) for quantification of immune cell subsets specifically counts of monocytes and t cells. | Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Secondary | Inflammatory cytokine responses to Conditions | Plasma will be used for a multiplex to measure inflammatory cytokines | Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Secondary | Changes in circulating reactive oxygen species | Investigators will use electron paramagnetic resonance to measure reactive oxygen species (spectra units) in whole blood samples treated with a spin probe. | Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Secondary | Changes in blood biomarkers of nitric oxide bioavailability | The investigators will measure nitric oxide metabolites (nitrate and nitrite nanomolar concentration). | Change from low salt to high salt to high salt + ketone (once per visit after each 10-day intervention periods) | |
Secondary | Objective sleep duration | Philips actiwatch spectrum will be used to quantify sleep duration. Participants will wear the watch units for 14 days. The investigators will assess sleep duration and cross-check actigraphy wear times with a sleep diary. | Pre-intervention (14 days) | |
Secondary | Objective sleep efficiency | Philips actiwatch spectrum will be used to quantify % of time in bed actually spent sleeping to calculate sleep efficiency. | Pre-intervention (14 days) | |
Secondary | Subjective sleep duration | The investigators will use the Pittsburgh Sleep Quality Index to asses sleep duration reflective of the one month period leading into the study. | Pre-intervention | |
Secondary | Subjective sleep quality | The investigators will use the Pittsburgh Sleep Quality Index to asses perceived sleep quality reflective of the one month period leading into the study. | Pre-intervention | |
Secondary | Physical activity | Participants will wear an ActiGraph GT3X accelerometer for 14 days to objectively quantify steps taken per day. | Pre-intervention (14 days) | |
Secondary | Cardiorespiratory fitness | The investigators will use indirect calorimetry to measure the participant's maximal oxygen consumption (VO2max) during incremental exercise on a treadmill. The investigators will use a Parvo TrueOne metabolic cart and Monarch stationary bike. | Pre-intervention | |
Secondary | Mental health - social anxiety | The investigators will administer the Liebowitz Social Anxiety Scale. The scale starts at 0 (none) and ends at 3 (severe) for 24 questions related to anxiety and avoidance, and a cumulative score is calculated. | Pre-intervention | |
Secondary | Mental health - depression | The investigators will administer the Beck's Depression Inventory. The scale starts at 0 and ends at 3 for 21 questions related to depression. | Pre-intervention | |
Secondary | Habitual dietary intake | The investigators will instruct participants to complete a diet log for 6 days which will be operationalized with Nutrition Data System for Research (NDSR). | Pre-intervention |
Status | Clinical Trial | Phase | |
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