Myofilament calcium sensitivity is decreased in skinned cardiac fibres of endotoxin-treated rabbits

Tavernier, B.; Garrigue, Delphine; Boulle, Claire; Vallet, B.; Adnet, P.

doi:10.1016/s0008-6363(98)00028-5

Cited by 50 publications

(30 citation statements)

References 31 publications

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“…In line with these findings, myocardial L-type calcium channels have been found to be decreased during endotoxemia (63). Second, a reduction in myofilament calcium sensitivity has been reported in endotoxemic rabbits (64,65). The exact mechanisms of these observations are only partially understood, but the decreased response of myofilaments to calcium may be involved in the impaired myocardial contractility and depression of systolic function in septic patients.…”

Section: Calcium Flux and Cardiomyofilamentsmentioning

confidence: 58%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

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Section: Calcium Flux and Cardiomyofilamentsmentioning

confidence: 58%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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“…A mechanism similar to that found for IL-1 in muscle (220) or in cerebro-microvascular endothelial cells (645) might be possible where endotoxin could enter through local membrane defects, e.g., also induced by NOS activation (427,673). Probably more important are subsequent inflammatory reactions induced by endotoxin in the tissue, i.e., immune activation of macrophages and release of pro-inflammatory cytokines that provide the grounds for subsequent alterations of contractile performance (692). During endotoxin shock, large amounts of NO, either released by endothelial cells but also by myocytes, seem to be causative for a deregulation of thin filament troponins by raising cGMP and phosphorylation of troponins by cGMP-dependent protein kinases, at least in the heart (75,629,673,693,791).…”

Section: Ca 2؉ Regulation Of the Contractile Apparatus In Criticalmentioning

confidence: 83%

“…However, another study in endotoxin-treated rabbits showed higher Ca 50 values for half-activation of papillary muscle isometric force (1.78 vs. 1.53 M) already 4 h after a 0.5 mg/kg iv endotoxin treatment, indicating a reduced myofibrillar Ca 2ϩ sensitivity. The latter even worsened after a higher LPS dose (1 mg/kg: Ca 50 ϭ 2.08 M) and with time (2.12 M after 24 h) but returned to normal after 5 days (692). Treatment of control papillary muscle strips with isoproterenol produced a reduction in myofibrillar Ca 2ϩ sensitivity similar to that seen in LPS-treated preparations, indicating a higher degree of protein kinase A-dependent phosphorylation as a cause for the changes in Ca 2ϩ sensitivity seen in septic hearts (693).…”

Section: B Altered Global Muscle Ca 2؉ Homeostasis In Critical Illnessmentioning

confidence: 95%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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“…Whether these findings might have an impact on organ function or integrity remains unknown. However, it is of interest that cardiac dysfunction (suppressed Ca 2ϩ sensitivity with decreased contractility [12,13]) and lung injury (acute respiratory distress syndrome) are commonplace in sepsis syndrome. This raises the intriguing but highly speculative question of whether tissue Fe loading potentially could worsen clinical sepsis syndrome or outcomes.…”

Section: Sites Of Fe-mediated Tnf-␣ Productionmentioning

confidence: 99%

Parenteral Iron Compounds

Zager

2006

Clinical Journal of the American Society of Nephrology

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Ferric iron (Fe)-carbohydrate complexes are widely used for treating Fe deficiency in patients who are unable to meet their Fe requirements with oral supplements. Intravenous Fe generally is well tolerated and effective in correcting Fe-deficient states. However, the complexing of Fe to carbohydrate polymers does not block its potent pro-oxidant effects; systemic free radical generation and, possibly, tissue damage may result. The purpose of this review is to (1) underscore the capacity of currently used parenteral Fe formulations to induce oxidative stress, (2) compare the severity of these oxidant reactions with those that result from unshielded Fe salts and with each other, and (3) speculate as to the potential of these agents to induce acute renal cell injury and augment systemic inflammatory responses. The experimental data that are reviewed should not be extrapolated to the clinical setting or be used for clinical decision making. Rather, it is hoped that the information provided herein may have utility for clinical hypothesis generation and, hence, future clinical studies. By so doing, a better understanding of Fe's potential protean effects on patients with renal disease may result.

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Myofilament calcium sensitivity is decreased in skinned cardiac fibres of endotoxin-treated rabbits

Abstract: Objective: The aim was to determine whether myofilament Ca 2q sensitivity is altered in skinned cardiac fibres from endotoxin-treated Ž .

Cited by 50 publications

References 31 publications

Molecular Events in the Cardiomyopathy of Sepsis

Molecular Events in the Cardiomyopathy of Sepsis

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Parenteral Iron Compounds

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