Insulin resistance and inflammation are a cause of hyperglycemia after pediatric cardiopulmonary bypass surgery

Floh, Alejandro A.; Manlhiot, Cedric; Redington, Andrew N.; McCrindle, Brian W.; Clarizia, Nadia A.; Caldarone, Christopher A.; Schwartz, Steven M.

doi:10.1016/j.jtcvs.2015.06.028

Cited by 25 publications

(17 citation statements)

References 25 publications

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“…Transient hyperglycemia following pediatric CPB surgery is nearly universal and has consistently been associated with increased morbidity, longer hospitalization, and higher mortality . Insulin resistance has been invoked as a potential mechanism, supported previously by an observed rise in plasma insulin and lower G:I in the setting of elevated plasma cytokine levels . This study confirms that there is a simultaneous increase in inflammatory cytokines and indices of insulin resistance following CPB.…”

Section: Discussionsupporting

confidence: 81%

“…Increased plasma glucose was not an independent predictor of increased inflammation. In contrast to the anticipated positive association between markers of insulin resistance and inflammation, the response of proinflammatory cytokines IL6 and IL8 to insulin resistance were opposite from each other. IL8 behaved as expected with increased plasma insulin and lower G:I associated with higher IL8, whereas markers of insulin resistance were associated with lower IL6.…”

Section: Discussioncontrasting

confidence: 64%

“…[1][2][3] Insulin resistance has been invoked as a potential mechanism, supported previously by an observed rise in plasma insulin and lower G:I in the setting of elevated plasma cytokine levels. 4,12 This study confirms that there is a simultaneous increase in inflammatory cytokines and indices of insulin resistance following CPB. However, unlike our initial theory, postoperative insulin resistance was not associated with increased morbidity after accounting for the heightened inflammatory response.…”

Section: Cpb-related Morbidity Is Often Attributed To the Incitement supporting

confidence: 74%

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Feeding May Modulate the Relationship Between Systemic Inflammation, Insulin Resistance, and Poor Outcome Following Cardiopulmonary Bypass for Pediatric Cardiac Surgery

Floh

McCrindle

Manlhiot

et al. 2019

J Parenter Enteral Nutr

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Background Hyperglycemia is common following cardiopulmonary bypass (CPB) surgery and is associated with poor outcomes, often attributed to hyperinsulinemia and an acquired state of insulin resistance. This study examined the underpinnings of hyperglycemia and the effects of nutrition on the association with inflammation and clinical outcomes. Methods This prospective, observational cohort study enrolled consecutive children (<18 years) undergoing CPB. Serial measurements of inflammatory cytokines, glucose, insulin, and nutrition delivery were obtained. Glucose‐insulin ratio (G:I) was calculated for each time point as a measure of insulin resistance (lower G:I reflects higher resistance). Clinical outcomes were recorded using a composite morbidity score. Results The 200 subjects studied were predominantly females (58%) undergoing biventricular repair (85%) at a median (interquartile range) age of 0.58 years (0.28, 3.4) and weight of 7.0 kg (3.1, 59.5). Hyperglycemia was common (49% of patients), coinciding with peak cytokine concentrations. Insulin levels were highest and G:I lowest immediately following separation from CPB but had no consistent relationship with cytokines. The morbidity outcome was reached by 23% of patients, with increased odds associated with higher interleukin (IL)6 and IL8 levels but not by glucose, insulin, or G:I. Providing higher feeding volumes attenuated this association between inflammation and morbidity. Higher feeds were not associated with G:I but appeared to decrease the strength of the relationship between cytokines and glycemic indices. Conclusion Postoperative morbidity is independently associated with increased inflammation but not with hyperglycemia or markers of insulin resistance. Higher feeding volume may modify these relationships and have a protective role.

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Section: Discussionsupporting

confidence: 81%

Section: Discussioncontrasting

confidence: 64%

Section: Cpb-related Morbidity Is Often Attributed To the Incitement supporting

confidence: 74%

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Feeding May Modulate the Relationship Between Systemic Inflammation, Insulin Resistance, and Poor Outcome Following Cardiopulmonary Bypass for Pediatric Cardiac Surgery

Floh

McCrindle

Manlhiot

et al. 2019

J Parenter Enteral Nutr

Self Cite

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“…38 Various insults, including mechanical, trauma, hypotension, coagulation disturbances, hypothermia, and hemodilution, took place during the CPB procedure, which result in severely disturbed imbalance in the internal environment such as hyperglycemia, and hyperlactatemia. 39 Moreover, these insults also inevitably suppress the insulin signal transduction pathway, 40 and simultaneously increase plasma level of glucocorticoids that also indirectly exacerbates insulin resistance. 41,42 Compared with insulin resistance that chronically develops in diabetics, the underlying mechanism of acute glucose metabolism disorders in acute injury and critical illness is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Activation of AMPK alleviates cardiopulmonary bypass‐induced cardiac injury via ameliorating acute cardiac glucose metabolic disorder

Wang

Cao

Yin

et al. 2018

Cardiovascular Therapeutics

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Summary Recent years, studies have demonstrated that hyperglycemia is one of the main manifestations after cardiac surgeries, which contributes to myocardial injuries and increases the chance of subsequent complications and mortality in such patients. However, strategies targeting at glucose metabolic disorder after cardiac surgeries to attenuate myocardial injuries are inadequately studied. In this study, a rat model of cardiopulmonary bypass (CPB) was applied to investigate the role of Adenosine 5'‐monophosphate‐activated protein kinase (AMPK) in modulating myocardial glucose metabolic‐induced cardiac injuries after cardiac surgery. The results revealed that CPB elicited significant cardiac dysfunction, and pronouncedly elevated the markers of myocardial injuries including serum creatine kinase MB and cardiac troponin I. Additionally, blunted myocardial glucose uptake after CPB was associated with decreased membrane glucose transporter 4 (GLUT4) content. However, pretreatment of AMPK agonist 5‐aminoimidazole‐4‐carboxamide1‐β‐D‐ribofuranoside (AICAR) at the beginning of CPB activated AMPK, enhanced phosphorylation of Akt substrate 160 (AS160), and increased myocardial membrane content of GLUT4. Meanwhile, improved myocardial glucose uptake and more importantly alleviated cardiac injury were also observed after CPB pretreated with AICAR. Moreover, the application of a mutant form of AS160 (AS160‐4P) abolished the beneficial effect of AICAR, as evidenced by impaired cardiac glucose uptake, reduced myocardial membrane GLUT‐4 translocation, increased cardiac injury markers, and deterioration of cardiac function after CPB. In conclusion, it was suggested in this study that preactivation of AMPK by AICAR improved myocardial glucose uptake by promoting AS160 dependent myocardial membrane GLUT‐4 translocation, which ultimately provided a potent cardioprotective effect.

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“…Cardiac surgery with cardiopulmonary bypass (CPB) results in systemic inflammatory responses that contribute to instability of circulation post-operatively [9, 10]. Preventza et al reported that CPB time is related to mortality after surgery [11].…”

Section: Introductionmentioning

confidence: 99%

Endothelial microparticles are increased in congenital heart diseases and contribute to endothelial dysfunction

Lin

et al. 2017

J Transl Med

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BackgroundWe previously demonstrated that endothelial microparticles (EMPs) are increased in mitral valve diseases and impair valvular endothelial cell function. Perioperative systemic inflammation is an important risk factor and complication of cardiac surgery. In this study, we investigate whether EMPs increase in congenital heart diseases to promote inflammation and endothelial dysfunction.MethodsThe level of plasma EMPs in 20 patients with atrial septal defect (ASD), 23 patients with ventricular septal defect (VSD), and 30 healthy subjects were analyzed by flow cytometry. EMPs generated from human umbilical vascular endothelial cells (HUVECs) were injected into C57BL6 mice, or cultured with HUVECs without or with siRNAs targeting P38 MAPK. The expression and/or phosphorylation of endothelial nitric oxide synthase (eNOS), P38 MAPK, and caveolin-1 in mouse heart and/or in cultured HUVECs were determined. We evaluated generation of nitric oxide (NO) in mouse hearts, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured HUVECs and in mice.ResultsEMPs were significantly elevated in patients with ASD and VSD, especially in those with pulmonary hypertension when compared with controls. EMPs increased caveolin-1 expression and P38 MAPK phosphorylation and decreased eNOS phosphorylation and NO production in mouse hearts. EMPs stimulated P38 MAPK expression, TNF-α and IL-6 production, which were all inhibited by siRNAs targeting P38 MAPK in cultured HUVECs.ConclusionsEMPs were increased in adult patients with congenital heart diseases and may contribute to increased inflammation leading to endothelial dysfunction via P38 MAPK-dependent pathways. This novel data provides a potential therapeutic target to address important complications of surgery of congenial heart disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1087-2) contains supplementary material, which is available to authorized users.

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Insulin resistance and inflammation are a cause of hyperglycemia after pediatric cardiopulmonary bypass surgery

Abstract: Hyperglycemia after pediatric CPB surgery is associated with hyperinsulinemia, which may reflect insulin resistance in some patients. Inflammation induced by CPB may play a causative role in insulin resistance.

Cited by 25 publications

References 25 publications

Feeding May Modulate the Relationship Between Systemic Inflammation, Insulin Resistance, and Poor Outcome Following Cardiopulmonary Bypass for Pediatric Cardiac Surgery

Feeding May Modulate the Relationship Between Systemic Inflammation, Insulin Resistance, and Poor Outcome Following Cardiopulmonary Bypass for Pediatric Cardiac Surgery

Activation of AMPK alleviates cardiopulmonary bypass‐induced cardiac injury via ameliorating acute cardiac glucose metabolic disorder

Endothelial microparticles are increased in congenital heart diseases and contribute to endothelial dysfunction

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