Einfluss des HMG-CoA-Reduktase-Inhibitors Simvastatin auf Überleben und hämodynamische Parameter im murinen Sepsismodell

Abstract

Sepsis remains one of the leading causes of death among patients treated in intensive care units. Despite significant advances in the understanding of the pathophysiology of sepsis with activation of multiple cellular and humoral pathways in the meantime, treating sepsis is still challenging. Recently, activated protein C and low-dose hydrocortisone demonstrated a reduction of mortality rate. However, the latter remains on a high level ranging between 30% and 50%. Clinical trials and studies in animal models demonstrated so-called pleiotropic effects for HMG-CoA reductase inhibitors beyond their lipid-lowering effects. These pleiotropic effects include anti-inflammatory, immunmodulatory, anticoagulative, antioxidative and antiapoptotic properties and furthermore improvement of endothelial function, which could affect the complex interactions of the pathophysiology of sepsis. The present study investigates whether treatment with the HMG-CoA reductase inhibitor simvastatin might improve survival and cardiovascular function in a murine model of sepsis. After intraperitoneal injection of simvastatin, sepsis was induced via cecum ligation and puncture (CLP). This polymicrobial model of sepsis closely resembles the hemodynamic and metabolic phases of human sepsis. We observed typical sepsis criteria in our model including bacteremia. To address possible changes in cardiovascular function we obtained cardiovascular parameters by echocardiography and intraarteriell blood pressure measurements. In addition we performed studies in an isolated heart Langendorff setup. Inducing sepsis via CLP resulted in 100% lethality in untreated animals. Median survival time was extended from 28 hours in untreated to 108 hours in simvastatin treated mice. Performing echocardiography we observed a hypodynamic state in untreated animals, which developed after a hyperdynamic state analog to human sepsis. In contrast to simvastatin treated animals, untreated mice exhibited a reduced peripheral vascular resistance in the intraarteriell blood pressure measurements. The application of ETU, an unspecific inhibitor of NO synthases, led to an increase of the mean arterial blood pressure in all animal groups indicating a high-level NO production causing vasodilatation and hypotension in sepsis. In untreated mice no significant changes in mean arterial blood pressure and cardiac output were detected after dobutamine stimulation indicating the well described hyporeactivity to catecholamines that occurs in sepsis. Regarding an acute septic cardiomyopathy a significant cardiac dysfunction was documented accompanied by reduction of left ventricular contractility of the isolated heart in the Langendorff setup. In simvastatin treated animals we observed that the responsiveness to the catecholamine dobutamine was restored. In this animal group we detected neither cardiac depression nor significant hypotension in comparison to sham-operated animals. As underlying mechanism for hemodynamic stabilization NO- modulating properties of simvastatin could play a crucial role. Application of the eNOS stimulator bradykinin potentized the already increased NO release by enhancing the eNOS activitiy in untreated septic mice. Consistently, the coronary flow reserve was exhausted in this group of animals. Treatment with simvastatin was followed by conservation of the coronary flow reserve indicating an eNOS-modulating effect of simvastatin. Besides modulating eNOS, iNOS modulation has been described in the literature. Furthermore statins influence leukocyte- endothelial interactions. In addition to anti-inflammatory and immunmodulatory effects of statins anticoagulative, antioxidative and antiapoptotic properties influence different components of the complex pathophysiology of sepsis. The present study demonstrates a hemodynamic stabilization and preserved cardiac function after application of simvastatin leading to a significantly improved survival time in a murine model of sepsis. Better understanding of the pleiotropic effects of statins in addition to retrospective clinical trials and prospective observational studies suggest that statins could possibly play a role in the prevention and therapy of sepsis in the future. Large placebo-controlled blinded randomised trials in patients are clearly needed to assess the value of statins as a new therapeutic approach for sepsis