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Modeling Cardiac Dysfunction Following Traumatic Hemorrhage Injury: Impact on Myocardial Integrity.

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 ?l vs. 46 ?l; 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.

SUBMITTER: Wall J

PROVIDER: S-EPMC6908477 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Modeling Cardiac Dysfunction Following Traumatic Hemorrhage Injury: Impact on Myocardial Integrity.

Wall Johanna J Naganathar Sriveena S Praditsuktavorn Banjerd B Bugg Oscar F OF McArthur Simon S Thiemermann Christoph C Tremoleda Jordi L JL Brohi Karim K

Frontiers in immunology 20191206

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 ...[more]

PMID: 31866998

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Project description:BACKGROUND:Proteomic analysis of cerebrospinal fluid (CSF) has shown great promise in identifying potential markers of injury in neurodegenerative diseases [1-13]. Here we compared CSF proteomes in healthy individuals, with patients diagnosed with traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) in order to characterize molecular biomarkers which might identify these different clinical states and describe different molecular mechanisms active in each disease state. METHODS:Patients presenting to the Neurosurgery service at the Louisiana State University Hospital-Shreveport with an admitting diagnosis of TBI or SAH were prospectively enrolled. Patients undergoing CSF sampling for diagnostic procedures were also enrolled as controls. CSF aliquots were subjected to 2-dimensional gel electrophoresis (2D GE) and spot percentage densities analyzed. Increased or decreased spot expression (compared to controls) was defined in terms of in spot percentages, with spots showing consistent expression change across TBI or SAH specimens being followed up by Matrix-Assisted Laser Desorption/Ionization mass spectrometry (MALDI-MS). Polypeptide masses generated were matched to known standards using a search of the NCBI and/or GenPept databases for protein matches. Eight hundred fifteen separately identifiable polypeptide migration spots were identified on 2D GE gels. MALDI-MS successfully identified 13 of 22 selected 2D GE spots as recognizable polypeptides. RESULTS:Statistically significant changes were noted in the expression of fibrinogen, carbonic anhydrase-I (CA-I), peroxiredoxin-2 (Prx-2), both ? and ? chains of hemoglobin, serotransferrin (Tf) and N-terminal haptoglobin (Hp) in TBI and SAH specimens, as compared to controls. The greatest mean fold change among all specimens was seen in CA-I and Hp at 30.7 and -25.7, respectively. TBI specimens trended toward greater mean increases in CA-I and Prx-2 and greater mean decreases in Hp and Tf. CONCLUSIONS:Consistent CSF elevation of CA-I and Prx-2 with concurrent depletion of Hp and Tf may represent a useful combination of biomarkers for the prediction of severity and prognosis following brain injury.

Project description:OBJECTIVES:To examine the impact of early myocardial workload on in-hospital mortality following isolated severe traumatic brain injury. DESIGN:Retrospective cohort study. SETTING:Data from the National Trauma Databank, a multicenter trauma registry operated by the American College of Surgeons, from 2007 to 2014. PATIENTS:Adult patients with isolated severe traumatic brain injury (defined as admission Glasgow Coma Scale < 8 and head Abbreviated Injury Score ? 4). INTERVENTIONS:Admission rate-pressure product, categorized into five levels based on published low, normal, and submaximal human thresholds: less than 5,000; 5,000-9,999; 10,000-14,999; 15,000-19,999; and greater than 20,000. MEASUREMENTS AND MAIN RESULTS:Data from 26,412 patients were analyzed. Most patients had a normal rate-pressure product (43%), 35% had elevated rate-pressure product, and 22% had depressed rate-pressure product at hospital admission. Compared with the normal rate-pressure product group, in-hospital mortality was 22 percentage points higher in the lowest rate-pressure product group (cumulative mortality, 50.2%; 95% CI, 43.6-56.9%) and 11 percentage points higher in the highest rate-pressure product group (cumulative mortality, 39.2%; 95% CI, 37.4-40.9%). The lowest rate-pressure product group was associated with a 50% increased risk of mortality, compared with the normal rate-pressure product group (adjusted relative risk, 1.50; 95% CI, 1.31-1.76%; p < 0.0001), and the highest rate-pressure product group was associated with a 25% increased risk of mortality, compared with the normal rate-pressure product group (adjusted relative risk, 1.25; 95% CI, 1.18-1.92%; p < 0.0001). This relationship was blunted with increasing age. Among patients with normotension, those with depressed and elevated rate-pressure products experienced increased mortality. CONCLUSIONS:Adults with severe traumatic brain injury experience heterogeneous myocardial workload profiles that have a "U-shaped" relationship with mortality, even in the presence of a normal blood pressure. Our findings are novel and suggest that cardiac performance is important following severe traumatic brain injury.

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Modeling Cardiac Dysfunction Following Traumatic Hemorrhage Injury: Impact on Myocardial Integrity.

Publications

Modeling Cardiac Dysfunction Following Traumatic Hemorrhage Injury: Impact on Myocardial Integrity.

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