Pathophysiology of cardiac dysfunction in burn disease

Introduction

Burns are the fourth most common injury worldwide, affecting more than 11 million people each year. An underestimated statistic is that mortality from burns is similar to that from acute myocardial infarction [1]. Burns are not only regional, but also systemic lesions that affect the entire body and progress with increasing area and depth of the burn [2]. Local thermal injury is accompanied by complex disturbances of hormonal homeostasis and disorders of the cardiovascular system [3–5].

Almost 60 years have passed since C.R. Baxter first described cardiac dysfunction (CD) as a consequence of burn disease (BD) [6, 7]. CD is associated with negative outcomes in combustiology. In adults and pediatric populations, it leads to increased length of stay in the intensive care unit, total hospitalization, duration of mechanical ventilation, and number of repeat surgeries. CD can manifest as decreased left ventricular ejection fraction, stroke volume, and increased myocardial metabolic demands. At the cellular level, processes such as decreased cardiomyocyte contractility and impaired calcium kinetics can activate CD [8, 9]. Burn injury (BI) causes hemodynamic disturbances and impaired cardiac function, leading to organ hypoperfusion, burn area expansion, and increased susceptibility to wound infection [10].

Articles of choice were included in the study if they (1) were published in Ukrainian and English, (2) were related to the pathophysiology of cardiac complications of BD, (3) used an observational study design (cohort or cross-sectional). A retrospective information search of literary sources and information data was carried out using the spatial-vector model of the descriptor system based on classifiers, supplemented by a manual search of the literature lists of the included articles.

Materials and methods

The acquisition of literary scientific information was carried out using the information search systems Scopus, Google Scholar, CrossRef and PubMed, which was also supplemented by a manual search of the articles used using the search terms: pathophysiology of BD; cardiac complications of BD. 30 relevant scientific sources were selected and analyzed, of which 93.3% were from the last 10 years, and 83.3% were from the last 5 years.

Results and discussion

BI induces a hypermetabolic, hyperinflammatory state characterized by muscle protein catabolism, immune disorders, and organ failure [4, 9]. Left ventricular function has been shown to be acutely impaired within 24 hours of BI and to remain depressed for up to 72 hours. Burn-induced CD can sometimes develop as early as 8 hours after injury and persist for years [8].

In local thermal injury, cardiac function undergoes certain changes starting from the moment of injury. Before any decrease in plasma volume is detected, stimulation of receptors in the thermally damaged skin indirectly triggers a neurogenic response, initiating a rapid limitation of cardiac output. This is associated with an initial decrease, and starting from the third day after BI, with a significant increase in cardiac index. Other parameters, such as sustained increase in cardiac work, increased myocardial oxygen consumption, and increased heart rate, remain elevated throughout the recovery period. Severe cardiac stress is accompanied by persistent myocardial depression, which may be related to hypovolemia, high vascular resistance, low venous return, and exposure to myocardial depressants. Fluid resuscitation usually does not fully restore normal cardiac output [11]. Myocardial ischemia and microvascular dysfunction occur when myocardial oxygen demand exceeds supply. Early ischemic signs include contractile dysfunction and increased vascular permeability [12]. Vascular smooth muscle hyperreactivity is likely driven by endothelial dysfunction [13]. Factors that limit the oxygen supply to the heart include tachycardia, hypoxemia, anemia, hypovolemia, decreased coronary artery patency, and decreased perfusion pressure. Most Starling forces are altered in burn patients and result in fluid filtration and relative hypovolemia. Increased capillary permeability usually occurs later and results in severe hypovolemia and decreased cardiac output. To maintain blood supply to vital organs and tissues, the release of catecholamines contributes to a compensatory increase in cardiac chronotropy, inotropy, bathmotropy, dromotropic, and systemic vascular resistance. Increased cardiovascular workload and oxygen demand in combination with a hypovolemic state can lead to myocardial hypoperfusion and relative ischemia [6]. Thus, burn shock includes distributive, hypovolemic, and cardiogenic components [14]. All this contributes to reduced or ineffective cardiac function, morbidity, and mortality of patients [6].

Dyshydria following primary trauma combined with massive fluid resuscitation has a significant impact on the cardiovascular system [15]. Plasma losses following burns can exceed 4 ml per kilogram of body weight per hour in burns of more than 30% of the total body surface area (TBSA). This can lead to intravascular hypovolemia, circulatory restriction, and central organ hypoperfusion, resulting in myocardial ischemia [6]. This results in a decrease in cardiac output, which subsequently progresses to a hyperdynamic-hypermetabolic phase with increased cardiac output [16]. Fluid displacement from the intravascular space contributes to edema, decreased vascular volume, and disturbances of fluid and electrolyte balance. Intravascular volume restriction is associated with a decrease in cardiac output (CO) and an increase in systemic vascular resistance [17]. The reduction in plasma volume limits venous return and end-diastolic volume (preload). Cardiac output is reduced through the Frank-Starling mechanism, which relates the energy of muscle contraction to myocyte length. Consequently, reduced right atrial filling pressure reduces myocardial contractile force and stroke v­olume [14]. Cardiac depression occurs as early as 15 minutes after BI, before aggressive volumes of standard crystalloid intravenous fluids can alleviate the early burn-related cardiac depression [18].

BI causes detachment of the endothelial glycocalyx, which lines the inner surface of blood vessels, leading to fluid loss and increased mortality. After a major burn, early sympathetic «stress» discharge, cardiac depression, and systemic hypoperfusion activate the endothelium, resulting in detachment of the glycocalyx, which becomes leaky, adhesive, proinflammatory, prothrombotic, and vasoactive. The degree of glycocalyx damage in burn patients is associated with increased fluid requirements [1].

After severe burns, local and systemic vascular permeability increases, causing extravasation of intravascular fluid, leading to a progressive decrease in effective blood volume, increased systemic vascular resistance, decreased cardiac output, peripheral edema, multiple organ failure, and even death [19].

Burns cause several systemic reactions: increased capillary permeability, decreased cardiac contractility, constriction of peripheral and visceral vessels, and an almost threefold increase in metabolism [20]. Activation of the inflammatory, coagulation, and complement cascades forms a positive feedback loop that leads to microvascular dysregulation, opening of junctions between adjacent endothelial cells, and detachment of the endothelial glycocalyx. The imbalance of hydrostatic and oncotic pressures across the damaged microvascular barrier shifts fluid from the vascular to the interstitial compartment in both burned and unburned tissues. This is followed by a decrease in cardiac output, which may precede a decrease in effective circulatory volume and may persist even after adequate fluid resuscitation [14]. The severe pain and mental stress experienced by burn patients are accompanied by a massive release of catecholamines. In extensive burns, serum catecholamine and corticosteroid levels are elevated 10- to 50-fold and persist for a long time [17]. Burn-induced CD has been documented for over five decades, including increased cardiac workload, tachycardia, systolic dysfunction, and increased energy expenditure. Many of these abnormalities can be attributed to cardiac β-adrenergic receptors (β-ARs), which are activated by circulating catecholamines that regulate cardiac function and also stimulate signaling pathways involved in apoptosis, inflammation, proliferation, and glucose homeostasis. Increased catecholamine levels due to hyperactivation of β-ARs are associated with cardiac hypertrophy. β-ARs also cross-react with a variety of signaling receptors, including the androgen receptor and peroxisome proliferator-activated receptor-α. Through these and other signaling mechanisms, prolonged β-AR activation leads to increased cardiac morbidity and mortality [9]. Vasoconstriction causes deterioration of left ventricular systolic and diastolic function and reduced coronary blood flow, reflecting microvascular dysfunction even in the absence of coronary artery obstruction or stenosis [8]. These factors stimulate the sympathetic nervous system, leading to increased levels of inflammatory markers and cardiovascular complications [1, 17, 21]. Hypercatecholaminemia promotes myocardial hypertrophy and endothelial inflammation by increasing heart rate and blood pressure [4, 22]. The initial stages of BI involve increased sympathetic activity, cardiovascular and hemodynamic adjustment, and promotion of wound healing. However, prolonged or excessive sympathetic activi­ty may have adverse consequences [17].

Cardiac stress is a characteristic feature of the acute phase response to severe BI, the severity of which determines post-burn outcomes. Elevated levels of catecholamines and other catabolic agents, such as glucagon and cortisol, cause a hyperdynamic cardiovascular response and increase oxygen consumption. The extensive tissue injury typical of severe BI results in marked tachycardia, increased myocardial oxygen demand, and decreased cardiac contractility. This response is unmatched by other forms of injury [17]. The cardiovascular response is classically thought to occur in 2 phases. The initial phase of myocardial depression or «ebb» phase, which is accompanied by a significant increase in vascular permeability, involves both right and left ventricular heart failure and a restriction of cardiac contractility mediated by circulating vasoconstrictors. There is suppression of cardiac contractility and output during the first 24 to 48 hours after injury. However, three days after BI, patients enter a hypermetabolic «rebound» phase in which energy expenditure, heart rate, and cardiac output remain elevated for a long time after injury. The two phases may be indistinct and sometimes partially apparent. CD in burns has a similar course to that of sepsis [9, 12, 17]. Burn survivors are more likely to develop psychiatric depression, which is associated with an increased risk of cardiovascular disease and mortality, and persistent changes in blood lipid levels [17].

Platelet aggregation is enhanced by adrenoreceptor stimulation, which, in combination with endothelial dysfunction, can contribute to the development of atherothrombosis, myocardial infarction, and other circulatory system diseases that worsen over the years even after a mild burn [4, 22].

The complex relationship between preload, afterload, and contractility challenges Starling’s law. Ventricular chamber compliance changes from low levels during diastole to high systolic compliance, affecting the relationship between intraventricular pressure and volume. Significant burns can cause decreased compliance of the left ventricle, limiting its ability to relax during diastole. Baroreceptor reflexes increase sympathetic activity, increasing heart rate, contractility, and peripheral resistance. Paradoxically, increased heart rate can reduce cardiac output by limiting diastolic filling time. Vasoconstriction and elevated hematocrit contribute to increased afterload, further reducing stroke volume and cardiac output. This process culminates in hypotension, coronary insufficiency, ischemia, and progressive myocardial dysfunction [14].

BI requires increased oxygen delivery and tissue perfusion due to increased metabolic demands, resulting in a hyperdynamic/hypermetabolic state with an increase in oxygen consumption of up to 200% [12, 17]. This also leads to activation of the sympathetic nervous system. When these demands are not met, shock develops. Increased catecholamine activity impairs myocardial oxygen delivery and consumption and causes focal myocardial degeneration and hypertrophy. In excess, they cause heart failure, local myocardial hypoxia, and cardiac death. With prolonged exposure, catecholamines have been implicated in the development of cardiomyopathies, myocarditis, and necrosis [17].

A significant and sustained increase in catecholamines, glucocorticoids, glucagon, and dopamine levels leads to hypermetabolic responses and catabolic states [17]. It is important to note that the release of catecholamines, glucocorticoids, and other stress hormones mediates a prolonged hypermetabolic and hyperdynamic cardiovascular response, allowing shock to coexist with normal or elevated blood pressure [5, 14]. The duration of the catecholamine surge that accompanies burns may be prolonged, as hormone levels may be elevated for months or years [23, 24]. Hypermetabolism contributes to impaired insulin sensitivity. Metabolic disorders may result from dyslipidemia, which is a secondary cause of insulin resistance. This disorder is directly related to the degree of BI. The hypermetabolic response to severe BI can lead to increased susceptibility to infection, muscle protein breakdown, and dysfunction of various physiological systems. Numerous studies have shown that these long-term hypermetabolic changes persist for up to 3 years after severe BI [17].

The hypermetabolic response to burns is characterized by increased blood pressure and heart rate, increased catabolism, body temperature, energy expenditure, muscle wasting, and release of acute phase reactants. The first phase of the metabolic response lasts approximately 2 days and is characterized by decreased cardiac output, oxygen consumption, metabolic rate, and hyperglycemia. The second phase peaks 5 days after the burn and results in a sustained elevation of catecholamines, cortisol, and other stress mediators that can persist for up to 24 months after the initial BI. The metabolic response correlates with the degree and extent of the burn, but even relatively minor injuries involving 10–20% of body surface area can elevate metabolic rate to 118–210% of basal metabolic rate. In children, heart rate and cardiac output may reach 150–180% of predicted values, respectively. The body’s response to burns may contribute to cardiac cachexia [1, 6, 25].

In a state of hypermetabolic shock, numerous myocardial depressants may circulate in the bloodstream. Some peptides, such as myocardial depression factor (MDF), are thought to be activated in BD. One of the functions of MDF is to inhibit myocardial contractility. Lipopolysaccharides induce further proliferation of interleukins and exert a negative inotropic effect. Studies in an animal model of burn followed by resuscitation have demonstrated rapid myocardial damage as early as 1 hour after BI, as morphologically demonstrated by cardiomyocyte edema, granular degeneration, and focal hemorrhages [6]. Systemic and pulmonary vascular resistance are increased after burns, leading to increased afterload on the left and right sides of the heart. Due to the increased myocardial oxygen consumption, the left ventricle maintains stroke volume and CO through adrenergic stimulation, while the right ventricle has only a minimal capacity to compensate. Isolated heart studies have shown a decrease in contractility after burns, resulting in decreased myocardial function due to direct damage. Massive burns of more than 45% TBSA can cause intrinsic contractile dysfunction and compliance dysfunction despite early and aggressive volume replacement, so hypovolemia is only one factor among others contributing to myocardial defects in the early stages of BD. Experimental burns of 40% TBSA or of the airways alone cause a decrease in myocardial contractility, which was not observed with carbon monoxide poisoning alone [6].

It has been shown that the inflammatory cascade alters the expression of immune-dependent genes in BI and endotoxe­mia. Such changes can also cause burn-related CD and lead to persistent cardiac stress [8]. BI is accompanied by a 64% decrease in maximal mitochondrial ATP (adenosine triphosphoric acid) production, hypoxia leads to a deficiency in the activity of mitochondrial complexes I and III. BI causes CD by disrupting the mitochondrial structure of the heart, inhibiting the replication of cardiac mitochondrial DNA (deoxyribonucleic acid), and disrupting the function of the cardiac electron transport chain due to the inhibition of the expression of mitochondrial DNA-encoded genes. Deficiency in DNA replication or nucleotide metabolism leads to point mutations and/or depletion of mitochondrial DNA. The mitochondrial D-loop is thought to play an important role in nucleoid organization, nucleotide homeostasis, and DNA replication. The morphological forms of cardiac mitochondria in BD are distorted with a decrease in their number, area, and size, leading to a replication deficiency. After burns, mitochondrial structure is largely damaged, DNA is depleted, and mitochondrial D-loop copy number is significantly reduced [25–27]. Burns cause systemic release of inflammatory mediators, contributing to organ dysfunction even in areas distant from the primary injury [8]. Burns induce a potent inflammatory response that can damage cardiac muscle cells (myocytes). Endothelial dysfunction is closely associated with the inflammatory response to burns and may contribute to persistent cardiovascular dysfunction. This type of injury results in a decrease in cardiac output, requiring a compensatory increase in heart rate and peripheral resistance [15, 17]. Inflammatory mediators and immune dysfunction modulate cardiac injury [28].

The immune cascade is one of the main factors leading to CD after BI. The Toll-like receptor (TLR) is a pattern recognition receptor and is crucial for the regulation of the innate immune system. TLR signaling genes are the main targets of the cardiac response to BI. They play a role in the injury of cardiac myocytes and function as key receptors in the recognition of pathogen-associated pattern molecules and damage-associated pattern molecules (DAMPs). This leads to the activation of innate immune cells in the immune cascade. It is generally accepted that patients with BI have increased expression of TLRs. These signaling pathways also contribute to inflammation, causing tissue damage. TLR signaling activates the expression of cytokines and adhesion molecules. They often promote the recruitment and activation of leukocytes. The extent of the BI correlates with the level of circulating DAMPs and cytokines [27].

Cytokines play an important role in promoting inflammation, and their concentrations in cardiomyocytes have been shown to be higher than in the systemic circulation immediately after BI [8, 27]. Altered sympathetic β-adrenergic receptor function after BI leads to suboptimal cardiac responses due to increased oxygen demand and decreased oxygen delivery. Elevated levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and the interleukins IL-1β and IL-6, have been shown to inhibit cardiac contractility, intracellular calcium currents, and induce cardiomyocyte apoptosis [6]. In burn models, IL-1β release occurs predominantly at the site of BI. Increased TNF-α expression was detected within 1 hour after BI, and left ventricular dysfunction occurred 8 hours after injury and persisted for more than 24 hours. Similar to TNF-α and IL-6, IL-1b expression also increases within 1 hour after BI and can remain elevated for more than 48 hours [8].

IL-1 exerts proapoptotic and hypertrophic effects on cardiomyocytes while simultaneously inhibiting cardiac contractility through several different pathways. IL-1β impairs cardiac myocyte viability and causes cardiac contractility disorders after BI. IL-10 is significantly elevated in serum within 6 hours after myocardial ischemia/reperfusion injury. Initial circulating levels of the pro-inflammatory IL-10 are positively associated with cardiovascular risk, as it plays a key role in the progression of cardiac fibrosis, which can lead to the cardiac damage described [27]. In the cardiovascular system of patients with burns, immunoglobulin secretion by cardiomyocytes and circulating TNF-α interact with other inflammatory cytokines to induce burn-mediated systolic dysfunction [19]. IL-1β-induced CD is more likely to be due to functional impairment of β1-receptor stimulation than to structural changes. In addition, the mechanism of decreased ventricular function may be due to a decrease in intracellular cyclic adenosine monophosphate due to a decrease in β1-receptor sensitivity [8]. In severe BI, increased levels of inflammatory cytokines (up to a 44.5-fold increase) can lead to depression of cardiac contractility, and the development of myocardial infarction in these patients can lead to cardiogenic shock [24]. All these factors contribute to a slowdown in isovolemic relaxation, impaired contractility, and reduced compliance, mainly of the left ventricle [6].

The decrease in cardiac output is attributed to circulating myocardial-depressant factors such as TNF-α, IL-1β, IL-6, and reactive oxygen species, which reduce myocardial contractility and induce myocardial cell apoptosis [14]. Mechanisms by which cytokines cause CD include dysregulation of calcium homeostasis, alterations in nitric oxide synthase activity, and induction of oxidative stress [8, 9, 26].

Posttranslational nitrosylation of proteins contributes to the accumulation of reactive oxygen species (ROS) and nitrogen, leading to intracellular damage [8]. Oxidant/antioxidant imbalance leads to heart failure, contributing to mortality after BI. Cardiac mitochondria are the major source of ROS. BI increases cardiac ROS production, inflammation, and fibrogenesis, while simultaneously decreasing cardiac antioxidant production and mitochondrial DNA-encoded gene expression. Antioxidants targeting mitochondria may be an effective treatment for burn-induced CD by reducing post-burn inflammatory cell infiltration and fibrogenesis [26–28]. Nitric oxide (NO) is a negative inotrope. BI increases NO levels through the activation of inducible nitric oxide synthase (iNOS). Sustained stimulation of β-adrenoceptors (β-ARs) promotes increased NO levels [8, 9, 26], leading to oxidative stress, DNA damage, and activation of nuclear factor NFκB. Inflammatory cytokines such as TNF-α can also promote iNOS activity, leading to persistent elevations in NO levels and may contribute to cytotoxicity and ventricular dysfunction [9]. Mitochondrial NO levels are typically significantly elevated after severe BI and mediate the formation of compounds that alter mitochondrial respiration and compete with calcium for binding sites on contractile proteins, which can severely impair cardiac function and negatively regulate cardiomyocyte inotropy. Conversely, NO also plays a vital role in cell survival by scavenging free radicals and inhibiting bacterial invasion when levels are relatively low [9, 10]. Thus, the circulating concentration of NO determines these effects, and overcompensation in either direction may contribute significantly to CD [9].

One cellular process by which TNF-α may contribute to CD is through disruption of calcium metabolism [8]. Calcium homeostasis is essential for the maintenance of cardiomyocyte function and viability. Calcium influx, extrusion, and storage determine the rate and force of cardiac contractility, as well as the rate of relaxation. Hyperactive ryanodine receptors initially promote calcium release, increasing cardiomyocyte contractility. However, prolonged efflux of calcium from the sarcoplasmic reticulum depletes its stores, leading to inhibition of myocardial contractility [9]. Calcium is highly cytotoxic, and its intracellular accumulation can lead to disruption of signaling pathways, cytokine release, and ventricular dysfunction. Increased mitochondrial calcium uptake may contribute to inflammation and myocardial injury. Mitochondrial calcium overload plays a crucial role in the release of TNF-α, IL-1β, and IL-6, thus completing the vicious cycle. Mitochondrial calcium levels are significantly elevated 1 hour after BI and remain elevated for 24 hours. After BI, the activities of Ca²⁺/Mg²⁺-ATPase and Na⁺/K⁺-ATPase are reduced, potentially increasing intracellular calcium accumulation. Calcium antagonists inhibit burn-induced calcium accumulation, TNF-α secretion, and left ventricular dysfunction [9].

Cardiac apoptosis is detected as early as 6 hours after injury, and its markers, such as DNA fragmentation and caspase-3 activity, have been observed 3 to 12 hours after BI. Increased apoptosis in BD correlates with defects in cardiac contractility and relaxation. Elevated intracellular calcium levels can activate this process in many tissues. Mitochondria also contribute to burn-induced apoptosis by releasing apoptosis-inducing factors and cytochrome C into the cytoplasm [9].

Thus, extensive burns lead to hypermetabolic states, inflammatory responses, and hemodynamic instability, which in turn contribute to sepsis, multiple organ failure, and increased mortality [6, 29].

In the septic state, functional rather than structural changes are responsible for the temporary decrease in cardiac output in BD. In addition to myocardial damage, patients are prone to developing sepsis during the acute hospital stay, which may exacerbate myocardial dysfunction. A «double whammy» has been reported in an experimental burn model with subsequent development of septic shock, where both the inflammatory response and cardiac damage are exacerbated [6, 29]. Severe BI is a specific type of injury that triggers a unique set of responses in the body and results in extreme elevations in stress hormones and pro-inflammatory cytokines. In the acute phase, there is an extreme increase in stress hormones and a massive response of pro-inflammatory cells and their cytokines. This hypermetabolic stress response is desirable in the early stages to maintain circulatory stability, but if this enhanced response persists in the long term, it can be detrimental through several mechanisms that lead to many late complications [3, 4]. The increased risk of cardiovascular disease in BI is associated with metabolic «memory» of previous burns, which is due to distinctive lipoprotein features. Higher concentrations of small dense subfractions of low-density lipoproteins are associated with an increased risk of cardiovascular complications [28]. Patients who have sustained severe BI have increased cardiac morbidity and mortality in the long term, which can last up to 2 to 3 years after injury. This prolonged time period distinguishes BI from other types of injuries [3, 4, 8, 23]. It has been shown that even 12 years after burns, pediatric patients had lower ejection fraction and impaired diastolic function compared to healthy controls, suggesting that early-life trauma leads to cardiac tissue remodeling over time through as yet unknown molecular mechanisms that remain to be investigated [6].

Heart failure with preserved ejection fraction is a long-term complication after severe BI. Chronic heart failure as a sequel to severe BI — a first look at a novel pathological «skin-heart» axis [30].

It has long been known that severe burns cause late systemic complications, but until recently the possibility of long-term cardiac sequelae of minor burns has been largely ignored. However, in developed countries, superficial burns account for more than 80% of hospitalizations, and therefore the potential consequences of long-term morbidity and healthcare costs are significant [21].

Conclusions

1. Local thermal injury and BD are accompanied by serious pathological changes in the cardiovascular system, which can aggravate the course of the pathological condition, prolong the duration of stay in the intensive care unit and the total duration of hospitalization.

2. Burns cause long-term disorders of the cardiovascular system, which can last up to 2–3 years after the BI and more.

3. Insufficient familiarization of doctors with the pathophysiology of BD, ignoring the likelihood of long-term cardiological consequences of minor burns leads to untimely prevention, diagnosis and treatment of cardiovascular disorders and increases the number of repeated hospitalizations and material costs for treatment.

References

Надійшла до редакції/Received: 07.05.2025
Прийнято до друку/Accepted: 19.05.2025