Echocardiographic Changes After 3-hydroxy Butyrate+Whey Intake

Background: A newly published study found beneficial cardiovascular effects of 3-OHB infusion in a population with chronic heart failure, significantly increasing cardiac output. Similar effects on cardiac output were observed in healthy volunteers. These findings pave the way for 3-OHB as a therapeutic nutritional supplement, since it is well-absorbed during oral consumption. However, it is unknown whether the cardiovascular effects of 3-OHB persist during a sepsis-like catabolic state and when administered orally.

Aim: This study aims to investigate the cardiovascular effects of adding the ketone body 3-hydroxy butyrate (3-OHB) to whey protein during a human disease model, comprising endotoxemia + bed rest + fast.

Hypothesis:

1. Adding the ketone body 3-OHB to an oral protein supplement increases cardiac output measures
2. Catabolic stress (endotoxemia/inflammation + 36 h fast and bed rest) induces cardiovascular changes compared with healthy conditions (overnight fast)

Interventions:

In a randomized crossover design, eight healthy, lean, young men will undergo either:

i) Healthy conditions (overnight fast) + whey protein\^

ii) Catabolic conditions (Inflammation (LPS) + 36-hour fast and bed rest*) + whey protein\^

iii) Catabolic conditions (Inflammation (LPS) + 36-hour fast and bed rest*) + 3-OHB/whey protein\^"

*LPS will be administered (1 ng/kg) the day prior to the study together with fast and bed rest. On the study day LPS (0.5 ng/kg) will be injected.

\^Beverages will be isonitrogenous and isocaloric (fat will be added) with 45 g whey protein + 20 g maltodextrin. Bolus/sip administration will be applied (1/3 bolus, 1/2 sip)

" 50 grams of 3-OHB will be orally administered (1/2 bolus, 1/2 sip)

• Whey (Dietary supplement): 45 g whey + 20 g maltodextrin
• 3-OHB + Whey (Dietary supplement): 50 g ketone + 45 g whey + 20 g maltodextrin

Primary outcomes

• Change in left ventricular outflow tract velocity time integral [Measured during the basal period and after 1.5 hours of intervention]: Echocardiographic changes in left ventricular outflow tract velocity time integral from the basal period and after 1.5 hours of intervention

Secondary outcomes

• Changes in Left Ventricular Ejection Fraction (LVEF) [Measured during the basal period and after 1.5 hours of intervention]: Echocardiographic changes in LVEF from the basal period and after 1.5 hours of intervention
• Changes in Global Longitudinal Strain (GLS) [Measured during the basal period and after 1.5 hours of intervention]: Echocardiographic changes in GLS from the basal period and after 1.5 hours of intervention
• Changes in S´ Max [Measured during the basal period and after 1.5 hours of intervention]: Echocardiographic changes in S´ Max from the basal period and after 1.5 hours of intervention
• Changes in blood pressure [Measured during the basal period and after 1.5 hours of intervention]: Changes in blood pressure from the basal period and after 1.5 hours of intervention
• Changes in heart rate [Measured during the basal period and after 1.5 hours of intervention]: Changes in heart rate from the basal period and after 1.5 hours of intervention
• Changes in axillary temperature [Measured during the basal period and after 1.5 hours of intervention]: Changes in axillary temperature from the basal period and after 1.5 hours of intervention
• Difference in Left Ventricular Ejection Fraction (LVEF) (Healthy vs catabolic conditions) [Measured after 2 hours of basal period]: Echocardiographic difference in LVEF during the basal period between healthy and catabolic conditions (a pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)
• Difference in Global Longitudinal Strain (GLS) (Healthy vs catabolic conditions) [Measured after 2 hours of basal period]: Echocardiographic difference in GLS during the basal period between healthy and catabolic conditions (a pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)
• Difference in S´ Max (Healthy vs catabolic conditions) [Measured after 2 hours of basal period]: Echocardiographic difference in S´ Max during the basal period between healthy and catabolic conditions (a pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)
• Difference in axillary temperature (healthy vs catabolic) [Measured after 2 hours of basal period]: Difference in axillary temperature after 2 hours basal period between healthy and catabolic conditions (a pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)
• Difference in heart rate (healthy vs catabolic) [Measured after 2 hours of basal period]: Difference in heart rate after 2 hours basal period between healthy and catabolic conditions (a pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)
• Difference in blood pressure (healthy vs catabolic) [Measured after 2 hours of basal period]: Difference in blood pressure after 2 hours basal period between healthy and catabolic conditions (a pooled mean of the two catabolic days, if there is no difference between the first and second time of LPS exposure)

Sex: Male, ages: 20 Years to 40 Years, accepts healthy volunteers

Inclusion Criteria:

* Between 20-40 years of age
* Body mass index between 20-30 kg/m\^2
* Healthy
* Oral and written consent forms obtained prior to study day

Exclusion Criteria:

* Recent immobilization of an extremity that is not fully rehabilitated
* Lactose, lidocain or rubber allergies
* Current disease
* Use of anabolic steroids
* Smoking
* Former major abdominal surgery (Or current problems with the GI tract)

  •>10 hours of exercise/weak
* Present ketogenic diets or high-protein diets
* Blood doner that does not want to discontinue blood donations until study completion
* Pending MR scan

• Niels Moeller, Professor, Principal investigator, Aarhus University Hospital and Institute of Clinical Medicine