Paper
Treatment of myocardial dysfunction in sepsis: the Toll-like receptor antagonist approach.
Published Dec 1, 2011 · DOI · A. Kimmoun, B. Levy
Shock
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Abstract
Despite a decreasing trend over the past decade, the mortality rate in septic shock remains high ranging between 20% and 65% (1). Death may occur from intractable cardiovascular failure, likely within the first 48 h, or from late multiple organ failure. Septic shock is characterized by both an alteration in vascular tone and a systolic and diastolic biventricular dysfunction. The overall incidence of global left ventricular hypokinesia in patients with septic shock and no prior cardiac history is 60% (2). Recent findings support a complex pathophysiology for myocardial failure involving myocardial depressor molecules such as cytokines (tumor necrosis factor [TNF-!], interleukin 1" [IL-1"]), endothelin 1, and lysozyme c. The most involved mediator is nitric oxide, which has complex negative and positive effects on cardiac contractility. The discovery of Toll-like receptor 4 (TLR) in 1997 enabled to complete the pathological understanding between endotoxin recognition by the ligand-binding proteinYCD14 complex and the translocation of nuclear factor .B (NF-.B) leading to cytokine production (3). Toll-like receptor 4 is also found in cardiac cells and mediates the inflammatory response to endotoxin (4, 5). However, chimeric mice with inactive TLR-4 on leukocytes and functional TLR-4 on cardiomyocytes were found not to experience cardiac depression in response to lipopolysaccharide (LPS) (6). In another study, TLR-4Yknockout mice who underwent a hematopoietic stem cell allograft (with normal leukocyte TLR-4 expression) demonstrated better cardiac resistance to LPS versus wild type (7). Thus, TLR-4 in cardiomyocytes may play a key role in cardiac dysfunction during septic shock. To date, there has been no new therapy for septic shock treatment since the advent of human recombinant activated protein C in 2001 and no specific therapy for cardiac dysfunction (8). E5564/eritoran tetrasodium, a synthetic lipodisaccharide, has been shown to block LPS-mediated activation of NF-.B and cytokine production by direct antagonism of TLR-4 (9). Hence, eritoran tetrasodium could represent a novel approach in septic shock treatment. Safety and tolerability to two dose regimens of eritoran tetrasodium (45 and 105 mg) were recently assessed in patients undergoing severe sepsis or septic shock during a phase 2 trial. In prespecified subgroups of patients with high Acute Physiology and Chronic Health Evaluation II scores receiving 105 mg of eritoran tetrasodium, a trend toward a lower mortality was observed (10). A phase 3 trial comparing eritoran tetrasodium versus placebo during severe sepsis is ongoing, although no patient has currently been included (clinicaltrial.gov: NCT00334828). Many studies have confirmed eritoran tetrasodium action in reducing proinflammatory cytokine production during severe sepsis (9, 11, 12). However, only a few studies have been concerned with the specific actions of eritoran tetrasodium on cardiomyocyte TLR-4. In an initial study in 2006, Baumgarten et al. (13) first demonstrated, in vitro, a direct alteration of myocyte contractility by TLR-4Ymediated endotoxin. In contrast, in nonfunctional TLR-4 mice, LPS did not affect cardiac cell contractility, while reducing NF-.B activation and inducible nitric oxide synthase (iNOS) induction. Cardiac myocytes from wild-type mice treated by eritoran tetrasodium, a TLR-4 antagonist, reduced the effect of LPS on myocyte contractility. In a subsequent study, LPS associated with eritoran tetrasodium did not alter the ex vivo vascular contractility of aortic rings. Moreover, in the aorta of LPS hyporesponsive mice (point mutation on cytoplasmic region of TLR-4), mRNA of proinflammatory cytokines (IL-1", IL-6, and TNF-!) did not increase after LPS application. Moreover, iNOS upregulation after LPS induction in control mice was almost completely abolished in LPS-hyporesponsive mice (14). The authors hence concluded that TLR-4 is a key component of hypovasoreactivity during sepsis and a potential pharmacological target of eritoran tetrasodium. In the work published in this issue, Ehrentraut et al. (15) confirm their previous in vitro results in an in vivo animal model. Using wireless hemodynamic monitoring in conscious free-moving mice, eritoran tetrasodium prophylactic injection prevents arterial hypotension induced by LPS. Moreover, the authors specifically assess cardiac function with a conductance catheter. Eritoran tetrasodium, after LPS induction, partially restores preload-dependent parameters: ejection fraction, dp/dtmax and dp/dtmin. Nevertheless, because in their experimental model, animals were not under mechanical ventilation, no data could be provided on contractility improvement from load-independent parameters. Clearly, these data are fundamental to definitely conclude that eritoran tetrasodium improves intrinsic cardiac contractility during endotoxemia. Associated with the hemodynamic results, the authors also found that, in presence of eritoran tetrasodium, iNOS mRNA levels in myocardium and aorta significantly decreased compared with LPS alone. Unfortunately, nitrite-nitrate levels or NO measured with paraelectromagnetic resonance were not
Eritoran tetrasodium, a Toll-like receptor antagonist, shows potential in treating cardiac dysfunction in septic shock by blocking NF-.B activation and cytokine production.
- PopulationOlder adults (50-71 years)
- Sample size24
- MethodsObservational
- OutcomesBody Mass Index projections
- ResultsSocial networks mitigate obesity in older groups.
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