Biochemical markers of myocardial contusion after blunt chest trauma

Abstract

One of the most common manifestations of cardiac injury because of trauma is myocardial contusion. Today, the blurred definition and wide range of nonspecific clinical presentations led to absence in consensus of diagnostic pathways and criteria. Currently, the marker of cardiac injury measured at clinical level is troponin and instrumental diagnostic tool is ECG. The patients with elevated troponin level after the chest trauma should be suspected to have myocardial contusion as cardiogenic shock or arrhythmia might take place as a complication. The release of DAMPs after the trauma has been observed as a part of inflammatory response to it. HMGB1 protein and histone levels were found to be elevated in patients with trauma and associated to recruit the inflammation. In this review the potential of these molecules to be used as diagnostic markers of myocardial contusion is discussed. Moreover, the obstacles for implementing DAMPS to clinical protocols and future research directions are included.

Introduction

Trauma is one of the most common reasons for visits to hospital and emergency. It is a significant burden to the healthcare system as it is one of the main causes of death and physical impairment among the working population [1]. Polytrauma is defined as trauma with several injuries, affecting multiple organ systems, resulting in threat to life and disabilities including psychosocial, physical and cognitive [2]. Chest trauma is a frequent form of trauma, where the impact causes the injury of organs located within the thoracic cage: heart, lungs, esopahus, trachea, lymph nodes. Among the patients with polytrauma more than 25% of mortality is due to chest trauma involvement, while patients with chest trauma only, the mortality is up to more than half of the cases [3]. The blunt cardiac trauma causes damage to the cardiovascular system due to direct hit to the chest or and indirectly by systemic reaction. Cardiac trauma is one of the rare complications of blunt chest trauma, which is associated with higher morbidity and mortality [1]. The incidence of cardiac trauma depends on the type of trauma, so for example in blunt trauma it happens in 10% of patients, but in high impact trauma it is reported to be as high as 70% [4]. Myocardial contusion is one of the most common manifestations of cardiac injury. However, it is often underdiagnosed as it might present without symptoms and there is no consensus on diagnostic methods. As a result, up to ¼ of the patients might die due to delayed arrhythmia [5]. It has no clear diagnostic criteria, no treatment guidelines. The patients with polytrauma undergo activation of different body systems, including the immune system, causing complicated inflammatory response and immunomodulation [6].

In this review the pathophysiology of chest trauma is described in detail, particularly the secondary immune response pathway is reviewed, adding what local changes occur and how distant systems can be damaged due to systemic reaction. To be specific, myocardial contusion as a type of blunt cardiac trauma is the focus of the given review. The objective of this work is to review specific molecules, which are associated with myocardial contusion in terms of their pathophysiological pathway of heart damage and their potential use in clinical settings.

Pathophysiology of trauma

Severe trauma affects the body in several ways, including complicated communication between different body systems. One of the major effects is basically loss of blood, which can cause hypovolemic shock in case of rapid blood loss, or it can start with hypoperfusion, initially with local endothelial damage [7]. Later, this endothelial damage spreads to other organs, causing change in permeability of all organ systems, while intestine and lungs are affected more.

Then, the tissue injury initiates the inflammatory response to it by activating body systems [6]. Although there are no pathogens within the body, the stress associated with trauma and death of cells due to direct hit causes the inflammatory response. The term sterile inflammation is used to describe this phenomenon and is injuries caused by chemicals, reperfusion or trauma [8].

The basic pathophysiology behind inflammation is recruitment of leukocytes, which was triggered by molecular patterns of pathogens. In sterile inflammation the immunity is stimulated by similar patterns, which appear because of damage caused to the tissue. So-called Damage Associated Molecular Patterns (DAMPs) are molecules released from intracellular and extracellular space due to the injury of tissue. There is a wide range of molecules, which have DAMPs, such as high mobility group box proteins, heat-shock proteins, nucleic acids, proteins including interleukins and histones [9]. This step is essential for the subsequent tissue repair.

These DAMPS are recognized by Pattern Recognition Receptors (PRRs) expressed by a variety of immune cells (Fig. 1). The attachment of DAMP to PRR results in release of proinflammatory cytokines, vasoactive substances, reactive oxygen species [10]. Moreover, there is a release of complement factors, acute phase proteins, neuroendocrine mediators and molecules of the coagulation system, which recruit further response to the trauma [11].

Fig. 1.

Pathophysiology of Myocardial Contusion

The systems are correlated by activating each other and enhancing the response to trauma overall. For instance, activation of coagulation pathways and the kallikrein-kinin system occurs due to DAMPs. From a complement system perspective, C1q, C3b and mannose-binding lectin are activated by DAMPs and further enhance cellular response. Interestingly, activation of the complement system occurs by formation of activation products, including C3a, C5a, MAC and consumption of the other complement factors. This might happen as early as initiation of haemorrhagic shock even before the patient is delivered to hospital [12]. The extent to which the complement system is activated is essential in recruiting further immune response and outcome of the trauma overall.

Besides activation of the complement, the coagulation cascade is activated after the trauma. Moreover, some studies revealed an association with the higher mortality of almost half of the patients due to uncontrollable bleeding [13]. Although the trauma outcome depends on bleeding control and absence of shock, the severity of trauma defines the coagulation response. Normally, hemostasis is based on formation of clot to the injury site, which not only stops bleeding, but also stimulates healing. In case of severe trauma there is a dynamic change in coagulation phenotypes depending on time [14]. To be precise, all factors of the coagulation cascade are affected in such patients. Early trauma induced coagulopathy presented by bleeding and is a result of sympathoadrenal activation, causing increased expression of activated protein C, tissue plasminogen activator (tPA). The late trauma induced coagulopathy is a hypercoagulable state. The transition from these two responses depends on the extent of tissue damage. Commonly, the early one happens within 6 h and late on within 24, therefore biological markers should be measured related to the timing [14].

“Two hit” theory

The two-hit theory is essential for understanding the mechanism of inflammation in patients with polytrauma to optimize the interventions to patients. It explains two major impacts of the trauma, which affect the body in a different way to make timely effective interventions to prevent organ injury in polytrauma patients [15]. According to this theory, the first hit is damage to the organ and tissue, giving the load from trauma itself. It causes local responses such as activating the immune system, hypoxia and decreased blood pressure aiding in stimulating the reparative mechanisms [11]. Here the pathophysiology is characterized by release of pro-inflammatory cytokines, complements, proteins of the coagulation system and mediators to recruit the immune cells at the place of the injury. The second hit is due to antigenic load, or consequences of the first load. Generally, it is injuries related to ischemia and reperfusion, metabolic acidosis, infections due to surgical interventions or other iatrogenic interventions such as tubes, catheters [11]. Understanding the pathophysiology of both hits aids in defining the therapy applied to polytrauma patients to prevent further complications and secondary organ damage.

Blunt cardiac trauma

Blunt cardiac trauma can be categorised according to the mechanism of the injury formation. Shoar et al. (2021) suggested six categories such as direct hit to the chest, fracture of the sternum, causing heart compression, injury in the result of speed change, hydraulic effect and blast injury [4]. In comparison, Huis in’t Veld et al. (2018) described blunt cardiac traumas in correlation to which part of the heart was affected [16]. The authors highlighted anatomical compartments of the heart to be determining in outcome of the trauma and suggested following rupture types:

· Myocardial rupture is a break of the atrial and ventricular walls or papillary muscles. Most frequently it happens due to direct hits to the anterior chest. It can also take place due to increased intracardiac pressure, bidirectional pressure to heart from back and chest, rapid speed change forces, penetration by rib or sternum. As a result of those impacts, commonly right heart compartments are affected. Although strikes that took place over the left ventricle but more peripherally can occasionally cause ventricular fibrillation. Strikes not over the cardiac silhouette have never caused ventricular fibrillation. The resuscitation success is quite low, in 1/3 of case the rupture would cause acute tamponade due to haemorrhage into pericardium and if pericardial laceration is present, then massive haemorrhage directly into the thoracic cavity takes place. The mortality rate with myocardial rupture is high.

· Pericardial ruptures because of blunt trauma are not common, most cases were found accidentally after the death of the patients. Higher risk mortality is observed in cases when joined myocardial injury is present, however pericardial rupture mostly is isolated and not significant clinically. The mortality of the patient was described in patients with cardiac strangulation and exsanguination.

· Septal injury is a rare type of myocardial injury when the septum between atria or ventricles becomes lacerated due to inflammation. This ‘inflammatory perforation’ is delayed and takes place a couple days after the trauma itself. The mortality rate depends on the extent of break as the defect can require immediate intervention or treated conservatively.

· Valvular injury is another rare type of cardiac trauma. The etiology of valvular injury is rupture of papillary muscle in most cases but can also happen due to rupture of chordae tendineae, tearing of the leaflets. The injury is dependent on the heart contraction cycle, so aortic and pulmonic valves are prone to be injured during early diastole and atrioventricular valves during early systole. The clinical presentation is in accordance with the valve location and consistent with valvular regurgitation.

· Myocardial contusion diagnosis has no clear definition, although it is commonly references. The evaluation of the patient presenting with discomfort and bruising after blunt trauma will reveal ECG changes and elevation of cardiac enzymes, therefore mimicking ischemia. Moreover, due to anatomic position, the right ventricle is more frequently affected, another possible presentation is arrhythmias, including right bundle branch block, nonsustained ventricular arrhythmias, heart block. This review focuses on molecules that can be used to diagnose myocardial contusion.

· Commotio cordis known as heart disturbance is a result of trauma from an accelerated projectile, for example baseball. Commotio cordis can cause sudden cardiac death by inducing ventricular fibrillation. Commotio cordis is a phenomenon in which a sudden blunt impact to the chest causes sudden death in the absence of cardiac damage. It affects mostly adolescent male, around 15 years of age (older are less likely to be involved in ball-related sport). The risk is involvement in all sports, but particularly playing baseball, lacrosse. The impacts must occur directly over the centre of the left ventricle.

Commotio cordis is to be differentiated from cardiac contusion (contusio cordis/myocardial contusion), which appears in a situation when blunt chest trauma causes structural cardiac damage, such as observed in motor vehicular accidents [1]. Generally, cardiac traumas result from high-impact trauma in half of motor vehicle accident cases, a third during motorcycle accidents and falls from height. Therefore, when blunt trauma takes place, an attentive approach towards the patient is required as high yield cardiac diagnostic tests are not routinely done, and complications are significant [4]. Common presentations of myocardial contusion are arrhythmias, ventricular fibrillation, sudden cardiac arrest and other impaired functions, depending on the structures involved. The common complications of myocardial contusion are hemodynamic instability, cardiogenic shock, and arrhythmia. Generally according to Advanced Trauma Life Support (ATLS) there are several diagnostic algorithms such as electrocardiogram (ECG), and systemic troponin concentrations with further echocardiography or CT investigations in case of cardiac trauma suspicion [17]. However, there is a range of emerging studies investigating the level of damage associated with molecular patterns released after the trauma, that have potential to be used as a diagnostic marker of myocardial contusion.

Biochemical markers of cardiac injury

The damage or stress to the heart muscle triggers release of cardiac biomarkers, which consequently aiding in diagnostics, risk assessment and management of the condition. For biomarkers to be informative and relevant, the sensitivity and specificity of the markers should be significant [18]. There are several biomarkers that are released by heart but are unstable or less specific such as creatine kinase (CK), CK-MB isoform, aspartate aminotransferase, lactate dehydrogenase myoglobin and Heart Fatty Acid Binding protein (HFABP) [18]. CK-MB is released within the first 4 h after the ischemic event, peaks within the first day and remains elevated up to 2–4 days afterwards. It is still frequently used to diagnose acute myocardial infarction; however, it is elevated in noncardiac conditions such as muscle injury, insufficiency of thyroid gland or chronic kidney disease [18]. HFABP is released into the circulation before the troponin and is the most sensitive marker of early cardiomyocyte injury. However, as this molecule is also present in skeletal muscle cells, it is less specific in comparison to troponin [4].

Troponins are common markers of cardiac injury which is measured in polytrauma patients. The increased level of this molecule is associated with increased mortality, but there was no difference in terms of long-term survival [4]. Currently it is a key biomarker of myocardial ischemia, which is elevated within 2–3 h after the ischemic event [18]. However, different isoforms of these enzymes have different specificity for heart conditions. For example, elevated levels of troponin I revealed to have 100% sensitivity for establishing blunt chest trauma with clinical significance [19]. Moreover, it is generally accepted that combination of normal ECG and troponin I excludes the cardiac contusion and there is no need to conduct further investigations from cardiac trauma perspective [19]. However, the troponin I is released not only in case of myocardial injury, but also hypotensive shock, traumatic brain injury, hypoxemia and others. Therefore, due poor specificity of this molecule the studies on finding more biochemical markers are continuing [20].

HMGB1

One of DAMPs released due to trauma are high mobility group box 1 protein (HMGB1) or amphoterins (Fig. 2). HMGB1 is a highly conserved non-histone nuclear protein that is present in the nucleus of almost all cell types in the body and participates in DNA replication, transcription [9]. There are also cytoplasmic and extracellular forms of this protein which play a role in pathological pathways. The eHMGB1 acts by binding toll-like receptors (TLR2 and TLR4), which are receptors for pro-inflammatory pathways including advanced-glycation-end- product, NF-kB inflammasome and CXCL-12-CXCR4-NF-kB inflammasome. This signalling causes the organ injury without any infection. This activation of the immune system occurs through macrophages and dendritic cells, recruiting further pathways [9]. HMGB1 acts directly on a wide range of cells, including fibroblasts, endothelial cells and immune cells. Extracellular HMGB1 release stimulates the release of inflammatory cytokines, each of which has the effect on different organs. For example, IL-6 resulted in decreased stroke volume, cardiac output and left ventricular function [17]. Therefore, HMGB1 exposure is associated with different types of cardiac dysfunctions such as ischemic heart disease, cardiac hypertrophy, and myocarditis. Moreover, it can be used as a prognostic biomarker in myocardial infarction, chronic heart failure and myocarditis as its level is elevated in patients with these conditions. To be precise, the level of HMGB1 was peaking for the first several hours after acute onset of the disease such as STEMI and remained elevated up to 1 week after the event, while in patients with unstable angina the increased level of HMGB1 was elevated up to almost 50 months, therefore preserving risk of adverse events [17]. The study measuring the level of HMGB1 in blood after trauma revealed 30 times elevation within the first hour from injury and significant elevation up to 6 h [9]. Furthermore, the HMGB1 has not only immunostimulatory effects, but it also has an ability to delay healing by preventing apoptotic cells from being phagocytized. So, binding to phosphatidylserine on apoptotic cells prolongs the inflammation [21]. So, the role of HMGB1 is critical in pathogenesis of post-trauma inflammation and organ injury.

Fig. 2.

Biomarkers Pathways

Histones

Histones are positively charged intranuclear proteins, whose primary roles include maintaining the chromosome structure and gene regulation. Within the cell, histones outside the nucleus exist in two different forms: free ones and as nucleosomes (bound to DNA). After cell death, the content is released outside, therefore initiating the cascade of reactions resulting in formation of thrombi, autoimmune reaction and cytotoxicity (Fig. 2) [22]. First, neutrophil extracellular traps (NETs), or combination of antimicrobials, myeloperoxidase-bound DNA with histones are released when protein arginine deiminase 4 (PAD4) induces death of immune cells. During infection, it plays the role of filter and destroys pathogens, but during trauma it leads to formation of thrombi, autoimmune reaction and cytotoxicity [22]. Histones have been shown to act by binding TLR2 and TLR4 in cardiomyocytes and therefore releasing cardiodepressive inflammatory cytokines TNF and IL-1b. The degree of cardiodepression is estimated by evaluating the vasodilation caused by the molecules. Moreover, the histones were involved in pathways stimulating release of HMGB1, which also has association with cardiac dysfunction [21]. Measuring the level of histones in patients after multiple traumas revealed a significant elevation of the protein in serum. As the level changes within the timeframe, this marker can be descriptive in terms of severity of patient condition [22].

Discussion

Although it is quite logical that a hit to the heart would cause stress to cells, making them release a range of molecules that can be used as diagnostic ones, there are controversies associated with indicating DAMPs as diagnostic. First, the HMGBI was found to be elevated in a range of other inflammatory conditions like systemic lupus erythematosus, rheumatoid arthritis, vasculitis, Behcet’s disease [23]. Moreover, it is linked to non-inflammatory conditions such as breast cancer, pancreatic, colorectal cancers, myocardial infarction and others. Patients with these conditions can have elevated levels of HMGB1 up to several years after the onset of disease. However, the level of DAMP released after trauma is much higher than in these chronic conditions. Next, to outline whether HMGB1 was released after the trauma, or it has been in a body for a long time it might be useful to measure pre-trauma level of this molecule. In addition, the HMGB1 is released from vascular endothelial cells in a dose-dependent manner [24]. If so, then it is necessary to outline what are the regulation mechanisms of this release in case of myocardial contusion and measure timely changes of these molecules in blood.

Targeting DAMPs has not only diagnostic potential, but also has the potential of treatment in animals, and some has positive results. For example, the animal model studies for administration of anti-HMGB1 antibodies to mice resulted in protection from endotoxin-induced lung injury and post-surgical sepsis [24]. Other studies report that treatment with competitive inhibitors reduced the size of heart infarction [25]. Another research group reported that early administration of HMGB1 inhibitors in rats with polytrauma reduced activation of the complement system and reduced damage to organs including lungs, liver [9].

It is also important to mention that HMGB1 has been reported to have a protective role in injury too. Zeng et al. (2023) studied the effect of HMGB1 suppression on lung inflammation caused by fungal infection [26]. They revealed that absence of HMGB1 resulted in the death of neutrophils, which are key in regulating autophagy and pyroptosis, which in turn caused more severe lung inflammation in mice [26]. Another study by Sun et al. (2023) revealed that cardiomyocyte specific HMGB1 deficient mice experienced more severe injury of myocardial cells during myocarditis caused by coxsackievirus B3 [27]. So, what is the effect of HMGB1, is it damage or protection? The answer was represented by Deng et al., who investigated HMGB1 from different organs and compartments of the cell. They highlight that protective HMGB1 can be cytoplasmic, intracellular and in any organ. But what defines the end effect is the balance between TLR4 and RAGE pathways [28].

Currently, the measurement of HMGB1 and histones is not measured clinically. To be included into the clinical protocols, there are several obstacles to overcome.

1. The very first one is that the differential diagnostics need to be done, to exclude other reasons of possible release of DAMPs. As it was mentioned HMGB1 as well as histones are related to different noncardiac conditions, therefore currently it is not relevant to rely on the measurement of these biomarkers only. The combination of other diagnostic tools as ECG or echocardiography with specific diagnostic criteria should be used among the patients with polytrauma.

2. Furthermore, as it was mentioned, the levels of HMGB1 in inflammatory and non-inflammatory conditions as well as in trauma are different. Therefore, close measurement at the dynamic level should be done for differential diagnostics and to promote the accuracy of the data and correlation with prognostic outcome. It is necessary to follow up the timely changes and trends in the level of blood. Moreover, it would be useful to measure the level of HMBG1 in patients with isolated cardiac contusion compared to polytrauma patients with cardiac contusion, variation between local DAMP release measurement and systemic measurements.

3. Next, the correct techniques of measuring HMGB1 concentrations need to be used. Ottestat with his research team represented that there is a difference in HMGB1 concentrations in blood within the body, with lower concentration in arterial blood compared to venous. Moreover, it was not detected using western blotting, therefore proper planning of studies aimed on investigating this DAMP should be proceeded [29].

These DAMPS have a significant clinical potential as the elevation of level of these molecules in blood can be observed in statistically significant parts of patients. As for the future directions, the comparison of HMGB1 and histone concentrations in blood for different conditions can be done. Then, it would be useful to outline the threshold for cardiotoxicity and the protective role of antibodies for other organs. There are many more research questions to appear when studying these ones, therefore future perspectives are not limited.

Conclusion

To conclude with, the role of DAMPs in pathophysiological body response to trauma has been studied excessively lately. To be precise, the cardiodepressive effect of HMGB1 and histones opened new insights into how trauma affects organs distantly and what other long-term health consequences might take place. Today there are still limitations to clinical implementations as a range of research questions remains open. In future, there is a potential for measurement of DAMPs with prognostic purposes and use them as a potential target to avoid health consequences.

Author contributions

Conceptualization, M.B. and M.M.; methodology, P.K.; software, Z.S.; validation, M.B., M.M. and A.B.; formal analysis, M.S.; investigation, P.K.; resources, A.K.; data curation, Z.S.; writing–original draft preparation, P.K.; writing–review and editing– M.M.; visualization, A.Z.; supervision, M.B.; project administration, Z.S.; funding acquisition, M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Committee of Science of the Ministry of Science and Higher Education of the Republic of Kazakhstan, grant number ИРН AP19678310. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.