Mitochondrial Dysfunction Contributes to Sepsis Induced Cardiac Dysfunction
试验速览
- 阶段
- 不适用
- 状态
- 撤回
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Mitochondria and SICD
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects 18 years old
- •With clinical symptoms suggestive of sepsis Control Group
- •age matched
- •gender matched
- •cardiovascular risk factor matched
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Suspected Sepsis Group - Diagnostic Measurements (Diagnostic Test)
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.
干预措施: Control Group - Diagnostic Measurements (Diagnostic Test)
结局指标
主要结局
Mitochondria and SICD
时间窗: after clinical recovery from sepsis (approximately 1 month)
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
Mitochondrial mechanisms to influence SICD
时间窗: after clinical recovery from sepsis (approximately 1 month)
changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation.
Mitochondrial function in heart
时间窗: after clinical recovery from sepsis (approximately 1 month)
changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation
Mitochondrial dysfunction characterized by bioenergetic changes
时间窗: after clinical recovery from sepsis (approximately 1 month)
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.
Mitochondrial bioenergetics and mtDNA DAMPs
时间窗: after clinical recovery from sepsis (approximately 1 month)
determine the mitochondrial bioenergetic profiles from platelets isolated from blood samples collected from sepsis patients and controls.
Mitochondrial dysfunction characterized by bioenergetic changes
时间窗: within 6 hours of admission to the ICU
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.
Mitochondrial dysfunction characterized by bioenergetic changes
时间窗: within 72 hours post admission
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.
Mitochondrial function in heart
时间窗: within 6 hours of admission to the ICU
changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation
Mitochondrial function in heart
时间窗: within 72 hours post admission
changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation
Mitochondria and SICD
时间窗: within 6 hours of admission to the ICU
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
Mitochondria and SICD
时间窗: within 72 hours post admission
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
Mitochondrial mechanisms to influence SICD
时间窗: within 6 hours of admission to the ICU
changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation.
Mitochondrial mechanisms to influence SICD
时间窗: within 72 hours post admission
changes in mitochondrial bioenergetics associated with sepsis can result in differential releases of mtDNA DAMPs, which contribute in inflammation.
Mitochondrial bioenergetics and mtDNA DAMPs
时间窗: within 6 hours of admission to the ICU
determine the mitochondrial bioenergetic profiles from platelets isolated from blood samples collected from sepsis patients and controls.
Mitochondrial bioenergetics and mtDNA DAMPs
时间窗: within 72 hours post admission
determine the mitochondrial bioenergetic profiles from platelets isolated from blood samples collected from sepsis patients and controls.
次要结局
未报告次要终点
研究者
Riaz Karukappadath
Principal Investigator
University of Alabama at Birmingham