Abstract-Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Morbidity and mortality are high, resulting in sepsis and septic shock being the 10th most common cause of death in the United States. 5 The incidence of sepsis and sepsis-related deaths appears to be increasing by 1.5% per year. 6 In a recent study, 6 the total national hospital cost invoked by severe sepsis in the United States was estimated at approximately $16.7 billion on the basis of an estimated severe sepsis rate of 751 000 cases per year with 215 000 associated deaths annually. A recent study from Britain documented a 46% in-hospital mortality rate for patients presenting with severe sepsis on admission to the intensive care unit. 7 As an important organ system frequently affected by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. In 1951, Waisbren was the first to describe cardiovascular dysfunction due to sepsis. 8 He recognized a hyperdynamic state with full bounding pulses, flushing, fever, oliguria, and hypotension. In addition, he described a second, smaller patient group who presented clammy, pale, and hypotensive with low volume pulses and who appeared more severely ill. With hindsight, the latter group might well have been volume underresuscitated...

The nitrite anion is reduced to nitric oxide (NO • ) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO • signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ( +/+ ) and knockout ( −/− ) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO • generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO • generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO • by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin +/+ but not in myoglobin −/− hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin +/+ mice, whereas in myoglobin −/− mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation. myoglobin knockout mice

Diets rich in flavanols reverse vascular dysfunction in diabetes, highlighting therapeutic potentials in cardiovascular disease.

The present study explored the role of myoglobin (Mb) in cardiac NO homeostasis and its functional relevance by employing isolated hearts of wild-type (WT) and myoglobin knockout mice. 1 H NMR spectroscopy was used to measure directly the conversion of oxygenated Mb (MbO2) to metmyoglobin (metMb) by reaction with NO. NO was applied intracoronarily (5 nM to 25 M), or its endogenous production was stimulated with bradykinin (Bk; 10 nM to 2 M). We found that infusion of authentic NO solutions dose-dependently (> 2.5 M NO) increased metMb formation in WT hearts that was rapidly reversible on cessation of NO infusion. Likewise, Bk-induced release of NO was associated with significant metMb formation in the WT (>1 M Bk and IIa skeletal and cardiac muscle tissue (1). As a major breakthrough in understanding globular protein structure, its tertiary structure was derived from x-ray diffraction studies by John Kendrew and his colleagues as early as the 1950s (2). Mb is a relatively small (M r 16,700) and densely packed protein consisting of a single polypeptide chain of 153 amino acid residues. It contains an iron-porphyrin heme group identical to that of hemoglobin (Hb), and like Hb is capable of reversible oxygenation and deoxygenation. In mammals, half O 2 saturation of Mb is achieved at an intracellular O 2 partial pressure as low as 2.4 mmHg (1 mmHg ϭ 133 Pa; ref.3), suggesting a predominance of oxygenated Mb (MbO 2 ) under basal conditions. Mb's function as an oxygen store is well accepted. Mb serves as a short-term O 2 reservoir in exercising skeletal muscle and in the beating heart, tiding the muscle over from one contraction to the next (4). In diving mammals, the concentrations of Mb exceed those of terrestrial mammals up to 10-fold, and Mb most likely serves for the extension of diving time when pulmonary ventilation ceases (5). Similarly, in mammals and humans adapted to high altitudes, Mb is expressed in high concentrations in skeletal muscle (6).It has been proposed that Mb facilitates intracellular delivery of O 2 , in that Mb adjacent to the cell membrane picks up oxygen, traverses the cytosol by translational diffusion to unload O 2 in the vicinity of mitochondria, and finally diffuses back to the cell membrane in the deoxygenated state (7). This circuit, termed ''facilitated O 2 diffusion,'' may be a critical link between capillary O 2 supply and O 2 -consuming cytochromes within mitochondria in the steady state. Facilitated O 2 diffusion has been unambiguously demonstrated in concentrated Mb solutions (8), but experiments carried out in isolated cells, papillary muscle, and at the whole organ level have yielded conflicting results (9-11). Likewise, model calculations have both refuted and supported the contribution of Mb-bound O 2 to total O 2 flux (11, 12).The recent generation of transgenic mice lacking Mb has shed new light on the role of Mb in the intracellular delivery of O 2 (13,14). Loss of Mb led to a surprisingly benign phenotype, with exercise and reproductive capacity, as well as cardiac and ...

Background-HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis. We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis. Methods and Results-Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice. This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice [eg, 20 hours after CLP, cardiac output declined from 1.24Ϯ0.09 to 0.87Ϯ0.11 mL · min Ϫ1 · g Ϫ1 in untreated mice (PϽ0.005; nϭ12), while remaining unaltered (1.21Ϯ0.08 mL · min Ϫ1 · g Ϫ1 at baseline and 1.15Ϯ0.1 mL · min Ϫ1 · g