Mitochondrial Dysfunction Contributes to Sepsis Induced Cardiac Dysfunction

NCT05148117 | Withdrawn

• 2 other identifiers: 300007609UAB
• Study Type: observational
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Sepsis

Outcome Measures

Primary Outcomes (15)

• 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

• 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

• 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)

• 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

• 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

• 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)

• 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

• 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

• 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)

• 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

• 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

• 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)

• 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

• 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

• 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)

Study Arms (2)

suspected sepsis group

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

Diagnostic Test: Suspected Sepsis Group - Diagnostic Measurements

control group

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.

Diagnostic Test: Control Group - Diagnostic Measurements

Interventions

Suspected Sepsis Group - Diagnostic Measurements DIAGNOSTIC_TEST

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.

suspected sepsis group

Control Group - Diagnostic Measurements DIAGNOSTIC_TEST

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• Subjects 18 years old
• With clinical symptoms suggestive of sepsis Control Group
• age matched
• gender matched
• cardiovascular risk factor matched

You may not qualify if:

• n/a

Sponsors & Collaborators

• University of Alabama at Birmingham: lead

Study Sites (1)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

MeSH Terms

Conditions

Sepsis

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Riaz Karukappadath, MD

  Department of Anesthesiology and Perioperative Medicine, Division of Critical Care Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 24, 2021
• First Posted: December 8, 2021
• Study Start: December 10, 2025
• Primary Completion: January 14, 2026
• Study Completion: January 14, 2026
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)