Effects of Add-On Left Ventricular Assist Device to Extracorporeal Membrane Oxygenation During Refractory Cardiac Arrest in a Porcine Model.

This study evaluated the effects of extracorporeal membrane oxygenation (ECMO) in combination with a percutaneous adjunctive left ventricular assist device (LVAD) in a porcine model during 60 minutes of refractory cardiac arrest (CA). Twenty-four anesthetized swine were randomly allocated into three groups given different modes of circulatory assist: group 1: ECMO 72 ml/kg/min and LVAD; group 2: ECMO 36 ml/kg/min and LVAD; and group 3: ECMO 72 ml/kg/min. During CA and extracorporeal cardiopulmonary resuscitation (ECPR), mean left ventricular pressure (mLVP) was lower in group 1 (p = 0.013) and in group 2 (p = 0.003) versus group 3. Mean aortic pressure (mAP) and coronary perfusion pressure (CPP) were higher in group 1 compared with the other groups. In group 3, mean pulmonary artery flow (mPAf) was lower versus group 1 (p = 0.003) and group 2 (p = 0.039). If the return of spontaneous circulation (ROSC) was achieved after defibrillation, up to 180 minutes of unsupported observation followed. All subjects in groups 1 and 3, and 5 subjects in group 2 had ROSC. All subjects in group 1, five in group 2 and four in group 3 had sustained cardiac function after 3 hours of spontaneous circulation. Subjects that did not achieve ROSC or maintained cardiac function post-ROSC had lower mAP (p < 0.001), CPP (p = 0.002), and mPAf (p = 0.004) during CA and ECPR. Add-on LVAD may improve hemodynamics compared with ECMO alone during refractory CA but could not substitute reduced ECMO flow. Increased mAP and CPP could be related to ROSC rate and sustained cardiac function. Increased mLVP was related to poor post-ROSC cardiac function.

Severe Neurological Sequelae after a Recreational Dose of LSD.

A young man with an unremarkable medical history suffered a seizure with subsequent cardiorespiratory arrest and severe neurological sequelae after ingesting a blotter. Analysis of a similar blotter and a serum sample obtained 3 h after the event detected lysergic acid diethylamide (LSD) at an amount of 300 µg in the blotter and at a concentration of 4.0 ng/mL (12.4 nmol/L) in the serum. No other drugs were present in concentrations which may confer significant effects. In addition, no individual traits which would make the patient particularly susceptible to adverse LSD effects have subsequently been identified. This suggests that LSD may confer toxic effects in previously healthy individuals.

Increased fatty acid oxidation and mitochondrial proliferation in liver are associated with increased plasma kynurenine metabolites and nicotinamide levels in normolipidemic and carnitine-depleted rats.

Dysregulation of the tryptophan (Trp)-NAD+ pathway has been related to several pathological conditions, and the metabolites in this pathway are known to influence mitochondrial respiration and redox status. The aim of this project was to investigate if stimulation of beta-oxidation and mitochondrial proliferation by the mitochondrial-targeted compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA) would influence metabolites of the Trp-Kyn-NAD+ pathway. We wished to investigate how carnitine depletion by meldonium-treatment influenced these metabolites. After dietary treatment of male Wistar rats with 1-triple TTA for three weeks, increased hepatic mitochondrial- and peroxisomal fatty acid oxidation resulted. The plasma content of total carnitines decreased compared to control animals, whereas hepatic genes involved in CoA biosynthesis were upregulated by 1-triple TTA treatment. The plasma Trp level and individual metabolites in the kynurenine pathway were increased by 1-triple TTA, associated with decreased hepatic gene expression of indoleamine2,3-dioxygenase. 1-triple TTA treatment increased conversion of Trp to nicotinamide (Nam) as the plasma content of quinolinic acid, Nam and N1-methylnicotinamide (mNam) increased, accompanied with suppression of hepatic gene expression of α-amino-α-carboxymuconate-ε-semialdehyde decarboxylase. A positive correlation between mitochondrial fatty acid oxidation and Trp-derivatives was found. Almost identical results were obtained by 1-triple TTA in the presence of meldonium, which alone exerted minor effects. Moreover, the plasma Kyn:Trp ratio (KTR) correlated negatively to mitochondrial function. Whether increased flux through the Trp-NAD+ pathway increased redox status and lowered inflammation locally and systemically should be considered.

Balanced Biventricular Assist Versus Extracorporeal Membrane Oxygenation in Cardiac Arrest.

Mechanical assist devices in refractory cardiac arrest are increasingly employed. We compared the hemodynamics and organ perfusion during cardiac arrest with either veno-arterial extracorporeal membrane oxygenation (ECMO) or biventricular assisted circulation combining left- and right-sided impeller devices (BiPella) in an acute experimental setting. Twenty pigs were randomized in two equal groups receiving circulatory support either by ECMO or by BiPella during 40 minutes of ventricular fibrillation (VF) followed by three attempts of cardioversion, and if successful, 60 minute observation with spontaneous, unsupported circulation. Hemodynamic variables were continuously recorded. Tissue perfusion was evaluated by fluorescent microsphere injections. Cardiac function was visualized by intracardiac echocardiography. During VF device output, carotid flow, kidney perfusion, mean aortic pressure (AOPmean), and mean left ventricular pressure (LVPmean) were all significantly higher in the ECMO group, and serum-lactate values were lower compared with the BiPella group. No difference in myocardial or cerebral perfusion was observed between groups. In 15 animals with sustained cardiac function for 60 minutes after return of spontaneous circulation, left ventricular subendocardial blood flow rate averaged 0.59 ± 0.05 ml/min/gm during VF compared with 0.31 ± 0.07 ml/min/gm in five animals with circulatory collapse (p = 0.005). Corresponding values for the midmyocardium was 0.91 ± 0.06 vs. 0.65 ± 0.15 ml/min/gm (p = 0.085). Both BiPella and ECMO could sustain vital organ function. ECMO provided a more optimal systemic circulatory support related to near physiologic output. Myocardial tissue perfusion and sustained cardiac function were related to coronary perfusion pressure during VF, irrespective of mode of circulatory support.

Correction: Plasma kynurenines and prognosis in patients with heart failure.

[This corrects the article DOI: 10.1371/journal.pone.0227365.].

Plasma kynurenines and prognosis in patients with heart failure.

BACKGROUND: Metabolites of the kynurenine pathway (mKP) relate to important aspects of heart failure pathophysiology, such as inflammation, energy-homeostasis, apoptosis, and oxidative stress. We aimed to investigate whether mKP predict mortality in patients with heart failure. METHODS: The study included 202 patients with heart failure (73.8% with coronary artery disease (CAD)), propensity score matched to 384 controls without heart disease, and 807 controls with CAD (71%). All underwent coronary angiography and ventriculography at baseline. Plasma mKP, pyridoxal 5'phosphate (PLP) and CRP were measured at baseline. Case-control differences were assessed by logistic regression and survival by Cox regression, adjusted for age, gender, smoking, diabetes, ejection fraction, PLP, eGFR and CRP. Effect measures are reported per standard deviation increments. RESULTS: Higher plasma levels of kynurenine, 3- hydroxykynurenine (HK), quinolinic acid (QA), the kynurenine-tryptophan-ratio (KTR) and the ratio of HK to xanthurenic acid (HK/XA) were detected in heart failure compared to both control groups. The mortality rate per 1000 person-years was 55.5 in patients with heart failure, 14.6 in controls without heart disease and 22.2 in CAD controls. QA [HR 1.80, p = 0.013], HK [HR 1.77, p = 0.005], HK/XA [HR 1.67, p < 0.001] and KTR [HR 1.55, p = 0.009] were associated with increased mortality in patients with heart failure, while XA [HR 0.68-0.80, p = 0.013-0.037] were associated with lower mortality in all groups. HK and HK/XA had weak associations with increased mortality in CAD-controls. CONCLUSION: Elevated plasma levels of mKP and metabolite ratios are associated with increased mortality, independent of CAD, in patients with heart failure.

A mitochondria-targeted fatty acid analogue influences hepatic glucose metabolism and reduces the plasma insulin/glucose ratio in male Wistar rats.

A fatty acid analogue, 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), was previously shown to have hypolipidemic effects in rats by targeting mitochondrial activity predominantly in liver. This study aimed to determine if 1-triple TTA could influence carbohydrate metabolism. Male Wistar rats were treated for three weeks with oral supplementation of 100 mg/kg body weight 1-triple TTA. Blood glucose and insulin levels, and liver carbohydrate metabolism gene expression and enzyme activities were determined. In addition, human myotubes and Huh7 liver cells were treated with 1-triple TTA, and glucose and fatty acid oxidation were determined. The level of plasma insulin was significantly reduced in 1-triple TTA-treated rats, resulting in a 32% reduction in the insulin/glucose ratio. The hepatic glucose and glycogen levels were lowered by 22% and 49%, respectively, compared to control. This was accompanied by lower hepatic gene expression of phosphenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, and Hnf4A, a regulator of gluconeogenesis. Gene expression of pyruvate kinase, catalysing the final step of glycolysis, was also reduced by 1-triple TTA. In addition, pyruvate dehydrogenase activity was reduced, accompanied by 10-15-fold increased gene expression of its regulator pyruvate dehydrogenase kinase 4 compared to control, suggesting reduced entry of pyruvate into the TCA cycle. Indeed, the NADPH-generating enzyme malic enzyme 1 (ME1) catalysing production of pyruvate from malate, was increased 13-fold at the gene expression level. Despite the decreased glycogen level, genes involved in glycogen synthesis were not affected in livers of 1-triple TTA treated rats. In contrast, the pentose phosphate pathway seemed to be increased as the hepatic gene expression of glucose-6-phosphate dehydrogenase (G6PD) was higher in 1-triple TTA treated rats compared to controls. In human Huh7 liver cells, but not in myotubes, 1-triple-TTA reduced glucose oxidation and induced fatty acid oxidation, in line with previous observations of increased hepatic mitochondrial palmitoyl-CoA oxidation in rats. Importantly, this work recognizes the liver as an important organ in glucose homeostasis. The mitochondrially targeted fatty acid analogue 1-triple TTA seemed to lower hepatic glucose and glycogen levels by inhibition of gluconeogenesis. This was also linked to a reduction in glucose oxidation accompanied by reduced PHD activity and stimulation of ME1 and G6PD, favouring a shift from glucose- to fatty acid oxidation. The reduced plasma insulin/glucose ratio indicate that 1-triple TTA may improve glucose tolerance in rats.

Left Versus Biventricular Assist Devices in Cardiac Arrest.

Maintaining adequate organ perfusion during cardiac arrest remains a challenge, and various assist techniques have been evaluated. We assessed whether a right ventricular impeller assist device (RVAD) in adjunct to a left ventricular impeller assist device (LVAD) is beneficial. Twenty anesthetized pigs were randomized to maximized circulatory support by percutaneously implanted left- or biventricular assist device(s) during 30 minutes of electrically induced ventricular fibrillation followed by three attempts of cardioversion. Continuous hemodynamic variables were recorded. Cardiac output and myocardial, cerebral, renal, and ileum mucosa tissue perfusion were measured with fluorescent microspheres, and repeated blood gas analyses were obtained. With biventricular support, an increased LVAD output was found compared with left ventricular (LV) support; 3.2 ± 0.2 (SEM) vs. 2.0 ± 0. 2 L/minute just after start of ventricular fibrillation, 3.2 ± 0.1 vs. 2.0 ± 0.1 L/minute after 15 minutes, and 3.0 ± 0.1 vs. 2.1 ± 0.1 L/minute after 30 minutes of cardiac arrest (pg < 0.001). Biventricular support also increased aortic and LV pressure, in addition to end-tidal CO2. Tissue blood flow rates were increased for most organs with biventricular support. Blood gas analyses showed improved oxygenation and lower s-lactate values. However, myocardial perfusion was degraded with biventricular support and return of spontaneous circulation less frequent (5/10 vs. 10/10; p = 0.033). Biventricular support was associated with high intraventricular pressure and decreased myocardial perfusion pressure, correlating significantly with flow rates in the LV wall. A transmural flow gradient was observed for both support modes, with better maintained subepicardial than midmyocardial and subendocardial perfusion.

Antibodies to receptors are associated with biomarkers of inflammation and myocardial damage in heart failure.

INTRODUCTION: Naturally occurring antibodies are linked to inflammation, tissue injury and apoptosis, processes also linked to heart failure. Associations between antibodies, inflammation and myocardial damage, have not been elucidated in heart failure. OBJECTIVE: We investigated if 25 antibodies to receptors expressed in the cardiovascular system were associated with troponin-T, biomarkers of inflammation and clinical measures of disease severity, in patients with heart failure. METHODS: Antibodies in sera from patients (n=191) with ischemic (n=155) or non-ischemic (n=36) heart failure were measured with full-receptor sandwich enzyme-linked immunosorbent assays. All patients underwent coronary angiography with determination of left ventricular ejection fraction (LVEF) and left ventricular end-diastolic pressure (LVEDP). Measured biomarkers included troponin-T, C-reactive protein, erythrocyte sedimentation rate, fibrinogen and neopterin. RESULTS: Stabilin-1-antibodies correlated with troponin-T (ß 0.23 p=0.008), soluble endoglin-antibodies with erythrocyte sedimentation rate (ß 0.19, p=0.007) and fibrinogen (ß 0.28, p<0.001). Platelet-derived growth factor subunit ß-antibodies were associated with neopterin (ß 0.17, p=0.002). All antibodies were correlated (R 0.26 to 0.91) and formed 4 principal components (PCs). Patients with high CRP and high PC2 had higher NYHA class and patients with high troponin-T and high PC1 had lower LVEDP (interactions, all p<0.05). CONCLUSION: Antibodies to receptors are correlated and are associated with biomarkers of inflammation and myocardial damage, which further modifies their association with disease severity in heart failure. Their functional activity and immunological function, remain undecided.

Insulin Postconditioning Reduces Infarct Size in the Porcine Heart in a Dose-Dependent Manner.

AIM: Insulin and glucose may have opposite effects when used to reduce ischemia-reperfusion injury. When insulin is administered alone, feeding state determines tolerance and further induces metabolic and hormonal changes. Higher insulin doses are needed for similar activation of cardioprotective Akt signaling in the fed compared to the fasted pig heart. Thus, the aim of the study was to investigate the effects of 2 prespecified insulin doses on infarct size, apoptosis, metabolism, and cardiac function in a clinically relevant, randomized large animal model using conventional percutaneous catheter intervention techniques and including different fasting states. METHODS AND RESULTS: Twenty-seven female pigs were subjected to 40-minute ischemia and 120-minute reperfusion. Pharmacological postconditioning with intracoronary infusions administered over 3 × 30 seconds was performed at immediate reperfusion. Animals were randomly assigned to 3 groups-preexperimental fasting and intracoronary saline ( controls), preexperimental fasting and 0.1U of insulin ( fasted Ins0.1U), and preexperimental feeding and 1.0U of insulin ( fed Ins1.0U). A significant reduction in infarct size was demonstrated in the fed Ins1.0U group ( P = .047) but not in the fasted Ins0.1U group ( P = .531) compared to controls (infarct size normalized to area at risk ± standard deviation: controls 70.2% ± 12.9%, fasted Ins0.1U 65.0% ± 9.4%, and fed Ins1.0U 54.4% ± 7.3%). Infarct limitation was associated with more uncleaved caspase-3 in the area of risk and the infarcted area, lower circulating free fatty acids, and less increase in heart rate during reperfusion. Fed animals had higher levels of glucose, carnitine, potassium, and normetanephrine and higher heart rate at baseline compared to controls. CONCLUSION: Insulin postconditioning reduced infarct size in the in vivo pig heart, but the beneficial effects were restricted to the highest dose, which is limited by side effects and can only be given to nonfasted animals. The finding challenges successful general use of insulin in the treatment of reperfusion injury in clinical acute myocardial infarction.

Effect of combined thermal and electrical muscle stimulation on cardiorespiratory fitness and adipose tissue in obese individuals.

BACKGROUND: To better understand how prolonged electrical muscle stimulation can improve cardiorespiratory risk markers in obese subjects, we investigated the effect of prolonged combined thermal and electrical muscle stimulation (cTEMS) on peak oxygen consumption (VO2peak) and body composition with subsequent lipolytic and mitochondrial activity in adipocytes. METHODS AND RESULTS: Eleven obese (BMI ≥ 30 kg/m(2)) individuals received cTEMS in three 60-minute sessions per week for 8 weeks. Activity levels and dietary habits were kept unchanged. Before and after the stimulation period, functional capacity was assessed by VO2peak, and body composition was analysed. Lipolytic activity was determined in abdominal adipose tissue by 24 hours of microdialysis on a sedentary day, and adipose tissue biopsies were taken for the gene expression analysis. Eight weeks of cTEMS significantly increased VO2peak from 28.9 ± 5.7 to 31.7 ± 6.2 ml/kg/min (p < 0.05), corresponding to an average increase of 1.2% per week. Oxygen uptake and work capacity also increased at the anaerobic threshold. Mean microdialytic glycerol concentration over 24 hours, an index of sedentary lipolytic activity, increased from 238 ± 60 to 306 ± 55 µM (p < 0,0001), but no significant changes in body composition were observed. In addition, PGC-1α and carnitine-palmitoyltransferase-2 mRNAs were significantly upregulated in subcutaneous abdominal adipose tissue. CONCLUSIONS: In obese individuals with unchanged lifestyles, 8 weeks of cTEMS significantly improved functional capacity towards a higher fatigue resistance. This increase also gave rise to elevated lipolytic activity and increased mitochondrial activity in abdominal adipose tissue.

Influence of feeding and intracoronary dose on insulin-mediated relative akt phosphorylation in the porcine myocardium.

AIMS: Insulin promotes Akt-dependent prosurvival signaling and reduces experimental ischemia reperfusion injury, but its clinical impact has been limited. Further understanding of the interplay between insulin and Akt in the myocardium of relevant large animal models is needed. We aimed to investigate (1) Akt phosphorylation, (2) influence of feeding state, and (3) impact of dose on the Akt response following intracoronary insulin administration in the nonischemic porcine heart. METHODS: Pigs fed 2 h preprocedure received 0.1 U (unit) or 1.0 U of insulin in the left coronary artery and fasting pigs 0.1 U. Left and right ventricle tissues harvested 15 min postinsulin administration were analyzed for Akt phosphorylation by densitometric analyses of total Akt and phosphorylated Akt immunoblots expressed as a ratio and normalized against left auricle biopsies at baseline. RESULTS: Median relative Akt phosphorylation across all biopsy locations increased significantly from baseline in both fasting and fed animals after insulin infusion: 371.4% (P < 0.001) in the fasting-0.1 U insulin group, 202.7% (P = 0.003) in the fed-1.0 U group and 131.5% (P < 0.001) in the fed-0.1 U group. The increase was significantly higher for the fasting-0.1 U and the fed-1.0 U groups as compared with the fed-0.1 U group. Baseline serum glucose in fed and fasting pigs was 6.3 ± 0.3 versus 5.2 ± 0.4 mm (P = 0.050), respectively. CONCLUSIONS: Preexperimental feeding attenuates the median relative rise in Akt phosphorylation mediated by exogenous insulin in the porcine heart, and higher insulin doses are therefore required in fed compared with fasting animals.

Percutaneous catheter-based intracoronary infusion of insulin--a dose finding study in the porcine model.

Insulin given at immediate reperfusion reduces myocardial infarct size in the in vitro and the ex vivo rat heart. In vivo, insulin may cause hypoglycaemia, hypokalaemia and elevation of catecholamines, potentially harmful during an acute myocardial infarction. The purpose of this study was to evaluate tolerance and safety of intracoronary insulin infusions in a porcine model applying percutaneous intervention techniques.