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Septic cardiomyophaty as a component of multiple organ dysfunction syndrome in severe sepsis


Cardiac dysfunction has been recognized as a serious manifestation in approximately 60% of patients with sepsis, with mortality rate from 70% to 90% in contrast with 20% in septic patients without cardiovascular involvement. However, the implication of the involvement of the heart as part of the syndrome of multiple organ dysfunction in sepsis has been rejected. The main proposed mechanism to explain cardiac dysfunction in sepsis derives from functional abnormalities and not from structural abnormalities. Although in recent years the concept of septic cardiomyopathy has evolved, which implies alterations in the myocardial phenotype in response to a variety of agents acting on heart cells, the importance of myocardial structural changes in sepsis has been overlooked. However, attempts to reduce high mortality rates of septic patients by manipulating these functional alterations have provided limited success. In 2007, work from our laboratory suggested that structural changes in the myocardium, classified as "inflammatory cardiomyopathy" could be responsible for sepsis-induced myocardial depression. Later, in experimental studies with the CLP model in mice, cellular and molecular changes directly dependent severe sepsis and septic shock correlated to cardiac dysfunction. Were demonstrated diffuse foci of necrosis myocytolytic not associated with inflammatory infiltrate characterized a cardiomyopathy in experimental animals but not an inflammatory cardiomyopathy similar to that in man: myocarditis associated with cardiac dysfunction. Furthermore, we demonstrate the prevention of molecular changes and cardiac dysfunction with calcium blocking drugs.Over years, many research groups have been trying to establish animal models that present an appropriate similarity to human sepsis such as endotoxin from Gram-negative bacteria or exotoxin from Gram-positive bacteria challenge and intraperitoneal or intravenous administration of live organisms. It is well known that during sepsis/septic shock, the entrance of bacteria or LPS into the circulation is small, raising the question whether these models really mimic the development of sepsis. The cecal ligation and puncture (CLP) model was proposed in 1980 mimicking the clinical condition of intestinal perforation and acute polymicrobial peritonitis. Since then, is the model has substantially contributed to our understanding of many pathophysiological and immunological features of sepsis, considered the gold standard model of sepsis. However it does not reproduce the whole complexity of the clinical situation. A major problem in the development of effective strategies for the treatment of sepsis is that the host immunologic response changes with disease progression. Early deaths in sepsis are usually a result of hyperinflammatory response and those that survive this initial state evolve to a period of immunosuppression that predispose the host to the development of a variety of secondary infections, particularly pneumonia caused by gram-negative bacteria. Thus, the understanding of both phases (pro- and anti-inflammatory) in the human sepsis requires animal models in which the hyperinflammatory response can be overcome and thereby allow the host defense is studied during the longer period of this syndrome. To carry out this study we will use the model of two-insults ("two-hit" - proposed by Muenzer et al (2006)), induction of moderate sepsis by CLP and, 3 or 7 days later, the surviving animals will be challenged with Pseudomonas aeruginosa (important pathogen causing nosocomial infections) intranasally to induce pneumonia in order to 1) reproduce the common clinical scenario, i.e., prolonged hospital course and susceptibility to secondary infections, and 2) characterize the inflammatory cardiomyopathy (with emphasis structural and functional changes in the heart) as a component of the Multiple Organ Dysfunction Syndrome in this model. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PRADO, FERNANDA P.; DOS SANTOS, DANIELE O.; BLEFARI, VALDECIR; SILVA, CARLOS A.; MACHADO, JULIANO; KETTELHUT, ISIS DO CARMO; RAMOS, SIMONE G.; BARUFFI, MARCELO DIAS; SALGADO, HELIO C.; PRADO, CIBELE M. Early dystrophin loss is coincident with the transition of compensated cardiac hypertrophy to heart failure. PLoS One, v. 12, n. 12 DEC 21 2017. Web of Science Citations: 2.
SILVA FREITAS, ANA CAROLINE; FIGUEIREDO, MARIA JOSE; CAMPOS, ERICA CAROLINA; SOAVE, DANILO FIGUEIREDO; RAMOS, SIMONE GUSMAO; TANOWITZ, HERBERT B.; CELES, MARA RUBIA N. Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition. PLoS One, v. 11, n. 11 NOV 23 2016. Web of Science Citations: 4.

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