Mitochondrial Dysfunction Contributes to Sepsis Induced Cardiac Dysfunction

Sepsis Clinical Trial

Official title:

Mitochondrial Dysfunction Contributes to Sepsis Induced Cardiac Dysfunction

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05148117
• Other study ID #: 300007609
• Status: Not yet recruiting
• Start date: December 10, 2024
• Est. completion date: May 7, 2025

Study information

• Verified date: March 2024
• Source: University of Alabama at Birmingham
• Contact: Kera N Marshall
• Phone: 205-934-4042
• Email: keramarshall[@]uabmc.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This proposal hypothesizes that mitochondrial bioenergetics in the patient will correspond to mtDNA DAMPs levels and markers of inflammation. We predict these will serve as a prognostic indicator of Sepsis induced cardiac dysfunction (SICD) outcomes. Successful completion of these studies will provide a clearer understanding of the etiology of SICD development and therefore will have a high impact on biomedical research by identifying a new mechanism for understanding sepsis induced organ failure. Importantly, they will also provide a means for more directed and focused therapies, based upon individual bioenergetic/mitochondrial-mediated inflammation profiles. The combined, complementary expertise of the Mentor/co-primary investigators (Drs. Mathru and Ballinger) provide an excellent combination in both basic and translational research. They also have experience conducting studies and publications that will strengthen this research project. Importantly, the methods for characterizing mitochondrial bioenergetics from platelets were developed here at UAB, and methods for quantitative assessment of mtDNA DAMPs have been recently developed.

Description:

Sepsis induced cardiac dysfunction (SICD) occurs in ~ 50% of the patients with severe sepsis and septic shock, with significant implications for patient's survival. Currently, the precise pathophysiological mechanisms leading to cardiac dysfunction are not fully understood, nor is there an effective therapy for SICD except antibiotics, source control and restoration of hemodynamics to improve organ perfusion.

SICD is characterized by minimal cell death, normal coronary perfusion, preserved tissue oxygen tension and reversibility in survivors. These characteristics point toward an oxygen utilization problem due to mitochondrial dysfunction; interestingly, sepsis mouse models demonstrated an improvement in cardiac function and decreased mortality when they were treated with mitochondrial targeted therapies, consistent with a growing body of evidence that suggests dysregulated mitochondrial metabolism plays a pivotal role in the pathogenesis of SICD. Ultrastructural and functional abnormalities of mitochondria have also been demonstrated in early sepsis, and reactive oxygen species (ROS) generated from mitochondria along with calcium overload trigger mitochondrial permeability transition pore (mPTP) opening which facilitates the externalization of mitochondrial DNA (mtDNA) fragments. These mtDNA fragments, or mtDNA Damage Associated Molecular Patterns (mtDNA DAMPs), activate innate immune response pathways - these pathways are well known to be significant components of intramyocardial inflammation.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: May 7, 2025
• Est. primary completion date: March 7, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subjects 18 years old

• With clinical symptoms suggestive of sepsis Control Group

• age matched

• gender matched

• cardiovascular risk factor matched

Exclusion Criteria:

• n/a

Related Conditions & MeSH terms

• Mitochondrial Diseases
• Sepsis
• Toxemia

Intervention

Diagnostic Test:
• Suspected Sepsis Group - Diagnostic Measurements
Blood samples (7.5ml) will be collected in cell free DNA collection tubes cfDNA will be extracted with the use of MagMAX cell free DNA isolation kit. Quantitative PCR will determine the total cfDNA. cfDNA (5micro litr) will be subjected to bisulphide conversion with use of EZ DNA methylation kit (Zymo research). We will perform digital PCR for interrogating bisulphide treated cfDNA for FMA 101A locus with the use of Quant Studio 3D digital PCR system. Copy numbers of unmethylated FAM 101A locus as determined by d PCR in the sample will be expressed as the copy numbers of cardiomyocyte specific cfDNA per plasma volume.Inflammatory markers IL-6.IL-8, IL 1-18 and C-reactive protein (CRP) will be measured using commercial assays. Speckle tracking imaging will be used to obtain tissue displacement, velocity, strain, and strain rate in radial longitudinal and circumferential planes EF and FS will be determined by conventional methods.
• Control Group - Diagnostic Measurements
Blood samples (7.5ml) will be collected in cell free DNA collection tubes cfDNA will be extracted with the use of MagMAX cell free DNA isolation kit. Quantitative PCR will determine the total cfDNA. cfDNA (5micro litr) will be subjected to bisulphide conversion with use of EZ DNA methylation kit (Zymo research). We will perform digital PCR for interrogating bisulphide treated cfDNA for FMA 101A locus with the use of Quant Studio 3D digital PCR system. Copy numbers of unmethylated FAM 101A locus as determined by d PCR in the sample will be expressed as the copy numbers of cardiomyocyte specific cfDNA per plasma volume.Inflammatory markers IL-6.IL-8, IL 1-18 and C-reactive protein (CRP) will be measured using commercial assays. Speckle tracking imaging will be used to obtain tissue displacement, velocity, strain, and strain rate in radial longitudinal and circumferential planes EF and FS will be determined by conventional methods.

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama

Sponsors (1)

Lead Sponsor	Collaborator
University of Alabama at Birmingham

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mitochondrial dysfunction characterized by bioenergetic changes	that mitochondrial dysfunction, characterized by bioenergetic changes (dysfunction) is associated with sepsis in humans, and will be significantly linked with mtDNA DAMPs levels and inflammatory markers in the pathophysiology of SICD.	within 6 hours of admission to the ICU
Primary	Mitochondrial dysfunction characterized by bioenergetic changes	that mitochondrial dysfunction, characterized by bioenergetic changes (dysfunction) is associated with sepsis in humans, and will be significantly linked with mtDNA DAMPs levels and inflammatory markers in the pathophysiology of SICD.	within 72 hours post admission
Primary	Mitochondrial dysfunction characterized by bioenergetic changes	that mitochondrial dysfunction, characterized by bioenergetic changes (dysfunction) is associated with sepsis in humans, and will be significantly linked with mtDNA DAMPs levels and inflammatory markers in the pathophysiology of SICD.	after clinical recovery from sepsis (approximately 1 month)
Primary	Mitochondrial function in heart	changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation	within 6 hours of admission to the ICU
Primary	Mitochondrial function in heart	changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation	within 72 hours post admission
Primary	Mitochondrial function in heart	changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation	after clinical recovery from sepsis (approximately 1 month)
Primary	Mitochondria and SICD	examining the potential roles for increased reactive oxygen species (ROS) and nitric oxide (NO) production in SICD using mouse models of sepsis have shown that genetic and/or pharmacologic manipulation of these species decreased oxidative stress, increased ATP generation and restored cardiac function in sepsis	within 6 hours of admission to the ICU
Primary	Mitochondria and SICD	examining the potential roles for increased reactive oxygen species (ROS) and nitric oxide (NO) production in SICD using mouse models of sepsis have shown that genetic and/or pharmacologic manipulation of these species decreased oxidative stress, increased ATP generation and restored cardiac function in sepsis	within 72 hours post admission
Primary	Mitochondria and SICD	examining the potential roles for increased reactive oxygen species (ROS) and nitric oxide (NO) production in SICD using mouse models of sepsis have shown that genetic and/or pharmacologic manipulation of these species decreased oxidative stress, increased ATP generation and restored cardiac function in sepsis	after clinical recovery from sepsis (approximately 1 month)
Primary	Mitochondrial mechanisms to influence SICD	changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation.	within 6 hours of admission to the ICU
Primary	Mitochondrial mechanisms to influence SICD	changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation.	within 72 hours post admission
Primary	Mitochondrial mechanisms to influence SICD	changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation.	after clinical recovery from sepsis (approximately 1 month)
Primary	Mitochondrial bioenergetics and mtDNA DAMPs	determine the mitochondrial bioenergetic profiles from platelets isolated from blood samples collected from sepsis patients and controls.	within 6 hours of admission to the ICU
Primary	Mitochondrial bioenergetics and mtDNA DAMPs	determine the mitochondrial bioenergetic profiles from platelets isolated from blood samples collected from sepsis patients and controls.	within 72 hours post admission
Primary	Mitochondrial bioenergetics and mtDNA DAMPs	determine the mitochondrial bioenergetic profiles from platelets isolated from blood samples collected from sepsis patients and controls.	after clinical recovery from sepsis (approximately 1 month)