Physiological Effects of Lactate in Individuals With Chronic Heart Failure

Heart Failure, Systolic Clinical Trial

Official title:

Physiological Effects of Lactate in Individuals With Chronic Heart Failure

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06121323
• Other study ID #: LACTATE-CHF
• Status: Recruiting
• Phase: N/A
• Start date: November 22, 2023
• Est. completion date: September 30, 2024

Study information

• Verified date: March 2024
• Source: Aarhus University Hospital
• Contact: Niels A. Jespersen, MD
• Phone: +45 22950990
• Email: nije[@]clin.au.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Systolic

Intervention

Other:
• Sodium lactate infusion
Dosage of sodium-lactate: 0.5 mol/L; 3 mL/kg/time; maximal 300 mL/hour.
• Sodium lactate ingestion
Oral dose is equal to the i.v. dose.

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital	Aarhus	Region Midtjylland

Sponsors (1)

Lead Sponsor	Collaborator
Henrik Wiggers

Country where clinical trial is conducted

Denmark, 

References & Publications (12)

Brooks GA. The tortuous path of lactate shuttle discovery: From cinders and boards to the lab and ICU. J Sport Health Sci. 2020 Sep;9(5):446-460. doi: 10.1016/j.jshs.2020.02.006. Epub 2020 Feb 21. — View Citation

Engelstoft MS, Park WM, Sakata I, Kristensen LV, Husted AS, Osborne-Lawrence S, Piper PK, Walker AK, Pedersen MH, Nohr MK, Pan J, Sinz CJ, Carrington PE, Akiyama TE, Jones RM, Tang C, Ahmed K, Offermanns S, Egerod KL, Zigman JM, Schwartz TW. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab. 2013 Sep 4;2(4):376-92. doi: 10.1016/j.molmet.2013.08.006. eCollection 2013. — View Citation

Goodwin ML, Harris JE, Hernandez A, Gladden LB. Blood lactate measurements and analysis during exercise: a guide for clinicians. J Diabetes Sci Technol. 2007 Jul;1(4):558-69. doi: 10.1177/193229680700100414. — View Citation

Johannsson E, Lunde PK, Heddle C, Sjaastad I, Thomas MJ, Bergersen L, Halestrap AP, Blackstad TW, Ottersen OP, Sejersted OM. Upregulation of the cardiac monocarboxylate transporter MCT1 in a rat model of congestive heart failure. Circulation. 2001 Aug 7;104(6):729-34. doi: 10.1161/hc3201.092286. — View Citation

Leverve XM, Boon C, Hakim T, Anwar M, Siregar E, Mustafa I. Half-molar sodium-lactate solution has a beneficial effect in patients after coronary artery bypass grafting. Intensive Care Med. 2008 Oct;34(10):1796-803. doi: 10.1007/s00134-008-1165-x. Epub 2008 Jun 18. — View Citation

Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, Sutton SW, Li X, Yun SJ, Mirzadegan T, Mazur C, Kamme F, Lovenberg TW. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem. 2009 Jan 30;284(5):2811-2822. doi: 10.1074/jbc.M806409200. Epub 2008 Dec 1. — View Citation

Murashige D, Jang C, Neinast M, Edwards JJ, Cowan A, Hyman MC, Rabinowitz JD, Frankel DS, Arany Z. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science. 2020 Oct 16;370(6514):364-368. doi: 10.1126/science.abc8861. — View Citation

Nalos M, Leverve X, Huang S, Weisbrodt L, Parkin R, Seppelt I, Ting I, Mclean A. Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial. Crit Care. 2014 Mar 25;18(2):R48. doi: 10.1186/cc13793. — View Citation

Nielsen R, Moller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, Harms HJ, Frokiaer J, Eiskjaer H, Jespersen NR, Mellemkjaer S, Lassen TR, Pryds K, Botker HE, Wiggers H. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation. 2019 Apr 30;139(18):2129-2141. doi: 10.1161/CIRCULATIONAHA.118.036459. — View Citation

Offermanns S. Hydroxy-Carboxylic Acid Receptor Actions in Metabolism. Trends Endocrinol Metab. 2017 Mar;28(3):227-236. doi: 10.1016/j.tem.2016.11.007. Epub 2017 Jan 10. — View Citation

Pedersen MGB, Sondergaard E, Nielsen CB, Johannsen M, Gormsen LC, Moller N, Jessen N, Rittig N. Oral lactate slows gastric emptying and suppresses appetite in young males. Clin Nutr. 2022 Feb;41(2):517-525. doi: 10.1016/j.clnu.2021.12.032. Epub 2021 Dec 24. — View Citation

Vincent JL, Quintairos E Silva A, Couto L Jr, Taccone FS. The value of blood lactate kinetics in critically ill patients: a systematic review. Crit Care. 2016 Aug 13;20(1):257. doi: 10.1186/s13054-016-1403-5. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.