Endotoxin-induced Cardiac Depression is Associated with Decreased Cardiac Dihydropyridine Receptors in Rabbits

Lew, Wilbur Y.W.; Yasuda, Satoshi; Yuan, Tony; Hammond, Kirk

doi:10.1006/jmcc.1996.0127

Cited by 39 publications

(21 citation statements)

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“…First, abnormalities in the myocardial calcium current have been described in endotoxemic guinea pigs (61), as well as in cultured rodent cardiomyocytes exposed to the cardiodepressive IL-1β (62). 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).…”

Section: Calcium Flux and Cardiomyofilamentsmentioning

confidence: 69%

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: 69%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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“…While the present study showed that contractility, as measured by Ees, was independent of extracellular ionized calcium, there are several instances where extracellular calcium correlates with increased contractility and where it does not [2,8,9,37]. Although several investigators have reported increases in CO and mean arterial pressure [28,35,36,38] with correction of hypocalcemia, others have not reported any differences [2,39].…”

Section: Discussionmentioning

confidence: 52%

Effects of Correction of Hypocalcemia on Cardiac Function in the Newborn Lamb

Moon

Milstein²,

Goetzman

et al. 2000

Neonatology

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The effect of correction of hypocalcemia on cardiac function in the neonate is unclear. Therefore, we evaluated changes in hemodynamic variables and cardiac contractility in a hypocalcemic neonatal lamb model. Baseline serum ionized hypocalcemia was induced via chelation with intravenous EGTA. Cardiac contractility, measured as end-systolic elastance, did not change with correction of hypocalcemia in this model. In contrast, the variable dP/dt_max, a load-dependent index of contractility, showed an increase with calcium administration while the end-diastolic volume decreased, suggesting that diastolic function or early systolic function had changed. Systemic vascular resistance, cardiac output, and heart rate did not change significantly with correction of hypocalcemia. The results of this study suggest that in our newborn lamb model, cardiac contractility is insensitive to ionized calcium and may reflect cardiac immaturity, but that there may be an effect of calcium administration on diastolic or early systolic function.

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“…Several studies have demonstrated that there is an endotoxemia-induced reduction in the L-type calcium current in ventricular myocytes in animal models. [12][13][14][15] These studies showed that the endotoxin-induced cardiac contractile LV dysfunction was associated with a decrease in the functional L-type calcium channels. In representative traces of action potentials from ventricular myocytes before and 4 hours after an intraperitoneal injection of LPS, the action potential duration of the LPS myocytes was significantly shorter than that of the control myocytes.…”

Section: Discussionmentioning

confidence: 99%

“…11) LPS also affects the ventricles via physiological and biochemical regulation which leads to LV dysfunction. [12][13][14][15] On the other hand, various predisposing factors including the thyroid, 16) ethanol, and glucocorticoids have been reported to potentially lead to AF occurrence due to cardiac ion channel remodeling. Therefore, LPS might cause some biochemical regulation effects in rat atria via cardiac ion channel gene expression leading to AF occurrence.…”

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confidence: 99%

Lipopolysaccharide Induces Atrial Arrhythmogenesis via Down-Regulation of L-Type Ca2+ Channel Genes in Rats

et al. 2009

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SummarySeptic shock has been reported as an independent risk factor for atrial fibrillation (AF), however, the mechanism remains unknown. We investigated whether lipopolysaccharide (LPS) could alter cardiac ion channel gene expression, thereby leading to atrial arrhythmogenesis.LPS (2.5 mg/kg) was injected intraperitoneally into 10 week old Sprague-Dawley rats (n = 5). Hemodynamic data were obtained and the atrial appendages were removed after LPS injection (0, 3, 6, 12, and 24 hours) for an RNase protection assay for α1C, β2, α1G, and SCN5A. An electrophysiological study in isolated perfused hearts was performed before and 12 hours after the LPS injection. Heart rate and body temperature were significantly increased (P < 0.05) and mean blood pressure was slightly decreased (P < 0.1) at 12 hours after LPS injection. The mRNA levels of the L-type calcium channel gene (β2 and α1C) were significantly decreased at 6 and 12 hours after LPS injection. Atrial ERP became significantly shortened and the number of repetitive atrial responses induced by an extrastimulus were significantly increased after LPS injection.LPS induced the down-regulation of L-type calcium channel gene expression and ERP shortening, which might be a mechanism underlying sepsis-induced AF. (Int Heart J 2009; 50: 353-363) Key words: Atrial fibrillation, Septic shock, L-type calcium channel, Lipopolysaccharide, Electrical remodeling IT has been reported that septic shock is one of the independent risk factors for atrial fibrillation (AF) in the surgical intensive care unit. [1][2][3] In a multivariate analysis of the risk factors for AF, the odds ratio of shock was high at greater than 6, and most cases of shock were septic shock.

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Endotoxin-induced Cardiac Depression is Associated with Decreased Cardiac Dihydropyridine Receptors in Rabbits

Cited by 39 publications

References 0 publications

Molecular Events in the Cardiomyopathy of Sepsis

Molecular Events in the Cardiomyopathy of Sepsis

Effects of Correction of Hypocalcemia on Cardiac Function in the Newborn Lamb

Lipopolysaccharide Induces Atrial Arrhythmogenesis via Down-Regulation of L-Type Ca2+ Channel Genes in Rats

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