C. Boer

Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats.

Aims/hypothesisDiabetic cardiomyopathy (DCM) is common in type 2 diabetes. In DCM, insulin resistance may alter cardiac substrate supply and utilisation leading to changes in myocardial metabolism and cardiac function. In rats, exposure to excessive alimentary fat, inducing a type 2 diabetic phenotype, may result in myocardial insulin resistance and cardiac functional changes resembling DCM.Materials and methodsRats received high-fat (HFD) or low-fat (LFD) diets for 7 weeks. Prior to killing, insulin or saline was injected i.p. Contractile function and insulin signalling were assessed in papillary muscles and ventricular lysates, respectively.ResultsFasting and post-load blood glucose levels were increased in HFD- vs LFD-rats (all p<0.02). Mean heart weight, but not body weight, was increased in HFD-rats (p<0.01). HFD-hearts showed structural changes and triglyceride accumulation. HFD-muscles developed higher baseline and maximum forces, but showed impaired recovery from higher workloads. Insulin-associated modulation of Ca2+-induced force augmentation was abolished in HFD-muscles. HFD reduced insulin-stimulated IRS1-associated phosphatidylinositol 3′-kinase activity and phosphorylation of protein kinase B, glycogen synthase kinase-3β, endothelial nitric oxide synthase, and forkhead transcription factors by 40–60% (all p<0.05). Insulin-mediated phosphorylation of phospholamban, a critical regulator of myocardial contractility, was decreased in HFD-hearts (p<0.05).Conclusions/interpretationHFD induced a hypertrophy-like cardiac phenotype, characterised by a higher basal contractile force, an impaired recovery from increased workloads and decreased insulin-mediated protection against Ca2+ overload. Cardiac dysfunction was associated with myocardial insulin resistance and phospholamban hypophosphorylation. Our data suggest that myocardial insulin resistance, resulting from exposure to excessive alimentary fat, may contribute to the pathogenesis of diabetes-related heart disease.

Intraoperative High-Dose Dexamethasone for Cardiac Surgery: A Randomized Controlled Trial

CONTEXTnProphylactic corticosteroids are often administered during cardiac surgery to attenuate the inflammatory response to cardiopulmonary bypass and surgical trauma; however, evidence that routine corticosteroid use can prevent major adverse events is lacking.nnnOBJECTIVEnTo quantify the effect of intraoperative high-dose dexamethasone on the incidence of major adverse events in patients undergoing cardiac surgery.nnnDESIGN, SETTING, AND PARTICIPANTSnA multicenter, randomized, double-blind, placebo-controlled trial of 4494 patients aged 18 years or older undergoing cardiac surgery with cardiopulmonary bypass at 8 cardiac surgical centers in The Netherlands enrolled between April 13, 2006, and November 23, 2011.nnnINTERVENTIONnPatients were randomly assigned to receive a single intraoperative dose of 1 mg/kg dexamethasone (n = 2239) or placebo (n = 2255).nnnMAIN OUTCOME MEASURESnA composite of death, myocardial infarction, stroke, renal failure, or respiratory failure, within 30 days of randomization.nnnRESULTSnOf the 4494 patients who underwent randomization, 4482 (99.7%) could be evaluated for the primary outcome. A total of 157 patients (7.0%) in the dexamethasone group and 191 patients (8.5%) in the placebo group reached the primary study end point (relative risk, 0.83; 95% CI, 0.67-1.01; absolute risk reduction, -1.5%; 95% CI, -3.0% to 0.1%; P = .07). Dexamethasone was associated with reductions in postoperative infection, duration of postoperative mechanical ventilation, and lengths of intensive care unit and hospital stays. In contrast, dexamethasone was associated with higher postoperative glucose levels.nnnCONCLUSIONnIn our trial of adults undergoing cardiac surgery, the use of intraoperative dexamethasone did not reduce the 30-day incidence of major adverse events compared with placebo.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00293592.

Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification

Aims/hypothesisChanges in cardiac substrate utilisation leading to altered energy metabolism may underlie the development of diabetic cardiomyopathy. We studied cardiomyocyte substrate uptake and utilisation and the role of the fatty acid translocase CD36 in relation to in vivo cardiac function in rats fed a high-fat diet (HFD).MethodsRats were exposed to an HFD or a low-fat diet (LFD). In vivo cardiac function was monitored by echocardiography. Substrate uptake and utilisation were determined in isolated cardiomyocytes.ResultsFeeding an HFD for 8xa0weeks induced left ventricular dilation in the systolic phase and decreased fractional shortening and the ejection fraction. Insulin-stimulated glucose uptake and proline-rich Akt substrate 40 phosphorylation were 41% (pu2009<u20090.001) and 45% (pu2009<u20090.05) lower, respectively, in cardiomyocytes from rats on the HFD. However, long-chain fatty acid (LCFA) uptake was 1.4-fold increased (pu2009<u20090.001) and LCFA esterification into triacylglycerols and phospholipids was increased 1.4- and 1.5-fold, respectively (both pu2009<u20090.05), in cardiomyocytes from HFD compared with LFD hearts. In the presence of the CD36 inhibitor sulfo-N-succinimidyloleate, LCFA uptake and esterification were similar in LFD and HFD cardiomyocytes. In HFD hearts CD36 was relocated to the sarcolemma, and basal phosphorylation of a mediator of CD36-trafficking, i.e. protein kinase B (PKB/Akt), was increased.Conclusions/interpretationFeeding rats an HFD induced cardiac contractile dysfunction, which was accompanied by the relocation of CD36 to the sarcolemma, and elevated basal levels of phosphorylated PKB/Akt. The permanent presence of CD36 at the sarcolemma resulted in enhanced rates of LCFA uptake and myocardial triacylglycerol accumulation, and may contribute to the development of insulin resistance and diabetic cardiomyopathy.

Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography

BackgroundIn vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.MethodsZucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.ResultsPET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase α1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).ConclusionUsing PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

Distinct alterations in sublingual microcirculatory blood flow and hemoglobin oxygenation in on-pump and off-pump coronary artery bypass graft surgery

OBJECTIVEnThe authors hypothesized that cardiopulmonary bypass (CPB) (on-pump) is associated with more severe changes in the microcirculatory blood flow and tissue oxygenation as compared with off-pump coronary artery bypass surgery.nnnDESIGNnAn observational study.nnnSETTINGnA university hospital and teaching hospital.nnnPARTICIPANTSnPatients undergoing on-pump (n = 24) or off-pump (n = 24) cardiac surgery.nnnINTERVENTIONSnMicrocirculatory measurements were performed before CPB and 10 minutes after the switch to CPB or before and during cardiac luxation in off-pump patients.nnnMEASUREMENTS AND MAIN RESULTSnSublingual microcirculatory perfusion was investigated using side-stream dark field imaging, and sublingual microcirculatory oxygenation was measured using reflectance spectrophotometry. Conversion to CPB resulted in an increase in cardiac output from 4.0 ± 0.2 to 4.8 ± 0.3 L/min (p < 0.01) and a 40% reduction in arterial hemoglobin concentration. Cardiopulmonary bypass was associated with an increase in venular blood velocity from 349 ± 201 μm/s to 563 ± 227 μm/s (p < 0.05), a reduction in functional capillary density of 43%, and an increase in hemoglobin oxygenation of the red blood cells in the remaining filled capillaries from 47.2% ± 6.1% to 59.7% ± 5.2% (p < 0.001). The decrease in cardiac output during cardiac luxation from 4.5 ± 1.7 to 1.8 ± 0.8 L/min (p < 0.01) without hemoglobin changes was associated with a complete halt of capillary blood flow and a reduction in maximum capillary blood velocity from 895 ± 209 to 396 ± 178 μm/s (p < 0.01). The functional capillary density remained unchanged, whereas the hemoglobin oxygenation declined from 64.2% ± 9.1% to 48.6% ± 8.7% (p < 0.01).nnnCONCLUSIONSnOn-pump and off-pump cardiac surgery are associated with distinct alterations in sublingual microcirculatory perfusion and hemoglobin oxygenation. Although on-pump surgery results in a fall out of capillaries resulting in decreased oxygen extraction, off-pump surgery results in a cessation of flow during luxation resulting in decreased convection of oxygen transport.

Diabetic cardiomyopathy in Zucker diabetic fatty rats: the forgotten right ventricle

BackgroundIn patients with myocardial infarction or heart failure, right ventricular (RV) dysfunction is associated with death, shock and arrhythmias. In patients with type 2 diabetes mellitus, structural and functional alterations of the left ventricle (LV) are highly prevalent, however, little is known about the impact of diabetes on RV characteristics. The purpose of the present study was to investigate whether LV changes are paralleled by RV alterations in a rat model of diabetes.MethodsZucker diabetic fatty (ZDF) and control (ZL) rats underwent echocardiography and positron emission tomography (PET) scanning using [18F]-2-fluoro-2-deoxy-D-glucose under hyperinsulinaemic euglycaemic clamp conditions. Glucose, insulin, triglycerides and fatty acids were assessed from trunk blood. Another group of rats received an insulin or saline injection to study RV insulin signaling.ResultsZDF rats developed hyperglycaemia, hyperinsulinaemia and dyslipidaemia (all p < 0.05). Echocardiography revealed depressed LV fractional shortening and tricuspid annular plane systolic excursion (TAPSE) in ZDF vs. ZL rats (both p < 0.05). A decrease in LV and RV insulin-mediated glucose utilisation was found in ZDF vs. ZL rats (both p < 0.05). LV associated with RV with respect to systolic function (r = 0.86, p < 0.05) and glucose utilisation (r = 0.74, p < 0.05). TAPSE associated with RV MRglu (r = 0.92, p < 0.05) and M-value (r = 0.91, p < 0.0001) and RV MRglu associated with M-value (r = 0.77, p < 0.05). Finally, reduced RV insulin-stimulated phosphorylation of Akt was found in ZDF vs. ZL (p < 0.05).ConclusionsLV changes were paralleled by RV alterations in insulin-stimulated glucose utilisation and RV systolic function in a rat model of diabetes, which may be attributed to ventricular interdependence as well as to the uniform effect of diabetes. Since diabetic patients are prone to develop diabetic cardiomyopathy and myocardial ischaemia, it might be suggested that RV dysfunction plays a central role in cardiac abnormalities in this population.

Experience in Prehospital Endotracheal Intubation Significantly Influences Mortality of Patients with Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Background Patients with severe traumatic brain injury (TBI) are at high risk for airway obstruction and hypoxia at the accident scene, and routine prehospital endotracheal intubation has been widely advocated. However, the effects on outcome are unclear. We therefore aim to determine effects of prehospital intubation on mortality and hypothesize that such effects may depend on the emergency medical service providers’ skill and experience in performing this intervention. Methods and Findings PubMed, Embase and Web of Science were searched without restrictions up to July 2015. Studies comparing effects of prehospital intubation versus non-invasive airway management on mortality in non-paediatric patients with severe TBI were selected for the systematic review. Results were pooled across a subset of studies that met predefined quality criteria. Random effects meta-analysis, stratified by experience, was used to obtain pooled estimates of the effect of prehospital intubation on mortality. Meta-regression was used to formally assess differences between experience groups. Mortality was the main outcome measure, and odds ratios refer to the odds of mortality in patients undergoing prehospital intubation versus odds of mortality in patients who are not intubated in the field. The study was registered at the International Prospective Register of Systematic Reviews (PROSPERO) with number CRD42014015506. The search provided 733 studies, of which 6 studies including data from 4772 patients met inclusion and quality criteria for the meta-analysis. Prehospital intubation by providers with limited experience was associated with an approximately twofold increase in the odds of mortality (OR 2.33, 95% CI 1.61 to 3.38, p<0.001). In contrast, there was no evidence for higher mortality in patients who were intubated by providers with extended level of training (OR 0.75, 95% CI 0.52 to 1.08, p = 0.126). Meta-regression confirmed that experience is a significant predictor of mortality (p = 0.009). Conclusions Effects of prehospital endotracheal intubation depend on the experience of prehospital healthcare providers. Intubation by paramedics who are not well skilled to do so markedly increases mortality, suggesting that routine prehospital intubation of TBI patients should be abandoned in emergency medical services in which providers do not have ample training, skill and experience in performing this intervention.

Multicenter Evaluation of the Course of Coagulopathy in Patients with Isolated Traumatic Brain Injury: Relation to CT Characteristics and Outcome

This prospective multicenter study investigated the association of the course of coagulation abnormalities with initial computed tomography (CT) characteristics and outcome in patients with isolated traumatic brain injury (TBI). Patient demographics, coagulation parameters, CT characteristics, and outcome data of moderate and severe TBI patients without major extracranial injuries were prospectively collected. Coagulopathy was defined as absent, early but temporary, delayed, or early and sustained. Delayed/sustained coagulopathy was associated with a higher incidence of disturbed pupillary responses (40% versus 27%; p<0.001) and higher Traumatic Coma Data Bank (TCDB) CT classification (5 (2-5) versus 2 (1-5); p=0.003) than in patients without or with early, but short-lasting coagulopathy. The initial CT of patients with delayed/sustained coagulopathy more frequently showed intracranial hemorrhage and signs of raised intracranial pressure (ICP) compared to patients with early coagulopathy only. This was paralleled by higher in-hospital mortality rates (51% versus 33%; p<0.05), and poorer 6-month functional outcome in patients with delayed/sustained coagulopathy. The relative risk for in-hospital mortality was particularly related to disturbed pupillary responses (OR 8.19; 95% CI 3.15,21.32; p<0.001), early, short-lasting coagulopathy (OR 6.70; 95% CI 1.74,25.78; p=0.006), or delayed/sustained coagulopathy (OR 5.25; 95% CI 2.06,13.40; p=0.001). Delayed/sustained coagulopathy is more frequently associated with CT abnormalities and unfavorable outcome at 6 months after TBI than early, short-lasting coagulopathy. Our finding that not only the mere presence but also the time course of coagulopathy holds predictive value for patient outcome underlines the importance of systematic hemostatic monitoring over time in TBI.

Reproducibility of non-standardised autonomic function testing in the pre-operative assessment screening clinic*

By convention, autonomic function tests are undertaken under standard test conditions that limit their implementation during routine pre‐operative assessment. We therefore evaluated the comparability of autonomic function tests under both non‐standardised and standardised test conditions in 20 healthy male subjects. Autonomic function was assessed using an ECG monitor and a continuous non‐invasive blood pressure measurement device. Under non‐standardised conditions, intraclass correlation for heart rate variability analysis was good for the low and high frequency bands (0.87; 95% CI 0.58–0.96 and 0.83; 95% CI 0.56–0.94, respectively), but moderate (0.65; 95% CI 0.14–0.86) for the very low frequency band; reproducibility was high for the expiration/inspiration ratio (0.89; 95% CI 0.71–0.96), Valsalva ratio (0.76; 95% CI 0.37–0.91) and handgrip test (0.76; 95% CI 0.35–0.91) (all pu2003<u20030.05) but was low for the response to quick standing. Reproducibility under standardised conditions was comparable to the above values. We demonstrated that reproducibility for most autonomic tests under non‐standardised conditions is acceptable and suggest that implementation of these tests during pre‐operative assessment may be feasible.

Dexamethasone for the prevention of postoperative atrial fibrillation

BACKGROUNDnPostoperative atrial fibrillation (AF) is a common complication after cardiac surgery. Inflammation is believed to play a pivotal role in the etiology of postoperative AF. There is a suggestion from small studies that perioperative treatment with corticosteroids may reduce postoperative AF. The DExamethasone for Cardiac Surgery (DECS) study was a large randomized trial showing no protective effect of dexamethasone on major adverse events. The aim of this study was to investigate the effect of dexamethasone treatment on the occurrence of AF after cardiac surgery.nnnMETHODSnThe DECS study compared intra-operative dexamethasone (1mg/kg) or placebo treatment in 4494 adult patients undergoing cardiac surgery. AF was defined by the occurrence of any reported AF within 30days after surgery. We also performed an in-depth analysis of a subset of 1565 patients on new-onset AF. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated.nnnRESULTSnThe incidence of any AF in the main study of 4494 patients was 33.1% in the dexamethasone and 35.2% in the placebo group (RR 0.94, 95% CI: 0.87-1.02, p=0.14). In the substudy of 1565 patients, the incidence of new-onset AF was 33.0% vs. 35.5% (RR 0.93, 95% CI: 0.81-1.07, p=0.31), respectively. There was no protective effect of dexamethasone across clinically important patient subgroups.nnnCONCLUSIONnIntraoperative administration of dexamethasone had no protective effect on the occurrence of any or new-onset atrial fibrillation after cardiac surgery. Therefore, the use of dexamethasone for the reduction of postoperative AF should not be recommended.