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To investigate the relationship between prognosis, changes in mitochondrial calcium uptake, and bioenergetic status in the heart during sepsis.In vivo and ex vivo controlled experimental studies.University research laboratory.Male adult Wistar rats.Sepsis was induced by intraperitoneal injection of fecal slurry. Sham-operated animals served as controls. Confocal microscopy was used to study functional and bioenergetic parameters in cardiomyocytes isolated after 24-hour sepsis. Electron microscopy was used to characterize structural changes in mitochondria and sarcoplasmic reticulum. The functional response to dobutamine was assessed in vivo by echocardiography.Peak aortic blood flow velocity measured at 24 hours was a good discriminator for 72-hour survival (area under the receiver operator characteristic, 0.84 ± 0.1; p = 0.03) and was used in ex vivo experiments at 24 hours to identify septic animals with good prognosis. Measurements from animals with good prognostic showed 1) a smaller increase in mitochondrial calcium content and in nicotinamide adenine dinucleotide fluorescence following pacing and 2) increased distance between mitochondria and sarcoplasmic reticulum on electron microscopy, and 3) nicotinamide adenine dinucleotide redox potential and adenosine triphosphate/adenosine diphosphate failed to reach a new steady state following pacing, suggesting impaired matching of energy supply and demand. In vivo, good prognosis animals had a blunted response to dobutamine with respect to stroke volume and kinetic energy.In situations of higher energetic demand decreased mitochondrial calcium uptake may constitute an adaptive cellular response that confers a survival advantage in response to sepsis at a cost of decreased oxidative capacity.

This special issue wants to contribute to a better understanding of cardiac involvement in sepsis. Sepsis is a complex syndrome that has recently been defined as “life-threatening organ dysfunction due to a dysregulated host response to infection” [1, 2]. It should be considered a major public health problem since it affects millions of people worldwide each year, and it accounts for most deaths in critically ill patients. The presence of myocardial dysfunction in sepsis is associated with higher mortality. A great attention has been dedicated to improving our knowledge and understanding of the intricate mechanisms underlying sepsis. However, data from the literature suggest the need to implement strategies to reliably measure sepsis morbidity and mortality. In fact, methods based on analyses of insurance claim data using sepsis-specific codes or separate codes for infection and organ dysfunction are unreliable in informing or measuring the effects of policy changes [3, 4], and the postmortem diagnosis of sepsis is often elusive since postmortem investigations lack certain pathognomonic macroscopic and histopathological findings [5, 6]. From a morphological and diagnostic point of view, the term “septic disease” has been created to describe the cardiac involvement in the syndrome. However, this definition, rather than describing a morphological finding, was instead referred to the clinical setting. Although in recent years the concept of septic cardiomyopathy has evolved and it involves pathological alterations of myocardial cells in response to the multiplicity of acting mechanism of damage, the importance of structural changes during sepsis is often overlooked. In patients with sepsis, death is usually the result of a progressive multiorgan dysfunction, overlooking the primary infection through the hyperinflammation. The cardiac involvement as fundamental part of septic multiorgan dysfunction syndrome has been discussed for a long time. C. Pomara et al. explored the state of current knowledge on the molecular and biohumoral mechanisms of sepsis and correlate them with our ability at postmortem diagnosis. The authors highlight that a complete methodological approach, integrating clinical data by means of autopsy and histological and laboratory findings aiming to identify and demonstrate the host response to infectious insult, is mandatory. Such an approach would be likely to produce an accurate objective surveillance of deaths due to sepsis and improve our knowledge of the clinical-pathological correlation in sepsis, thus contributing to the evaluation of the effectiveness of therapies. Sepsis is characterized by symptoms and manifestations of organ dysfunction that may lead to fatal outcome. Myocardial dysfunction in sepsis is mediated by a complex interplay among several factors that still remains incompletely understood [7]. Circulatory compromise and microcirculatory alterations may, in part, explain cardiac impairment in sepsis. However, in recent years increasing attention has been paid to the study of other possible pathways of myocardial dysfunction in sepsis. The effects of the host's immune-inflammatory response with particular focus on depressant molecules, complement molecules, cellular adhesion molecules, and altered intracellular energetic, dysregulated intracellular calcium fluxes have been called upon in the pathophysiology of myocardial depression in sepsis. Oxidative-nitrosative stress may contribute to cardiac dysfunction in sepsis, and mitochondria are one of the major sites for generation of reactive oxygen species and reactive nitrosative species as a detrimental side product of oxidative energy metabolism [8]. M. Neri et al. reviewed the evidence for a role of oxidative-nitrosative stress unbalance and mitochondria dysfunction in myocardial depression in sepsis. NADPH oxidase-derived reactive oxygen species, the role of mitochondria, and finally the involvement of nitric oxide and peroxynitrite as critical factors in mediating myocardial dysfunction in sepsis are discussed. Measurement of biomarkers is a potential approach to early prediction of the risk of mortality in patients with sepsis. Over the years, a great amount of molecules has been proposed as potential biological markers [9]. However, only 20% of these biomarkers have been assessed specifically in appropriate studies for use in the diagnosis of sepsis [10]. To date an ideal clinical and postmortem marker of sepsis does not exist. Proadrenomedullin and copeptin are peptides cosynthesized together with adrenomedullin and vasopressin in endothelial cells and pituitary gland, respectively. These peptides are increased during sepsis. They have vasoactive, immune modulating, and metabolic properties. It was recently reported that adrenomedullin plays a central role in initiating the hyperdynamic response during the early stages of sepsis and was a useful predictor for development of severe sepsis and septic shock [11, 12]. W. Hu et al. discuss the prognostic value of adrenomedullin and atrial and brain natriuretic peptides in uroseptic patients induced by ureteroscopy. In their research article the authors suggest that the prognostic value of adrenomedullin is superior to atrial and brain natriuretic peptides and that all these molecules are robust independent predictors of in-hospital death in uroseptic patients. They conclude that adrenomedullin and atrial and brain natriuretic peptides may participate in initiating the hyperdynamic response during the early stages of sepsis in uroseptic patients and that these biomarkers could be considered strong predictors of adverse outcome in patients with urosepsis. Finally, two articles of the special issue discuss the potential link existing between inflammatory status and cardiometabolic disorders. It has been well established that inflammation is also able to affect lipoprotein metabolism. However, the precise mechanisms pathophysiologically linking metabolic dysfunction and inflammation are still under investigation. The biological basis for these associations includes both systemic and local tissue effects. Metabolic Syndrome (MetS) is a constellation of diseases that include obesity, diabetes, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. These metabolic derangements trigger a persistent inflammatory cascade, whit recruitment of immune cells to the site of injury, and subsequent expression of cytokines and chemokines that amplify the inflammatory response [13]. A common link between inflammation and MetS has been suggested. In cardiometabolic disorders a high serum lipopolysaccharides activity has been demonstrated, thus suggesting a potential role of bacterial infections and immune response in their etiology [14]. One article discussed the serum adiponectin levels and the homeostasis model assessment-insulin resistance (HOMA-IR) that are reportedly associated with MetS. Y.-S. Ding et al. concluded that the adiponectin to HOMA-IR ratio (A/H) may be a better diagnostic marker for MetS than either HOMA-IR or adiponectin alone, and it may serve as an important biomarker to determine an increased risk for MetS in healthy middle-aged population. Y. Zhang et al. investigated the relationship between inflammatory markers and the atherogenic lipoprotein subfractions, and they hypothesized presence of heterogeneity in the relationship of systemic inflammatory markers with atherogenic lipoprotein subfractions, which would aid our understanding of their interplay in the pathogenesis of atherosclerotic disease. This special issue is dedicated to the cardiovascular involvement in sepsis. The high mortality associated with sepsis makes a thorough knowledge of its underlying mechanisms and its pathophysiological connections with the cardiometabolic disorders important.

ObjectiveStatins are among the most prescribed drugs worldwide and their recently discovered anti-inflammatory effect seems to have an important role in inhibiting proinflammatory cytokine production, chemokines expression and counteracting the harmful effects of sepsis on the coagulation system. We decided to perform a meta-analysis of all randomized controlled trials ever published on statin therapy in septic patients to evaluate their effect on survival and length of hospital stay.Data sources and study selectionArticles were assessed by four trained investigators, with divergences resolved by consensus. BioMedCentral, PubMed, Embase and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocation to treatment and comparison of statins versus any comparator in septic patients.Data extraction and synthesisData from 650 patients in 5 randomized controlled studies were analyzed. No difference in mortality between patients receiving statins versus control (44/322 [14%] in the statins group vs 50/328 [15%] in the control arm, RR = 0.90 [95% CI 0.65 to 1.26], p = 0.6) was observed. No differences in hospital stay (p = 0.7) were found.ConclusionsPublished data show that statin therapy has no effect on mortality in the overall population of adult septic patients. Scientific evidence on statins role in septic patients is still limited and larger randomized trials should be performed on this topic.

La sepsis continúa siendo una de las principales causas de muerte alrededor del mundo a pesar de los grandes avances en su investigación. Representa un desequilibrio en los diferentes mecanismos inmunológicos responsables de neutralizar la invasión de un agente infeccioso. En este artículo se presenta una revisión sobre los conceptos fisiopatológicos de la sepsis, así como sobre las diferentes alteraciones genéticas que hacen a un individuo susceptible a desarrollarla. Worldwide, sepsis continues to be a major cause of death, in spite of the impressive advances in its research. This condition represents an imbalance in the different immunological mechanisms responsible for neutralizing the infectious agent invasion. In this paper, a review of the physiopathological concepts of sepsis is presented, including the different genetic variations which make an individual susceptible to sepsis.

INTRODUCTION: Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. METHODS: This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. RESULTS: Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). CONCLUSIONS: The novel findings of our study on patients with severe sepsis (to our knowledge, the largest series reporting data about MMP levels in sepsis) are that reduced MMP-9/TIMP-1 ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that TIMP-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis.

PURPOSE: Low tidal volume ventilation and permissive hypercapnia are required in patients with sepsis complicated by ARDS. The effects of hypercapnia on tissue oxidative metabolism in this setting are unknown. We therefore determined the effects of moderate hypercapnia on markers of systemic and splanchnic oxidative metabolism in an animal model of endotoxemia. METHODS: Anesthetized rats maintained at a PaCO(2) of 30, 40 or 60 mmHg were challenged with endotoxin. A control group (PaCO(2) 40 mmHg) received isotonic saline. Hemodynamic variables, arterial lactate, pyruvate, and ketone bodies were measured at baseline and after 4 h. Tissue adenosine triphosphate (ATP) and lactate were measured in the small intestine and the liver after 4 h. RESULTS: Endotoxin resulted in low cardiac output, increased lactate/pyruvate ratio and decreased ketone body ratio. These changes were not influenced by hypercapnia, but were more severe with hypocapnia. In the liver, ATP decreased and lactate increased independently from PaCO(2) after endotoxin. In contrast, the drop of ATP and the rise in lactate triggered by endotoxin in the intestine were prevented by hypercapnia. CONCLUSIONS: During endotoxemia in rats, moderate hypercapnia prevents the deterioration of tissue energetics in the intestine.