Clinical trial NCT05148117: Mitochondrial Dysfunction Contributes to Sepsis Induced Cardiac Dysfunction
Official title: Mitochondrial Dysfunction Contributes to Sepsis Induced Cardiac Dysfunction
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Sepsis
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
First posted: 2021-12-08
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: study patients admitted to the intensive care unit with suspected sepsis shock will be enrolled and compared to the control group.

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Mitochondrial dysfunction characterized by bioenergetic changes
timeFrame: within 6 hours of admission to the ICU
measure: Mitochondrial dysfunction characterized by bioenergetic changes
timeFrame: within 72 hours post admission
measure: Mitochondrial dysfunction characterized by bioenergetic changes
timeFrame: after clinical recovery from sepsis (approximately 1 month)
measure: Mitochondrial function in heart
timeFrame: within 6 hours of admission to the ICU
measure: Mitochondrial function in heart
timeFrame: within 72 hours post admission
measure: Mitochondrial function in heart
timeFrame: after clinical recovery from sepsis (approximately 1 month)
measure: Mitochondria and SICD
timeFrame: within 6 hours of admission to the ICU
measure: Mitochondria and SICD
timeFrame: within 72 hours post admission
measure: Mitochondria and SICD
timeFrame: after clinical recovery from sepsis (approximately 1 month)
measure: Mitochondrial mechanisms to influence SICD
timeFrame: within 6 hours of admission to the ICU
measure: Mitochondrial mechanisms to influence SICD
timeFrame: within 72 hours post admission
measure: Mitochondrial mechanisms to influence SICD
timeFrame: after clinical recovery from sepsis (approximately 1 month)
measure: Mitochondrial bioenergetics and mtDNA DAMPs
timeFrame: within 6 hours of admission to the ICU
measure: Mitochondrial bioenergetics and mtDNA DAMPs
timeFrame: within 72 hours post admission
measure: Mitochondrial bioenergetics and mtDNA DAMPs
timeFrame: after clinical recovery from sepsis (approximately 1 month)
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
Study officials:
affiliation: Department of Anesthesiology and Perioperative Medicine, Division of Critical Care Medicine
name: Riaz Karukappadath, MD
role: PRINCIPAL_INVESTIGATOR
References: