Mitochondrial Dysfunction Contributes to Sepsis Induced Cardiac Dysfunction

The University of Alabama at Birmingham

Status: Not yet enrolling

Conditions: Sepsis

Treatments: Diagnostic Test: Control Group - Diagnostic Measurements; Diagnostic Test: Suspected Sepsis Group - Diagnostic Measurements

Study type: Observational

Funder types: Other

Identifiers

NCT05148117

300007609

Details and patient eligibility

About

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.

Full 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.

Enrollment: 40 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

40 participants in 2 patient groups

suspected sepsis group

Description:

We will perform a prospective observational study of patients admitted to the intensive care units (ICU) with suspected sepsis or septic shock.

Treatment:

Diagnostic Test: Suspected Sepsis Group - Diagnostic Measurements

control group

Description:

This group will be compared to suspected sepsis or sepsis shock patients. The control group will be age matched, gender-matched, and cardiovascular risk-factor matched controls.

Treatment:

Diagnostic Test: Control Group - Diagnostic Measurements