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A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Published on: July 17, 2012
Modeling Cardiac Dysfunction Following Traumatic Hemorrhage Injury: Impact on Myocardial Integrity
Johanna Wall1, Sriveena Naganathar1, Banjerd Praditsuktavorn1
1Centre for Trauma Sciences, Neuroscience, Surgery and Trauma, Blizard Institute, Queen Mary University of London, London, United Kingdom.
Insights
Trauma hemorrhage shock causes cardiac dysfunction in mice, mimicking human trauma patients. This study reveals myocardial injury and reduced heart function, offering a model for developing new treatments.
Area of Science:
- Cardiovascular Biology
- Trauma Pathophysiology
- Mitochondrial Biology
Background:
- Cardiac dysfunction (CD) is a significant cause of mortality in trauma survivors.
- The underlying pathophysiology of CD after severe injury remains poorly understood.
- Biomarkers indicate myocardial injury, but the precise mechanisms are unknown.
Purpose of the Study:
- To investigate the pathophysiology of acute cardiac dysfunction following trauma hemorrhage shock (THS).
- To establish and utilize a mouse model of THS-induced CD for studying myocardial integrity and function.
- To assess the impact of THS and resuscitation on cardiac performance and cardiomyocyte health.
Main Methods:
- A mouse model of trauma (soft tissue and bone fracture) and hemorrhage (MABP < 35 mmHg or <65 mmHg) was employed.
- Echocardiography guided fluid resuscitation to baseline stroke volume was performed.
- Cardiac function, myocardial injury biomarkers (H-FABP, troponin I), histopathology, flow cytometry, and ultrastructural analysis were assessed.
Main Results:
- Severe THS induced significant reductions in cardiac output and stroke volume.
- Elevated heart fatty acid-binding protein (H-FABP) and troponin I indicated myocardial injury.
- Histopathology revealed leukocyte infiltration, sarcomere/mitochondrial disorganization, and signs of apoptosis.
- Cardiac dysfunction persisted despite resuscitation, with significant cardiomyocyte damage.
Conclusions:
- Trauma hemorrhage shock in mice causes cardiomyocyte damage and impaired myocardial function, mirroring clinical CD in trauma patients.
- This validated THS model provides a platform for understanding CD mechanisms.
- The model can aid in developing and testing novel cardioprotective therapies to improve outcomes after severe injury.
Abstract:
Cardiac dysfunction (CD) importantly contributes to mortality in trauma patients, who survive their initial injuries following successful hemostatic resuscitation. This poor outcome has been correlated with elevated biomarkers of myocardial injury, but the pathophysiology triggering this CD remains unknown. We investigated the pathophysiology of acute CD after trauma using a mouse model of trauma hemorrhage shock (THS)-induced CD with echocardiographic guidance of fluid resuscitation, to assess the THS impact on myocardial integrity and function. Mice were subjected to trauma (soft tissue and bone fracture) and different degrees of hemorrhage severity (pressure controlled ~MABP < 35 mmHg or <65 mmHg) for 1 h, to characterize the acute impact on cardiac function. In a second study, mice were subjected to trauma and hemorrhage (MABP < 35 mmHg) for 1 h, then underwent two echocardiographic-guided resuscitations to baseline stroke volume at 60 and 120 min, and were monitored up to 180 min to study the longer impact of THS following resuscitation. Naïve and sham animals were used as controls. At 60 min post-THS injury, animals showed a lower cardiac output (CO) and stroke volume (SV) and an early rise of heart fatty acid-binding protein (H-FABP = 167 ± 38 ng/ml; 90% increase from shams, 3.54 ± 3.06 ng/ml), when subjected to severe hemorrhage and injury. Despite resuscitation, these animals maintained lower CO (6 ml/min vs. 23 ml/min), lower SV (10 μl vs. 46 μl; both ~75% decreased), and higher H-FABP (levels (340 ± 115 ng/ml vs. 10.3 ± 0.2 ng/ml; all THS vs. shams, P < 0.001) at 180 min post-THS injury. Histopathological and flow-cytometry analysis of the heart confirmed an influx of circulatory leukocytes, compared to non-injured hearts. Myocardial injury was supported by an increase of troponin I and h-FABP and the widespread ultrastructural disorganization of the morphology of sarcomeres and mitochondria. DNA fragmentation and chromatin condensation driven by leakage of apoptosis-inducing factor (AIF) may suggest a mitochondria-driven progressive cell death. THS modeling in the mouse results in cardiomyocyte damage and reduced myocardial function, which mimics the cardiac dysfunction seen in trauma patients. This CD model may, therefore, provide further understanding to the mechanisms underlying CD and act as a tool for developing cardioprotective therapeutics to improve survival after injury.
