Therapeutic Strategies to Reduce Endothelial Ischemia-reperfusion Injury

Gary Van Guilder

Status and phase: Begins enrollment in 9 months; Early Phase 1

Conditions: Endothelial Dysfunction; Ischemic Preconditioning; Endothelial Function (reactive Hyperemia); Vascular Injury; Metabolic Syndrome

Treatments: Drug: Normal Saline Infusion (Placebo); Procedure: Ischemic preconditioning; Procedure: No ischemic preconditioning (control); Combination Product: Ischemic preconditioning and intravenous lactate; Drug: Intravenous lactate infusion

Study type: Interventional

Funder types: Other

Identifiers

NCT06825143

HRC-2024-02-06-R33

Details and patient eligibility

About

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.

Full 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 injury are urgently needed. Because lactate has extensive endothelial protective effects, the recruitment of additional protective pathways with lactate that cannot be activated with IPC alone provides an innovative and powerful strategy to greatly enhance cardioprotection in the clinical arena. Little is understood about whether including lactate with IPC as a dual approach can bolster protection in adults with CVD risk in which the endothelial protective effects of IPC are already weakened. The long-term goal of this research is to develop improved combination therapeutic strategies to expedite the clinical application of IPC for cardioprotective purposes. The objective is to better understand how lactate administration can be used to alleviate endothelial I/R injury. In a model of endothelial I/R injury, our central hypothesis is that lactate administration alone will reduce endothelial dysfunction, and when included as a combination strategy with IPC, will improve protection with metabolic syndrome. The rationale for the proposed research is based on the poor translatability of existing cardioprotective strategies to date. The central hypothesis will be tested by pursuing three aims: 1) Determine the degree to which lactate administration attenuates endothelial I/R injury; 2) Determine the superiority of a combined multi-targeted therapeutic strategy against endothelial I/R injury in adults with metabolic syndrome; and 3) Establish mechanistic insight into the endothelial protective effects of lactate. In Aim #1, the investigators will utilize a randomized equivalence trial comparing the effects of lactate administration versus IPC on endothelial function in 32 adults. For Aim #2, a randomized superiority trial in 36 adults with metabolic syndrome will compare the dual effects of IPC combined with lactate versus IPC alone. For Aim #3, a series of biomarker studies by which lactate is likely to modify the therapeutic response to I/R injury are proposed. For Aims #1 and #2, endothelium-dependent vasodilation (primary endpoint) will be compared between trials for equivalence, and superiority, respectively. For Aim #3, the investigators expect lactate will protect against endothelial I/R injury, in part, by reducing circulating microparticles of endothelial activation and vascular inflammation, and increasing total antioxidant capacity, nitric oxide bioavailability, and angiogenic factors. The approach is conceptually innovative because the findings are likely to be the first in vivo evidence supporting the development of a multi-faceted approach that exploits the potential for synergistic cytoprotection involving IPC combined with lactate. This contribution would advance the development of new translatable strategies for cardioprotection.

Enrollment: 68 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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 index greater than or equal to 35
• Smoking or using smokeless tobacco and electronic cigarettes
• Cardiovascular, cerebrovascular, liver, respiratory, and renal disease
• Atrial fibrillation or other sustained supraventricular/ventricular arrhythmia
• Familial hypercholesterolemia
• Rheumatoid arthritis
• Sleep apnea
• Currently pregnant, recent pregnancy, or breast-feeding
• Autonomic nervous system dysfunction
• Raynaud's disease
• Active malignancy excluding basal cell carcinoma of the skin
• Three or more days of at least 30 minutes of aerobic exercise in the past 3 months
• Inability to provide consent

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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68 participants in 2 patient groups

Ischemic preconditioning versus intravenous lactate infusion

Active Comparator group

Description:

To goal of this Arm is to compare the capacity of ischemic preconditioning (IPC) to protect against endothelial ischemia/reperfusion injury to the capacity of an intravenous lactate infusion to protect against endothelial ischemia/reperfusion injury. To achieve this goal, investigators will test the hypothesis that the capacity for intravenous lactate to reduce endothelial injury will be equivalent to that of IPC. Participants will be randomized to one of two Interventions. One Intervention will be the IPC intervention which is thought to be effective in treating the condition under study. The other intervention is the intravenous lactate intervention, which is the main focus of the study.

Treatment:

Drug: Intravenous lactate infusion

Procedure: No ischemic preconditioning (control)

Drug: Normal Saline Infusion (Placebo)

Procedure: Ischemic preconditioning

Ischemic preconditioning combined with an intravenous lactate infusion

Experimental group

Description:

To goal of this Arm is to compare the capacity of ischemic preconditioning (IPC) combined with an intravenous lactate infusion to protect against endothelial ischemia/reperfusion injury to IPC by itself. To achieve this goal, investigators will test the hypothesis that the capacity to protect against endothelial injury will be better when IPC and lactate are combined compared to IPC alone. Participants will be randomized to one of two Interventions. One Intervention will be the IPC intervention by itself. The other intervention will be adding an intravenous lactate infusion together with IPC which is the main focus of the study.

Treatment:

Combination Product: Ischemic preconditioning and intravenous lactate

Procedure: Ischemic preconditioning