Therapeutic Strategies to Reduce Endothelial Ischemia-reperfusion Injury with Metabolic Syndrome: a Combination Approach with Lactate Administration and Ischemic Preconditioning
Gary Van Guilder
Summary
The objective of this clinical trial is to better understand how lactate, a naturally occurring energy substance, can be used to lessen damage to the vascular system in adults with a high cardiovascular disease risk. The main questions it aims to answer are: 1. Does giving lactate intravenously reduce injury to the vascular system? 2. Does giving lactate intravenously together with blood flow occlusion - known as ischemic preconditioning, reduce vascular injury better than blood flow occlusion by itself? 3. How does lactate help the vascular system? Researchers will compare lactate to a placebo (a look-alike substance that contains no lactate) to see if lactate works to lessen vascular injury. Researchers will also compare lactate to blood flow occlusion to see which one is better at preventing vascular injury. Researchers will also compare lactate and blood flow occlusion together to see if combining them works better than either one alone. In one visit to the laboratory, participants will: Obtain a measurement of vascular health in an arm Be given liquid lactate, a liquid placebo, and/or arm blood flow occlusion Obtain a second measurement of vascular health in an arm.
Description
Much of the mortality burden of ischemic heart disease is due to untreatable complications of ischemia-reperfusion (I/R) injury, greatly undermining the translation of cardioprotective interventions. Endothelial damage and dysfunction are centrally involved in many of the clinical consequences of myocardial I/R injury. While a very promising therapeutic defense mechanism against I/R-induced endothelial dysfunction is ischemic preconditioning (IPC), it has not fared well in multi-center phase III clinical trials. Complementary strategies that elicit additive or synergistic benefits against I/R…
Eligibility
- Age range
- 18–65 years
- Sex
- All
- Healthy volunteers
- Yes
Inclusion Criteria: * Sedentary men and women between the ages of 18-65 years of all races and ethnicity * Diet and weight stable for the past 3 months * Non-smoking and not using tobacco or electronic cigarettes Exclusion Criteria: * Use of medications known to affect cardiovascular function * Hyperlactemia * Type A lactic acidosis * Type B lactic acidosis * Extracellular hyperhydration or hypervolemia * Hyperkaliemia * Hypercalcemia * Metabolic alkalosis * Metabolic acidosis * McArdle's Disease * Diabetes Type 1 and 2 * Taking oral contraceptives or hormone replacement therapy * Body mass…
Interventions
- ProcedureIschemic preconditioning
The objective of this Intervention is to show that ischemic preconditioning (IPC) protects against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm, followed by 3 × 5-minute cycles of IPC in the opposite arm. IPC will be induced using a blood pressure cuff placed on the opposite upper arm and inflated to 220 mmHg for 5 min, followed by 5 min of deflation. This procedure will be repeated two additional times taking about 30 minutest to complete. Following a 10-minute rest phase, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.
- DrugIntravenous lactate infusion
The objective of this Intervention is to show that an intravenous infusion of lactate protects against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm. Thereafter, a continuous intravenous infusion of lactate will be delivered in the contralateral arm. After systemic lactate reaches \~3 mmol/L, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.
- ProcedureNo ischemic preconditioning (control)
The objective of this Intervention is to show that a control experiment without ischemic preconditioning does not provide protection against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm, followed by 3 × 5-minute cycles of no upper arm occlusion in the opposite arm. To avoid upper arm occlusion, a blood pressure cuff will be placed on the upper arm and inflated to a low pressure of 20 mmHg pressure to not influence blood flow through the arm. This control procedure will be repeated two additional times taking about 30 minutes to complete. Following a 10-minute rest phase, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.
Location
- High Altitude Physiology Laboratory at Western Colorado UniversityGunnison, Colorado