NCT05148117

Mitochondrial Dysfunction Contributes to Sepsis Induced Cardiac Dysfunction

• Status: Withdrawn
• Phase: —
• Study type: Observational
• Enrollment: 0 (actual)
• Sponsor: University of Alabama at Birmingham · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Detailed 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.

Conditions

• Sepsis

Interventions

Type	Name	Description
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.
DIAGNOSTIC_TEST	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.

Timeline

• Start date: 2025-12-10
• Primary completion: 2026-01-14
• Completion: 2026-01-14
• First posted: 2021-12-08
• Last updated: 2026-02-20

Locations

1 site across 1 country: United States