Physiological Effects of Lactate in Individuals With Chronic Heart Failure

Study Overview
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Brief Summary
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Background: Lactate is continuously produced in the human body through two primary processes: glycolysis and microbial fermentation in the gastrointestinal tract. At rest, its concentration in the bloodstream typically ranges from 1 to 2 mmol/L. However, during periods of physical exertion or insufficient oxygen supply, such as during intense exercise, lactate levels significantly increase. Traditionally, lactate was perceived as a byproduct of anaerobic metabolism. Nevertheless, emerging research has illuminated its vital role as both a signaling molecule and a crucial energy source for vital organs like skeletal muscle, brain, and the heart. Objectives: The primary aim of this study is to investigate the impact of physiological levels of circulating lactate on the hemodynamics of individuals with chronic heart failure. This research seeks to understand how lactate affects the cardiovascular response in this specific patient population. Design and Endpoints: The study design employs a double-blind, randomized crossover approach involving 12 heart failure patients. Each participant will undergo two separate visits. Visit 1: Participants will receive a three-hour intravenous infusion of either a racemic (D/L) mixture of sodium lactate or an intravenous isotonic sodium chloride placebo, with a subsequent crossover to the opposite infusion on the same day. Visit 2: Similar to the first visit, participants will receive either an orally administered racemic (D/L) mixture of sodium lactate or an isocaloric, isovolumic oral placebo (maltodextrin), with a crossover to the opposite administration after three hours. The study's endpoints include cardiac output (primary), mixed venous saturation (SVO2), pulmonary wedge pressure, resting echocardiography (left ventricular ejection fraction and myocardial work efficiency), and measurements of vasoactive substances in blood samples. Methods: The study employs invasive Swan-Ganz monitoring to measure cardiac output, echocardiography, and frequent venous blood sample collections. These measurements and samples will be taken at specific intervals during the study visits. Intervention: To investigate the isolated hemodynamic and physiological effects of lactate, the study utilizes lactate infusion and ingestion to induce a state of hyperlactatemia within the physiological range. The intended dosages aim to stay within the physiological range, with no values expected to exceed 3-4 mmol/L.

Official Title
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Physiological Effects of Lactate in Individuals With Chronic Heart Failure

Conditions
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Heart Failure, Systolic

Intervention / Treatment
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* Other: Sodium lactate infusion
* Other: Sodium lactate ingestion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic heart failure NYHA II-III Left ventricular ejection fraction <40% Negative urine-HCG for women with childbearing potential Exclusion Criteria: Diabetes or HbA1c >48 mmol/mol Significant cardiac valve disease Severe stable angina pectoris Severe comorbidity as judged by the investigator Inability to give informed consent Age <18 years Other disease or treatment making subject unsuitable for study participation as judged by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lactate infusion<br>All participants will be randomized to first receive a three-hour intravenous infusion with either a racemic (D/L) mixture of sodium lactate or intravenous isotonic sodium chloride placebo. All participants will then cross over to the converse infusion on the same day. | Other: Sodium lactate infusion<br>* Dosage of sodium-lactate: 0.5 mol/L; 3 mL/kg/time; maximal 300 mL/hour.<br>|
| Active Comparator: Lactate ingestion<br>All participants will be randomized to first receive either an orally administered racemic (D/L) mixture of sodium lactate or isocaloric, isovolumic oral placebo (maltodextrin). The oral dose of lactate will be equal to the intravenous dose. All participants will be studied for three hours and then cross over to receive the converse oral administration following additional three hours of observation time on the same day. | Other: Sodium lactate ingestion<br>* Oral dose is equal to the i.v. dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac output Cardiac output | Unit: L/min. It represents the amount of blood that the heart pumps out of the left ventricle per minute. | Two visits of six hours each separated by a one-week washout period. Thus, outcome measures for the intravenous route will be assessed at week one, and outcome measures for the oral route will be assessed at week 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mixed venous saturation (SVO2) | Unit: % It represents the percentage of oxygen saturation in the blood as it returns to the right side of the heart after circulating through the body's tissues. | Two visits of six hours each separated by a one-week washout period. Thus, outcome measures for the intravenous route will be assessed at week one, and outcome measures for the oral route will be assessed at week 2. | 
| Pulmonary wedge pressure | Unit: mmHg It reflects the pressure within the left atrium and the left ventricle of the heart, and it is an important indicator of left ventricular preload. | Two visits of six hours each separated by a one-week washout period. Thus, outcome measures for the intravenous route will be assessed at week one, and outcome measures for the oral route will be assessed at week 2. | 
| Left ventricular ejection fraction | Unit: % It is a measure of the percentage of blood that is pumped out of the left ventricle with each heartbeat. | Two visits of six hours each separated by a one-week washout period. Thus, outcome measures for the intravenous route will be assessed at week one, and outcome measures for the oral route will be assessed at week 2. | 
| Global longitudinal strain | Unit: % It quantifies the deformation or shortening of the heart muscle fibers along the longitudinal (lengthwise) axis of the left ventricle during the cardiac cycle. | Two visits of six hours each separated by a one-week washout period. Thus, outcome measures for the intravenous route will be assessed at week one, and outcome measures for the oral route will be assessed at week 2. |