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.
Highlights
Trauma is a large and growing problem worldwide, accounting for 10.1% of the global burden of disease [1], with half of all trauma deaths being due to excessive bleeding and the subsequent severe shock [2, 3]
In the traumatic hemorrhagic shock state (THS) 30–40 group, with over 30% blood loss, cardiac output was 87% lower than baseline (Figure 1E) at 1 h post trauma compared to sham and trauma-only groups (p < 0.001, Figure 1E)
Our study confirms that the preclinical modeling approach that we have developed physiologically and biochemically mirrors the cardiac dysfunction seen in bleeding trauma patients
Summary
Trauma is a large and growing problem worldwide, accounting for 10.1% of the global burden of disease [1], with half of all trauma deaths being due to excessive bleeding and the subsequent severe shock [2, 3]. Over half of all critically injured trauma patients admitted to intensive care develop cardiovascular dysfunction within the first 48 h, of which 20% will die [6]. Identifying these patients early in their care and rescuing them from this downward trajectory would have a dramatic impact on trauma mortality. There is some pre-clinical evidence for the development of cardiac injury and dysfunction arising as an indirect consequence of trauma and hemorrhage in pigs [13] and in rodents [14,15,16], suggesting a local cardiac inflammatory response as the main driver of cardiomyocyte structural and functional damage
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