Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock.

BACKGROUND: Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death. During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function. We aimed to identify these mediators of myocardial depression in meningococcal septic shock. METHODS: We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock. We identified genes that were significantly upregulated in blood after exposure to meningococci. We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor--specifically a 12-25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection. FINDINGS: We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor. Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock. INTERPRETATION: Interleukin 6 is a mediator of myocardial depression in meningococcal disease. This cytokine and its downstream mediators could be a target for future treatment strategies.

Impaired venous return causes circulatory failure in experimental pancreatitic shock in dogs.

The haemodynamic effects in the early phase of canine acute experimental pancreatitis (AP) were studied using a cardiac catheterization technique. AP was induced in anaesthetized dogs with an infusion of trypsin-sodium-taurocholate into the pancreatic duct. The initial haemodynamic measurements were performed after the preparation of the animal and 5 min after the induction of AP. Thereafter, pressure and volume parameters were measured at 10 min intervals. AP induced significant increases in heart rate, dP/dtmax and mean arterial pressure, but a decrease in Vmax 5 min after the induction of AP. After the initial phase, the heart rate remained significantly increased, while constant and significant decreases of stroke volume, cardiac output, end-diastolic volume and end-diastolic pressure developed. The parameters of the contractility of the left ventricle were not affected to the same extent. It is suggested that the circulatory failure observed in AP, characterised by a prompt reduction of cardiac output, was primarily due to a heavy reduction in preload. This supports the theory that cardiac output is primarily affected by impaired venous return with consequently decreased preload rather than by a loss of ventricular contractility. Hence, the existence of a myocardial depressant factor in the early phase of experimental AP does not gain support from the present results.

Beneficial effects of a specific leukotriene receptor antagonist in splanchnic artery occlusion shock.

The purpose of this study was to examine the effects of a new potent peptidoleukotriene receptor antagonist, SK&F 104353, in splanchnic artery occlusion shock. SK&F 104353 was administered as a 1 mg/kg initial bolus followed by an infusion of 3 mg/kg per h for the entire 2 h post-reperfusion observation period. In a group of conscious rats, this dose of SK&F 104353 shifted the LTD4 dose response curve rightward 10-fold, indicating effective antagonism of peptidoleukotriene responses in the rat. Anesthetized rats subjected to splanchnic artery occlusion shock survived an average of only 98 +/- 8 min whereas all animals receiving SK&F 104353 survived the 2 h reperfusion period (P less than 0.02 from vehicle). Therefore, the survival rate of the splanchnic artery occlusion shock group of rats receiving SK&F 104353 was improved to 100% compared with 50% survival for the vehicle-treated splanchnic artery occlusion shock group (P less than 0.025). In the splanchnic artery occlusion shock + SK&F 104353 group the increase in the plasma activities of the lysosomal hydrolase, cathepsin D, and the cardiotoxic peptide, myocardial depressant factor, were significantly attenuated in comparison to the splanchnic artery occlusion shock + vehicle group (P less than 0.025). These data indicate that the peptidoleukotriene receptor antagonist, SK&F 104353 is beneficial in splanchnic artery occlusion shock, and furthermore suggests that it may be a therapeutically useful agent in bowel ischemic shock.

A study of the myocardial depressant factor and its relative influence in drug/alcohol mortality.

A shock factor, a low molecular weight peptide, has been isolated from postmortem blood. High levels of this peptide, which depresses the myocardium, were seen in cases where drug overdose or alcoholism, or both, were the cause of death. An elevated myocardial depressant factor (MDF) level also demonstrated in a fire victim and a patient in cardiogenic shock. The peptide analysis was accomplished by using an isolated cat papillary muscle followed by paper chromatographic confirmation. Postmortem electrolytes, alcohol, and various toxic agents were eliminated as causes of myocardial depression in the isolated cat papillary muscle assay. The presence of elevated MDF levels may be significant in the overall death process.

The interaction between myocardial depressant factors in endotoxemic cardiac dysfunction: role of TNF-alpha in TLR4-mediated ICAM-1 expression.

UNLABELLED: Multiple pro-inflammatory mediators contribute to cardiac dysfunction caused by bacterial lipopolysaccharide (LPS). The rapid TNF-alpha response is likely involved in the induction of down-stream myocardial depressant factors. Studies by our laboratory and others indicate an important role for ICAM-1 in endotoxemic cardiac dysfunction through leukocyte-independent mechanisms. The purpose of this study was to determine: whether ICAM-1 knockout improves cardiac function during endotoxemia and whether TLR4 and TNF-alpha regulate LPS-induced myocardial ICAM-1 expression. METHODS AND RESULTS: Mice were treated with Escherichia coli LPS (0.5mg/kg iv). Myocardial ICAM-1 levels were analyzed by immunoblotting and left ventricular developed pressure (LVDP) was assessed by the Langendorff technique. In wild-type mice, peak ICAM-1 levels were observed at 4h when myocardial contractility was depressed. Myocardial contractility was improved following LPS in mice lacking functional TLR4, TNF-alpha or ICAM-1. TLR4 mutation abolished ICAM-1 expression with abrogation of precedent TNF-alpha response. Similarly, TNF-alpha knockout reduced myocardial ICAM-1 level following LPS treatment. CONCLUSIONS: ICAM-1 contributes to the mechanism of endotoxemic cardiac dysfunction. TNF-alpha is involved in the regulation of myocardial ICAM-1 expression by TLR4.

Current concepts on myocardial depressant factor.

In the present work the authors have tried to offer a vast and detailed summary of theories and questions concerning the role of the MDF in shock. One of the major problems that surrounds this molecule is the myocardial contractility depression, the solution of which could allow a more rationalistic therapeutic approach to that which remains one of the most complex and delicate clinical framework.

[The role of the myocardial depressant factor in the pathogenesis of the shock]. / Ruolo del myocardial depressant factor nella patogenesi dello shock.

Examination of the pathogenesis of shock has directed attention to the microcirculation, the kidneys, and the lungs. Today, apart from other tissues and organs, particularly the splanchnic organs, the pancreas is also incriminated. The lysosomes (also present in other tissues) and zymogen granules it contains are responsible, during the ischaemia and hypoxia typical of shock, for the instigation of a process of cell autolysis that releases enzymes and frequently toxic protein fragments into the bloodstream. These include myocardial depressant factor (MDF), whose physical, chemical and biological identification and rôle are now fairly clear. First described by Brand & Lefer in 1966, MDF has been explored by Lefer and other workers at both the experimental and clinical level. An account is given of the main researches that have led to the determination of the characteristics and action of MDF in numerous types of shock, the pattern of its formation, and the routes by which it is introduced into the circulation. Reference is made to work showing the close relation between MDF and the lysosomial hydrolases, and its biological effects on the whole animal, on isolated preparations, and in vitro. In addition to the myocardial depressant effect that has given it its name, MDF has been shown to provoke ischaemia of the splanchnic circulation and depression of the RES. The evidence on both sides is presented, including that derived from personal investigations of district haemodynamics in experimental shock. In substance, material is presented from which an objective approach can be taken to the cultural contribution of MDF in the matter of shock, its prospects, and its limitations.

hemofiltration reverses left ventricular dysfunction during sepsis in dogs.

Depressed left ventricular (LV) contractility in sepsis has been ascribed to the presence of circulating cardiodepressant substance (filterable cardiodepressant factor in sepsis [FCS]); however, this finding is controversial. The authors hypothesized that if a decrease in LV contractility indeed occurred due to a circulating depressant substance, then removal of this substance by hemofiltration would reverse by dysfunction. In this study, LV mechanics were examined before and after hemofiltration in anesthetized dogs during continuous intravenous infusion of live Escherichia coli. Left ventricular anterior-posterior and apex-base dimensions were measured by subendocardial ultrasonic crystal transducers implanted 4 weeks before the experiments. Left ventricular contractility was determined from the end-systolic pressure-dimension relationship. The slope of this relationship (Emax) is an index of contractility. After 4 h of sepsis, Emax was reduced by one half. Hemofiltration resulted in a return of Emax to control values. The FCS activity in the plasma was also assessed by the percent reduction in isometric contraction of electrically stimulated, isolated right ventricular trabeculae obtained from nonseptic dogs. The FCS activity reached a peak 4 h after sepsis and was reduced after 2 h of hemofiltration. The results show that during experimental sepsis, a circulating substance of less than 30,000 d produces a decrease in LV contractility and that this LV dysfunction may be improved by hemofiltration.

The effects of burn injury and fluid resuscitation on cardiac function in vitro.

The effects of a 30% full-thickness total body surface area scald burn on in vitro mechanical cardiac function was studied in Sprague-Dawley rats. The findings were a 50% decrease in tension development and velocities of contraction and relaxation, when papillary muscle functions from sham and unresuscitated burned animals were compared. Fluid resuscitation synchronous with burning completely reversed the defects in papillary muscle function. This defect in function was partially transferable to normal muscles incubated in serum from burned rats.

Salutary effects of anisodamine in murine traumatic shock.

Anisodamine, an alkaloid originally extracted from the Chinese herb Anisodus tanguticus, has been reported to possess beneficial actions in septic, superior mesenteric artery occlusion, and hemorrhagic shock. We have investigated its actions in traumatic shock in rats. Anisodamine (2.5 mg/kg) increased survival time from 1.4 +/- 0.2 h to 3.1 +/- 0.3 h (P less than 0.001) in traumatized rats with 50% of the drug-treated animals surviving at least 3.5 h. Drug treatment had no significant effect on plasma cathepsin D activity (12.0 +/- 2.3 vs 10.4 +/- 1.7; vehicle- vs drug-treated, respectively). However, plasma myocardial depressant factor accumulation was significantly blunted by anisodamine, 62 +/- 5 vs 41 +/- 5 U/ml (P less than 0.02), indicating that prevention of MDF formation may be one protective mechanism of this substance.

Cardiac dynamics following shock: role of circulating cardiodepressant substances.

This article seeks to answer the questions "Is cardiac function depressed in shock states, and if so, what is the mechanism for this depression?" The behavior of cardiac contractile function in shock states covers two broad areas of investigation: cardiac function and the cardiovascular response to shock. The major techniques used to examine cardiac function in shock have included pump function vs. end diastolic volume, indices of cardiac work and efficiency, parameters of shortening rate, and the end systolic pressure-volume relationship. The results obtained from these studies, especially those which employed the former three technologies, have yielded divergent results. The main thesis of this article is that the confusion concerning the effects of circulatory shock upon cardiac dynamics is due in large part to the failure of most technologies to distinguish between shock-induced alterations in peripheral vascular function and shock-induced alterations in cardiac dynamic function. However, recent evidence obtained from the end systolic pressure volume relationship, which appears to be sensitive to changes in cardiac dynamic function but independent of changes in peripheral vascular function, indicates that cardiac dynamic function is indeed depressed following endotoxin administration. Several possible mechanisms for this depression are reviewed.

The myocardial depressant factor (MDF) in acute hemorrhagic pancreatitis.

Myocardial depression (measured by ventricular function curves on response to a fluid load) has been shown in 10 patients with acute hemorrhagic pancreatitis. Significant inadequate responses were found on evaluation of both the left and right heart. The increased pulmonary vascular resistance associated with adult respiratory distress syndrome (ARDS) of this disease was shown to correlate inversely with pulmonary wedge pressure, thereby excluding myocardial failure and pulmonary edema as mechanisms for the production of the ARDS.

The pathophysiologic role of myocardial depressant factor as a mediator of circulatory shock.

Myocardial Depressant Factor (MDF) is a small peptide circulating in the blood of all mammalian species tested in a variety of shock states including endotoxic, hemorrhagic, cardiogenic, bowel ischemic, acute pancreatitis, burn, and traumatic shock. MDF is produced by the action of proteolytic enzymes released by the ischemic pancreas. MDF acts to depress myocardial contractility, constrict the splanchnic arteries and impair reticuloendothelial system phagocytosis. Several pharmacologic agents prevent the formation of MDF including membrane stabilizers (e.g., glucocorticoids), protease inhibitors (e.g., aprotinin), converting enzyme inhibitors (e.g., captopril), prostaglandins (e.g., PGE1 and PGI2), thromboxane synthetase inhibitors (e.g., imidazole, PTA2) and local anesthetics (e.g., lidocaine). Prevention of MDF formation or action improves survival. Thus, MDF is an important mediator of shock pathophysiology and should be considered in the therapy of circulatory shock states.