Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum.

Kumar, Anand; Thota, V; Dee, Linda; Olson, Jeanne; Uretz, Eugene; Parrillo, Joseph E.

doi:10.1084/jem.183.3.949

Cited by 677 publications

(371 citation statements)

References 37 publications

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“…Studies examining the basis of depressed myocardial contractility in sepsis showed that TNF-a and IL-1b impair cardiac and cardiomyocyte contractility (46)(47)(48). These cytokines also induce mitochondrial injury (44).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Takasu

Gaut

Watanabe

et al. 2013

Am J Respir Crit Care Med

407

315

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Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined. Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death. Methods: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study. Measurements and Main Results: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (,1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P , 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 6 9.5% and 32.3 6 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P , 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes. Conclusions: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction.Keywords: sepsis; apoptosis; necrosis; autophagy; kidney Sepsis causes profound myocardial depression, and echocardiography frequently reveals severe biventricular dysfunction (1-5). Sepsis also induces renal insufficiency in 30 to 60% of patients, up to half of whom require dialysis (6-10). The mechanistic basis for cardiac and renal dysfunction occurring in sepsis is controversial (1,5,7,9,(11)(12)(13)(14)(15)(16). The degree to which apoptosis, necrosis, or autophagy contribute to cardiac and renal dysfunction in sepsis is unresolved (2,3,(16)(17)(18)(19).Although a few well controlled studies have been performed, extensive cell death in hearts or kidneys in patients dying of sepsis has not been described, leading investigators to postulate that cellular "hibernation" or metabolic suppression and not cell death is the basis of sepsis-induced organ failure (11,13,14,16,18,(20)(21)(22). Cardiac dysfunction in sepsis is reversible, and the majority of renal failure patients who survive sepsis recover baseline renal function; these observations are consistent with organ "hibernation" (1, ...

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Section: Discussionmentioning

confidence: 99%

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Takasu

Gaut

Watanabe

et al. 2013

Am J Respir Crit Care Med

407

315

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“…15 Because some of these cytokines are also released by adipocytes, we tested whether proinflammatory cytokines are responsible for the adipocyte-induced cardiodepressant effect. Concentrations of TNF-a, IL-6, IL-1b and IL-2 were measured in the AM and end concentrations in the experiment (dilution 1:6) were calculated (Table 1).…”

Section: Role Of Adipose Tissue In Cardiac Dysfunctionmentioning

confidence: 99%

Adipocyte-derived factors suppress heart contraction

et al. 2010

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Background: Obesity is strongly associated with cardiovascular diseases including systemic hypertension, coronary artery disease and heart failure. Despite several investigations the pathophysiological mechanisms involved remain unclear. We have previously shown that adipose tissue exerts a highly potent activity with an acute depressant effect on cardiomyocytes, thus suggesting direct involvement of adipose tissue in the development of heart dysfunction. Objective and Design: This study investigates the effects of adipocyte factors obtained from subcutaneous adipose tissue on the whole cardiac function by using isolated perfused rat hearts in a Langendorff mode. We recorded changes in coronary flow, developed isovolumetric left ventricular pressure, contraction rate and relaxation rate. Results: We observed a significant decrease in heart contractility parameters as well as in coronary flow within a few seconds of incubation with adipocyte factors. The cardiodepressant effects could not be blocked by the nonselective cyclooxygenase-inhibitor indomethacin. Human adipocytes release tumor necrosis factor-a, interleukin-6 (IL-6) and IL-1b into extracellular medium. These cytokines were tested for their potential effect but were, however, not responsible for the cardiodepressant effect observed. Conclusion: These data indicate that human adipocytes secrete factors with a strong acute depressant effect on cardiac force generation and coronary flow due to contraction of the coronary vessels, thus suggesting a direct role of adipose tissue in the pathogenesis of cardiac dysfunction.

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“…An increased level of BNP and vasodilation in septic shock is a consequence of the cytokine production (9,25,26). Tumour necrosis factor-alpha and interleukin-1beta are important cytokines released during sepsis, which are associated with myocardial depression (25).…”

Section: Discussionmentioning

confidence: 99%

Nonheart failure-associated elevation of amino terminal pro-brain natriuretic peptide in the setting of sepsis

Bar

Swiggum

Straatman

et al. 2006

Canadian Journal of Cardiology

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O ne-half of a century has been spent debating the etiology of depressed myocardial function in septic shock (1). Brain natriuretic peptide (BNP) is a new biomarker for cardiac dysfunction, and most data in the literature associate its increased levels with depressed myocardial function (2-5). However, increased levels of BNP have also been found in critical illnesses associated with shock (eg, sepsis), apparently not related to myocardial dysfunction. In human myocardium, BNP is secreted in response to myocardial stretch. Its release promotes natriuresis and diuresis, and it has a vasodilatory effect on systemic circulation (6). As such, it reduces preload, venous return and filling pressures with a subsequent reduction in cardiac output (7). The measured BNP increases in response to increases in left ventricular (LV) end-diastolic pressure, pulmonary artery wedge pressure, atrial pressure and LV hypertrophy (8). BNP level is also associated with echocardiographic dysfunction and clinical outcomes (9). The degree of cardiac dysfunction determines the magnitude of increase in BNP level (10).The BNP gene contains an encoded protein consisting of 108 peptides, called pro-BNP (11). The cleavage of pro-BNP within the heart results in two components produced in equal amounts: BNP 32 (the active hormone) and N-terminal (NT) pro-BNP (the inactive fragment) (12). The plasma half-life of NT pro-BNP is approximately 2 h in comparison with that of BNP 32 (20 min) (13), which explains the higher level of NT pro-BNP in myocardial dysfunction (14).In addition to the documented relationship between BNP and myocardial dysfunction mentioned above, there are other conditions associated with increased BNP level that include primary pulmonary hypertension, myocarditis, cardiac allograft rejection, arrhythmogenic right ventricle with decreased LV ejection fraction (EF), renal failure, Kawasaki disease, ascitic cirrhosis and endocrine diseases (Cushing's syndrome, primary hyperaldosteronism) (8). Other patient characteristics that may influence the BNP level, independent of disease, are advancing age, probably reflecting LV subclinical abnormalities (15) and female sex, both of which result in increased BNP level (15,16). Two additional studies have confirmed the correlation of NT pro-BNP with age, but not with sex (17,18). In contrast, obesity is associated with decreased levels of BNP, probably as a result of increased clearance through a receptor contained in adipose tissue (19).Parker et al (20) demonstrated that myocardial depression is also present in human septic shock and is associated with ventricular dilation and decreased LVEF (20). We present two cases of septic shock with markedly increased levels of NT pro-BNP with no evidence of myocardial dysfunction based on evaluation using echocardiography and catheterization. Also described are possible explanations of elevated NT pro-BNP in a setting not related to myocardial dysfunction. Thus, there are situations where the predictive value of BNP is not correlated with the magn...

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Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum.

Cited by 677 publications

References 37 publications

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Adipocyte-derived factors suppress heart contraction

Nonheart failure-associated elevation of amino terminal pro-brain natriuretic peptide in the setting of sepsis

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