Left Ventricular Contractile Dysfunction as a Complication of Thermal Injury

INTRODUCTION As early as 1931, Blalock (1) proposed that impaired cardiovascular function was a major component of organ dysfunction and failure after major burn injury. Burn-related alterations in cardiac function were initially attributed to fluid shifts that occurred as a result of plasma loss into the burn area, producing a fall in venous return and a decrease in preload (2, 3). Numerous studies during the early 1960s described that cardiac output fell precipitously after burn injury, but this change in cardiac output occurred before the loss of plasma into the burn wound and in the presence of a normal blood volume. Studies in animals and man described that cardiac output improved rapidly with aggressive fluid resuscitation from burn injury, whereas others showed that volume resuscitation, adequate to replace or exceed intravascular fluid loss, did not always restore left ventricular stroke work (4, 5). The burn-related fall in cardiac output was attributed to changes in the microcirculation and coagulopathies that produced “sludging” of the blood (4) and peripheral vasoconstriction (5-7). Others proposed that the mismatch between the fall in cardiac output and alterations in circulating plasma volume was related to burn-mediated myocardial injury (8, 9). The finding of myocardial lesions after burn injury in humans (10, 11) led Baxter and colleagues (12) to study the presence of a “myocardial depressant factor” in serum from burn patients. In 1984, Adams and colleagues (13-15) established a model of burn injury in adult guinea pigs and examined the effects of burn injury on left ventricular contractility and compliance. These studies described that burn injury over 47% of the total body surface area (TBSA) slowed isovolumic relaxation, decreased diastolic compliance, and impaired left ventricular contractility. The authors concluded that intrinsic changes in contraction and relaxation impaired filling of the left ventricle, reducing ejection fraction and contributing to the postburn decrease in cardiac output described in experimental and clinical burn subjects. Our studies over the past 25 years have confirmed this early work by Baxter, Adams, and others. In addition, we have addressed an initial concern with Baxter’s work, which determined the myocardial depressant capabilities of burn serum by adding human burn serum to isolated perfused guinea pig hearts (12). Our approach included collecting serum from rats given burn over 40% TBSA and adding the rat burn serum to the perfusate of a control naïve rat heart, eliminating confounding effects of species-related differences (15). A study by Ferrara and colleagues (17) also extended Baxter’s initial observation of burn-related myocardial depressant factors, showing that lymph isolated from the scalded hind limb of animals impaired regional myocardial blood flow, coronary vascular reactivity and contractile performance. More recently, Sambol and associates (18) described that mesenteric lymph diversion prevented burn-related myocardial contractile depression. Collectively, these data have suggested that burn injury promotes the mobilization or release of potent factors that exert negative inotropic effects on the myocardium. Postburn myocardial contractile dysfunction has been confirmed by numerous experimental approaches, and a variety of animal models have been used to examine burn-related myocardial contractile responses to inotropic stimuli. Animal species used to examine contractile responses to burn injury include mice, rats, hamsters, guinea pigs, rabbits, dogs, pigs, and sheep. The time course of myocardial contraction and relaxation defects appear to be species-related (8, 12, 13, 16-23). However, there is remarkable similarity in the degree of myocardial contractile depression across species. As shown in Figure 1, postburn myocardial contractile deficits were evident in all hearts harvested 24 h after burn injury regardless of species. These data are consistent with numerous reports of burn-related decreases in ventricular responsiveness to increases in either cardiac filling, coronary flow rate, perfusate calcium, or isoproterenol challenge (14, 18-21). The decreased ventricular responsiveness to inotropic stimuli has been shown to correlate with a rise in serum troponin I levels, a biochemical indicator of significant cardiac injury (21). Recent data confirmed that burn trauma in healthy adults produces a rise in serum troponin I levels that were remarkably similar to the rise in troponin levels measured in burned animals. This recent clinical study indicated that serum troponin I was not detected in patients with burns smaller than 10% TBSA but was elevated on admission for patients with greater than 20% TBSA. Serum troponin levels remained elevated 12 h postburn, providing clinical evidence of cardiac injury after major burn injury (24).Fig. 1.: Comparison of ventricular performance in mice, rats, guinea pigs, and rabbits. All values are ±SEM. An asterisk indicates a significant difference between sham and burn at P < 0.05.Time-course studies have shown that myocardial contraction and relaxation deficits after burn injury are transient, appearing as early as 2 h postburn, reaching a nadir 24 to 30 h postburn, and gradually resolving 48 to 72 h postburn (21, 25, 26). The presence of transient myocardial contractile depression may pose a relatively limited risk in young adult healthy burn subjects. However, burn intensive care units have an increasing proportion of elderly and immune-suppressed patients in whom even transient cardiac deficits may complicate their responses to aggressive fluid resuscitation. Recent preliminary studies from our laboratory have suggested that the early postburn cardiac dysfunction that occurs in the burn population may also provide an indicator of the subject’s susceptibility to subsequent infection. Thus, postburn cardiac dysfunction may contribute not only to the overall morbidity and mortality associated with burn injury, but may also predict those patients at particular risk for infectious complications during the postburn period. Over the last 20 years, we and others have developed excellent model systems for investigating the pathophysiology of postburn cardiac dysfunction, and the use of these models has emphasized the uncontrolled and adverse myocardial inflammatory responses that occur after burn injury. A number of inflammatory mediators have been identified and have been shown to contribute, in part, to the overall pathogenesis of multiple organ failure in burn trauma (25-28). Recent attention has focused on the source of these inflammatory mediators, for example, gut-derived factors, wound-derived mediators, or cytokines secreted by one organ, which then act in a paracrine fashion on neighboring cells and/or on downstream organs, modulating several aspects of myocardial function. In addition, considerable attention has focused on the cell signaling cascade, which regulates the cardiomyocyte responses to burn injury. MECHANISMS BY WHICH BURN INJURY IMPAIRS CARDIAC CONTRACTILE FUNCTION Inflammatory cytokines Over the last 20 years, attention has focused on the identity of myocardial depressant factors as well as the source of these factors present in the systemic circulation after burn injury. The finding of tumor necrosis factor α (TNF-α) or cachectin in the systemic circulation of patients with either sepsis, hemorrhagic shock, meningococcal infection, as well as burn injury, suggested that this mediator was a common contributor to hemodynamic collapse and death in numerous injury and disease states (29-42). Administration of TNF-α in healthy subjects produced hemodynamic and cardiodynamic profiles that resembled those observed to occur in several types of trauma (31, 32). While serum TNF-α levels in burn patients were reported to correlate with the development of infection (35, 36), others suggested that the postburn rise in serum TNF-α provided a measure of immune response, indicating increased risk for sepsis and increased mortality (37, 38). Subsequent studies examined systemic levels of TNF-α, interleukins 1β and 6 after burn injury and described that these cytokines provided a better prognostic indicator of patient susceptibility to sepsis than measures of single cytokines (38-42). In 1992, Giroir and Beutler (43) described that although TNF-α was synthesized by a variety of cell types (i.e., macrophages, endothelial cells, and blood monocytes) and by a variety of organs, the heart was a particularly rich source of this inflammatory cytokine. Subsequent studies by Giroir and Horton examined the role of TNF-α in myocardial contractile dysfunction after burn injury, confirming that burn trauma over 40% of the body surface area increased myocardial synthesis of TNF-α; anti-TNF strategies were shown to prevent burn-related myocardial contractile dysfunction and to improve outcome (44). Considerable evidence has accumulated that TNF-α serves as a proximal mediator of the postburn inflammatory cascade. In animal models, intravenous infusion of recombinant TNF-α produced cardiac contractile depression (30, 45, 46), and the addition of TNF-α to ventricular muscle preparations and to isolated cardiac myocytes produced concentration-dependent negative inotropic effects (47-50). Further evidence supporting TNF-mediated myocardial contractile dysfunction has been provided by studies describing that transgenic mice overexpressing TNF-α exclusively in the myocardium have myocardial TNF-α levels sufficient to cause dilated cardiomyopathy and severe congestive heart failure (51). Furthermore, elevated serum TNF-α levels have been reported in adult burns that had no evidence of concomitant infection (37). Burn trauma has been shown to increase hepatic TNF-α mRNA and to prime several cell types for enhanced TNF-α production with a subsequent challenge after burn injury (35, 52). Finally, cardiomyocytes harvested from burn rats have been shown to secrete 15 times the TNF-α levels secreted by myocytes prepared from control rats (52, 53), and TNF-α inhibition provides considerable cardioprotection after burn trauma (44). Collectively, these data provide convincing evidence that TNF-α is an early mediator of a cytokine cascade that produces organ dysfunction and injury after burn trauma. factor Recent attention has focused on the role of as a cardiac myocardial depressant This cytokine has been shown to an role in as inflammatory myocardial and and colleagues confirmed in the as burn and an infectious as produced a significant decrease in cardiac levels, a that was consistent with release from The of was confirmed animals given major burn injury or sepsis had better cardiac function with animals given an body surface area burn in the of The and the of release from the heart after burn trauma suggested that in part, for the effects of burn injury the by which cardiac contractile function have to be is from cardiomyocytes and has and In addition, has been shown to several aspects of a cell signaling that regulates inflammatory cytokine release by cardiomyocytes In addition to modulating cytokine may act in a of cardiomyocyte cell signaling that in performance of the myocardial contractile in as mediators of cardiac injury after injury of that and after burn trauma of resuscitation concern was that volume resuscitation and the of into to the production of in produced The source of in burn trauma has also been by several and proposed that the was a major source of that injury. peripheral decreases to peripheral that is for with the of in is to volume resuscitation after burn injury and the return of to produces which then serves as a for to and to produces and studies suggested that this of and the of The of to postburn cardiac dysfunction has been examined by rats with a of the to be the major source of in several types of injury burn trauma A postburn rise in cardiac levels indicated the presence of a postburn aggressive fluid resuscitation from burn injury produced a fall in cardiac and improved cardiac to fluid resuscitation from burn injury burn-related cardiac cell and improved cardiac contractile dysfunction and of in burn studies have examined and as a source of in injury. A of has been proposed to producing in burn subjects In addition, burn injury the burn to injury In this burn decreases in and that and cell In addition, burn trauma producing a fall in and levels Further for the role of in postburn organ injury and dysfunction has been provided by studies that confirmed a rise in plasma and cardiac levels, increased of and was confirmed by increased Recent strategies have focused on and in burn trauma. and 2 and as well as of the and have been shown to provide considerable hemodynamic and cardiac in models of injury and disease studies have used and P mice to examine the role of and in burn-related organ injury, and myocardial injury and dysfunction to organ injury and dysfunction after burn trauma has included Administration of or have been shown to burn related changes in and levels, and or was shown to postburn levels, to improve and to prevent burn related Finally, and colleagues described that the total volume of fluid resuscitation adequate cardiac More recently, our laboratory examined the effects of in burn trauma on several aspects of the signaling cascade that had been shown to of TNF-α and by cardiomyocytes These studies examined the that of biochemical species as and as and an inflammatory that of and myocardial injury 3). Administration of an that included and and given to adult rats by was shown to prevent burn-related myocardial and to prevent postburn cardiomyocyte of TNF-α, and This in cardiomyocyte inflammatory and fall in cytokine with significant of myocardial contractile performance. As in Figure burn injury in the of impaired left ventricular developed responses to increases in coronary flow rate, and perfusate calcium, and these postburn contractile defects were by the of inflammatory cytokines 24 h of cytokines 24 h that a signaling cascade that regulates cardiac synthesis and of of on burn-related responsiveness to increases in preload increase in coronary flow or increases in perfusate All values are ±SEM. An asterisk indicates a significant difference from sham at P < and these studies that major burn injury produces and cardiomyocytes to an inflammatory signaling cascade that in cardiac contractile dysfunction or the release of inflammatory mediators as TNF-α by organs, in release and subsequent inflammatory signaling the myocardium The role of in burn-related cardiac contractile dysfunction studies have suggested that TNF-α may organ by is a 6 and synthesized by a of The effects of and negative and inotropic effects of have been described in isolated heart, and cardiomyocyte preparations In the presence of is to and However, inflammatory cytokines as TNF-α or and the of may exceed levels of with to the levels of produced exert effects on cell function. serves as a and and in the The addition of to fluid resuscitation from burn trauma provided myocardial that burn injury levels, the of to function The effects of were attributed to of levels, of peripheral and of and However, to the fluid resuscitation for as well as the effects of in a model of burn injury is that of fluid resuscitation aspects of burn-mediated dysfunction, providing that was not related to In major burn injury, a of produced peripheral and vascular of the factor which an inflammatory signaling and in and necrosis The role of in myocardial function has been addressed by our laboratory the and The addition of of and to left ventricular muscle preparations dysfunction, whereas of the dysfunction, indicating concentration-dependent effects of Our recent studies have examined and to and data confirmed that burn trauma in mice produced significant of myocardial whereas was of the for the improved postburn left ventricular contractile performance over that in mice given burn over 40% TBSA. Administration of a of burn-mediated cardiac contractile dysfunction, a that was similar to that with burn injury in mice in myocardial levels after burn trauma studies by and others have examined the that a major injury as burn trauma over greater than 40% TBSA to function. The that is to function and contractile of the heart from of by a decrease in the of production after burn trauma decrease the for the of from the and contributing to cardiomyocyte of that has been described after major burn injury Furthermore, a decrease in levels be to after burn injury, burn-related cell Our studies cardiac by or confirmed that cardiac was after major burn in our cardiac levels fell after to postburn cardiomyocyte and occurred myocardial eliminating burn-related changes in as a for after burn trauma However, and colleagues described burn-related alterations in and heart reported as changes in and total These authors described that burn-mediated change in and heart were by postburn sepsis but by These differences in postburn measures of levels may be related to differences in for CARDIAC Over the last 20 years, a number of mediators that contribute to the postburn pathogenesis of multiple organ failure have been and several signaling by which these mediators contribute to myocardial defects have been example, has been shown to cytokine synthesis in cell types and has been in a number of cardiac cardiac injury, and Studies by and colleagues confirmed that burn over 40% TBSA increased myocardial as determined by and in The burn-related increase in in the early postburn and h was by the of a whereas was not inhibition TNF-α and burn-related myocardial contractile defects studies have shown that of a role in of a in burn trauma Recent studies have confirmed that burn injury over 40% TBSA increases myocardial 1, and h postburn and recently, was shown to in part, cardiomyocyte synthesis and of the inflammatory cytokines and has also been shown to several aspects of myocardial and cardiac contractile Burn injury myocardial and of the of present in the adult was also in the early postburn whereas was increased only in the postburn the role of in burn injury recent studies have this in myocardial synthesis of inflammatory The or prevented burn-related cardiomyocyte of inflammatory cytokines and improved myocardial contractile performance The factor is downstream of and regulates the of that contribute to myocardial dysfunction example, TNF-α and 3). and colleagues described that myocardial was increased to 24 h after burn over 40% cardiomyocyte of TNF-α and and of these inflammatory cytokines the development of cardiac contractile dysfunction h after burn studies used a or a approach to to examine the effects of on myocardial and Burn injury in mice 2 to 24 h postburn, whereas mice overexpressing only in the heart and given an burn no postburn myocardial overexpressing mice had TNF-α and by cardiomyocytes and cardiac contractile dysfunction with myocardial and dysfunction that occurred after burn injury in a of in cell prevented burn-related myocardial cardiomyocyte of and and improved postburn cardiac performance These strategies to cardiac have suggested that serves as an of cardiomyocyte of inflammatory cytokines and that this signaling a significant role in burn-related myocardial CARDIAC FUNCTION As early as Baxter and colleagues (12) described the presence of a myocardial depressant factor in the serum of burn patients. Ferrara and colleagues (17) showed that lymph from experimental burns the function of isolated left ventricular and and colleagues described that burn serum a signaling cascade in cardiomyocytes that included and More recently, we have described that the effects of burn serum were by isolated perfused hearts with recombinant increasing a of of as TNF-α, and several aspects of burn or sepsis related myocardial contractile dysfunction However, myocardial contractile dysfunction, present in the early postburn course h occurs in the of than of the patients with and multiple organ failure after burn have no infection and to has not been reported in the circulation of experimental or clinical burn injury. The as one source of myocardial depressant factors Thus, although we have identified a number of mediators that contribute to the overall pathogenesis of multiple organ failure in burn trauma and we have identified a number of the signaling by which cardiomyocytes to burn injury, we have not identified the signaling that the cardiomyocyte inflammatory to burn injury. Recent studies by Sambol and colleagues showed that mesenteric lymph before burn injury injury and limited More recently, this confirmed that with mesenteric lymph but not sham lymph prevented cardiac contractile dysfunction These data that gut-derived myocardial depressant factors, in the mesenteric may contribute to burn-related of contractile dysfunction of myocardial depressant role of the as a source of myocardial depressant factors is not a area of injury has been shown to decrease blood flow to the vascular and to release blood flow after burn injury to decreased and as well as a loss of function and and colleagues described a decrease in release over the 12 h postburn, and the loss of this to of this and the loss of the function after burn injury to of to mesenteric lymph and our study showed that blood remained negative during the 48 h after burn injury to is a relatively early in the postburn and is by aggressive fluid resuscitation to replace fluid loss may contribute to from the and into the and systemic a as to these signaling the shown to on cardiomyocyte the is a in the release of inflammatory mediators as TNF-α, and by numerous cell Our recent studies have confirmed that signaling this also several aspects of myocardial and the is to the to infection, all of this are in the heart Furthermore, that the and are also present in cardiac and has also been identified in heart failure signaling cascade in cardiac numerous described that the heart a that to and colleagues confirmed that signaling to the pathogenesis of cardiac dysfunction in injury. In one mice a or no or were to postburn myocardial contractile In of a that and h after burn injury in rats provided remarkable cardioprotection and decreased cardiomyocyte inflammatory cytokine Thus, improved myocardial contractile performance in burn injury be by signaling the or by circulating supporting the that or an contribute to impaired myocardial contractility after burn injury Recent studies the role of burn-related loss of function and gut-derived on cardiomyocyte function have used of the In this and were given by for several before burn injury and for 24 h after burn injury. burn injury increased myocardial of TNF-α, and and impaired myocardial contractile performance. burn-related myocardial cytokine and improved myocardial contractile performance these studies have suggested that in postburn cardiac contractile dysfunction, these data not the that that and be by contribute to contractile However, the is one source of that after burn injury. The and of at than the or as from the of is not by In addition, as may be by burn injury, an immune and cardiac a may be produced a a than the by a injury as burn the systemic circulation and myocardial effects cardiomyocyte of in postburn myocardial dysfunction Recent reports a significant between and of a of shown to provide considerable in injury. Our recent studies have confirmed that are in the myocardium after a burn injury and that the of burn-related myocardial contractile dysfunction Others have shown that with cell surface these signaling factors in and of and Our finding that burn trauma myocardial one by which burn injury to myocardial and dysfunction 5). may myocardial injury and dysfunction Numerous studies have described that the burn wound provides a rich of and that may peripheral to an inflammatory cascade and organ dysfunction In this burn wound-derived a of that several of the have been described in the burn wound While increased of may of the normal wound the effects of increased and of on burn wound the of and 20 years patients and showed that early of the burn wound improved of the burn wound postburn and postburn organ to challenge In addition, and colleagues reported that early burn wound blood loss, improved and improved postburn mortality the burn wound provides a source of or to the systemic early of this may signaling in downstream as the heart, myocardial cytokine synthesis and myocardial contractile function. this our laboratory examined wound of a burn injury over 20% or TBSA. was 30 to after the burn injury, and harvested from a rat was used to the loss during the was and by a were harvested 24 h after burn injury to contractile function in myocardial As shown in Figure wound in the early postburn provided a measure of cardioprotection as indicated by the improved left ventricular responses to increases in coronary flow or perfusate In addition, wound in the to after burn injury myocardial inflammatory cytokine of early wound on myocardial responses to increases in coronary flow rate, and perfusate experimental burn injury models have the presence of intrinsic myocardial contractile defects after major burn injury, cardiac output is in the human burn In addition, cardiac dysfunction in experimental burn is transient, and may pose a relatively limited risk in young adult healthy burn subjects. However, the presence of even transient myocardial contractile depression may present a significant risk factor for an increasing population of immune patients or elderly patients in whom transient cardiac defects may complicate their responses to aggressive fluid resuscitation and may increase the risk for sepsis or a Recent has focused on measures of heart a and of patients are at risk for a has been used as a of cardiac mortality in patients were of heart there has been limited of heart to predict outcome in intensive burn care of heart during the 24 after burn injury has been suggested to subjects with are to of in with of of myocardial performance in the postburn period. This approach with measures of serum troponin to provide a measure of cardiac injury may provide an overall of patients cardiac to improve morbidity and the presence of burn-related myocardial injury and dysfunction to inotropic for burn of postburn deficits and a of hemodynamic of strategies provide not only to of burn trauma but also to numerous patient in whom impaired cardiac contraction and relaxation deficits contribute to increases in morbidity and The for the