bluuebunny/crossref_metadata_2025_split huggingface dataset:
P6219Can too much exercise “burn” your endothelium?
Authors: Terentes-Printzios D , Vlachopoulos C , Kardara D , Anastasakis A , Vogiatzi G , Xaplanteris P , Georgakopoulos C , Lazaros G , Tousoulis D 
Published: October 2019

Abstract

Background/Introduction
Regular aerobic exercise has beneficial effects on the cardiovascular system. Marathon running is an aerobic and extremely vigorous exercise. Endothelial function and carotid subclinical atherosclerosis are independent predictors of cardiovascular risk.

Purpose
We investigated the chronic alterations of these indices in marathon runners.

Methods
We studied 30 marathon runners and 20 age- and sex-matched recreationally active control subjects. Endothelial function was evaluated with flow-mediated dilatation of the brachial artery (FMD) and early atherosclerosis with carotid intima-media thickness (cIMT). All subjects completed analytical questionnaires about their medical history and training.

Results
Marathon runners had significantly higher systolic and pulse pressure compared to controls. They also had reduced body-mass index, waist to hip ratio and heart rate compared to controls (p<0.05, for all). Common cIMT was significantly lower in athletes than controls (0.56±0.11 vs. 0.63±0.07, p=0.029), while there was no difference in carotid bulb IMT between groups. FMD was higher in marathon runners compared to controls and nitrate-mediated dilatation (NMD) was similar in the two groups (9.0±3.7 vs. 6.4±1.7 and 12.6±5.7 vs. 12.3±3.4; p=0.002 and p=0.821, respectively). We also observed a reverse U-shaped curve between endothelial function and amount of exercise. (Figure)
Effect of amount of exercise on FMD

Conclusions
Our study shows, that marathon runners have higher FMD compared to controls, indicating better vascular endothelial function, and also have lower cIMT compared to controls. Increased amount of exercise training seems to abolish the beneficial effect of exercise on endothelial function. These findings provide further insights in the effects of marathon running on endothelial function and carotid atherosclerosis.
P6231Iron status and risk of cardio-metabolic diseases in European adults: a Mendelian randomization study
Authors: Gan W , Bennett D , Mahajan A , Du H , Chen Z , McCarthy M , Clarke R 
Published: October 2019

Abstract

Background
Observational studies have reported conflicting results about the associations of iron status with risk of cardio-metabolic diseases but such studies are constrained by confounding and reverse causality.

Purpose
To assess the causal relevance of iron status biomarkers (transferrin, serum iron, and ferritin) for risk of coronary artery diseases (CAD), ischaemic stroke (IS), and type 2 diabetes (T2D), using Mendelian randomization (MR).

Methods
Effect size estimates for genetic variants associated with iron status biomarkers were obtained from the Genetics of Iron Status consortium (transferrin saturation, serum iron, and ferritin: n=48,972). The corresponding effects of these variants on the risk of CAD, IS and T2D were obtained from a meta-analysis of unrelated participants of European ancestry in the UK Biobank (UKB), together with previously recruited participants in CARDIOGRAMplusC4D (total n=90,377 CAD cases), MEGASTROKE (total n=43,381 IS cases) and DIAGRAM (total n=74,124 T2D cases), respectively. The main analysis used a two-sample inverse-variance weighted MR, while the sensitivity analyses used weighted-median, weighted-mode, MR-PRESSO, and MR-Egger approaches.

Results
MR analysis demonstrated significant inverse association of each of the three genetically-instrumented iron status biomarker with risk of CAD (transferrin saturation OR=0.96 [95% CI: 0.92–0.99], p=0.02; serum iron OR=0.93 [0.89–0.97], p=0.001; and ferritin OR=0.86 (0.79–0.94), p=0.001, per 1 SD higher level). In contrast, these iron status biomarkers showed positive associations with risk of T2D (transferrin saturation OR=1.06 [1.01–1.11], p=0.01; serum iron OR=1.06 [0.99–1.13], p=0.07; and ferritin OR=1.12 [0.99–1.26], p=0.06, per 1 SD higher level). There was positive, but non-significant, association of IS with each of the iron status biomarker analysed. Sensitivity analyses using several different MR approaches yielded concordant results.

Conclusions
Among European adults, iron status appeared to have causal associations, but in opposite directions, with the risk of CHD and T2D. Our findings highlight the need for caution about strategies for advocating iron supplementation in individuals with normal haemoglobin levels for prevention of CAD.

Acknowledgement/Funding
British Heart Found, Medical Research Council, Wellcome Trust, NIHR Biomedical Research Centre, Oxford
P6253Electrocardiographic characteristics for prediction of irreversible fulminant hepatitis in patients with acute hepatic failure
Authors: Im S I , Park H S 
Published: October 2019

Abstract

Background
There was limited data about the association between the electrocardiographic characteristics and irreversible fulminant hepatitis (IFH) in patients with acute hepatic failure (AHF) in the long-term follow up.

Purpose
The aim of this study was to analysis the electrocardiographic characteristics for prediction of IFH in patients with AHF.

Methods
Our University echocardiography, electrocardiogram (ECG) and viral hepatitis database were reviewed from 2008 to 2017 to identify patients with AHF. Patients were followed for a mean 32.0±0.8 months and were analyzed to find out the predictors for IFH.

Results
Among 202 patients with AHF, 23 (11.4%) patients had IFH. In our study, there are 118 (58.7%) viral hepatitis patients (hepatitis A, 83 patients, 41.3%; hepatitis B, 19 patients, 9.5%; hepatitis C, 15 patients, 7.5%) and alcoholic hepatitis patients (83 patients, 41.3%). Based on the ROC curve, we set the corrected QT interval (QTc) cutoff value of 425 msec for prediction of IFH, which gave a sensitivity of 66.7% and a specificity of 66.0% (P=0.002). In univariate analysis, age, QTc, diabetes mellitus (DM), heavy alcoholics, labile INR, hemoglobin, albumin, total bilirubin, sodium, and c-reactive protein were significantly associated with IFH. In multivariate analysis, age, QTc, DM, heavy alcoholics, and total bilirubin were independent risk factors for IFH at the long-term follow-up.

Conclusion
Longer QTc (>425msec) in patients with AHF was associated with higher IFH, suggesting close clinical and electrocardiographic follow-up will be required.

Acknowledgement/Funding
None
P6268Cardiovascular outcomes of new anti-diabetic agents - A meta-analysis of randomized controlled trials
Authors: Lin Y , Parco C , Brockmeyer M , Karathanos A , Schulze V , Krieger T , Heinen Y , Perings S , Kelm M , Wolff G 
Published: October 2019

Abstract

Background and purpose
The risk of major cardiovascular events (MACE) is increased in patients with diabetes mellitus. Recently published clinical trials of three different pharmacological classes (DPP4 inhibitors (DPP4i), SGLT2-inhibitors (SGLT2i), GLP-1-receptor-antagonists (GLP1RA)) of new anti-diabetic agents (ADA) showed potential benefits for cardiovascular (CV) outcomes. We thus aimed to perform a meta-analysis of randomized controlled trials (RCTs) of these ADA to elucidate benefits on CV outcomes in diabetic patients.

Methods
Following a systematic online database search, all RCTs reporting CV outcomes of DPP4i, SGLT2i or GLP1RA vs. Placebo in diabetic patients up until December 2018 were eligible for inclusion in the meta-analysis. Studies including patients with acute coronary syndrome (ACS) were excluded. Data were abstracted and analyzed with the inverse-variance method and a random-effects model, hazard ratios (HR) with 95% confidence intervals (CI) were used as summary statistics. CV outcomes of MACE, myocardial infarction (MI), stroke, heart failure (HF), CV death and all-cause mortality were analyzed.

Results
Eleven RCTs (DPP4i: SAVOR, TECOS, CARMELINA; GLP1RA: LEADER, SUSTAIN-6, EXSCEL, Harmony; SGLT2i: EMPA-REG OUTCOME, CANVAS Program, DECLARE) with 109,316 patients were selected for inclusion. ELIXA and EXAMINE were excluded due to their inclusion of patients with ACS, CAROLINA was excluded for lack of placebo-control. In the pooled meta-analysis of all trials, ADA significantly reduced the risk for MACE (Hazard ratio (HR) 0.91, CI 0.86–0.96, p=0.0004), MI (HR 0.91, CI 0.85–0.96, p=0.02), CV death (HR 0.9, CI 0.82–0.99, P=0.02) and all-cause mortality (HR 0.92, CI 0.85–0.99, p=0.03). There was no difference in the risk for stroke (HR 0.94, CI 0.87–1.02, p=0.16) and HF (HR 0.88, CI 0.76–1.02, p=0.08). In agent-specific subgroup analyses, GLP1RA and SGLT2i showed significant reductions in MACE (GLP1RA: HR 0.85, CI 0.78–0.92, p<0.0001; SGLT2i: HR 0.89, CI 0.83–0.96, p=0.001), MI (GLP1RA: HR 0.86, CI 0.76–0.98, p=0.02; SGLT2i: HR 0.88, CI 0.79–0.97, p=0.01) and all-cause mortality (GLP1RA: HR 0.88, CI 0.81–0.95; p=0.001; SGLT2i: HR 0.83, CI 0.70–0.99; p=0.03). GLP1RA significantly reduced risk for stroke (HR 0.85, CI 0.75–0.96, p=0.008) and CV death (HR 0.86, CI 0.78–0.95, p=0.002). SGLT2I were especially effective in the reduction of risk for HF (HR 0.69, CI 0.61–0.79; p<0.0001). DPP4i inhibitors however failed to show superiority in all analyzed outcomes.

Conclusions
This meta-analysis lends evidence to GLP1RA and SGLT2i benefits for MACE, MI and all-cause mortality, while DPP4i failed to show superiority in cardiovascular outcomes. Individualized medication for diabetic patients depending on CV disease status should be considered.
P6279Mitochondria targeted catalase overexpression protects against beta-adrenergic receptor mediated cardiac remodeling in mice
Authors: Uribe E , Andersson D 
Published: October 2019

Abstract

Background
Beta-adrenergic receptor signaling is widely recognized as a fundamental component in the pathogenesis of chronic heart failure. However, the mechanisms behind beta-adrenergic receptor-mediated remodeling in cardiomyocytes and the myocardium are not fully understood. Oxidative stress has been proposed as a central pathophysiological mediator in cardiovascular disease and heart failure. The triggers and sources of oxidative stress in heart failure remain unclear. In this study we use mice with mitochondria-targeted overexpression of the antioxidant enzyme catalase (mCAT) to link beta-adrenergic receptor-mediated stress to mitochondrial reactive oxidative species (ROS) and the progression of heart failure.

Hypothesis
Mitochondrial ROS, induced by beta-adrenergic receptor-activation, is a mediator in the progression of the heart failure phenotype.

Methods
mCAT and wild type mice (n=10) were administered the non-selective beta-adrenergic agonist Isoprotenerol (Iso; 50mg/kg/day) through subcutaneous osmotic pumps for 3 weeks. Hearts were taken for biochemistry (western blotting, qPCR). Cardiomyocytes were isolated and loaded with Fluo-3 AM to study intracellular Ca2+ transients and fractional shortening using confocal line scan microscopy. All experiments were performed in accordance with the Stockholm ethical committee for animal research.

Results and conclusions
The WT mice displayed an increased heart/body weight ratio following chronic Iso administration. In contrast, mCAT mice displayed resistance to Iso-induced cardiac hypertrophy (p<0.05). Furthermore, chronic Iso exposure in WT mice induced increased ROS-dependent post-translational protein modifications, impaired cardiomyocyte Ca2+ handling and reduced contractility in isolated cardiomyocytes (p<0.05). Cardiomyocytes from mCAT mice did not display the deleterious effects of chronic Iso exposure on cardiomyocyte Ca2+ and contractility.

Our study demonstrates that beta-adrenergic receptor stimulation-induced remodeling of the heart, which is similar to what is seen in heart failure, can be prevented by overexpressing catalase in the mitochondria. This indicates an important role of mitochondrial ROS in the link between adrenergic signaling and the development of cardiomyopathy and heart failure.

Acknowledgement/Funding
Hjärtlungfonden
P6286Old age significantly worsens stroke outcome in old mice through a mechanism of inflamm-aging successfully countered by the tumour necrosis factor alpha antibody infliximab
Authors: Bonetti N R , Liberale L , Pasterk L , Diaz-Canestro C , Akhmedov A , Gobbato S , Luescher T F , Beer J H , Camici G G 
Published: October 2019

Abstract

Background
Stroke is the second leading cause of death and the number one cause of adult disability worldwide. As a strongly age-dependant disease, its prevalence is expected to rise along with the average age in western populations. While the epidemiological evidence linking stroke to age is non-refutable, the specific and independent effects of age on stroke remain elusive.
This presents an important missing link for developing targeted treatments tailored to the growing elderly population.
A potential mechanism pertinent to stroke outcome in the elderly is a chronic low-grade inflammatory state, coined “inflamm-aging”. Such a phenomenon could not only increase the risk for stroke, but also negatively affect its outcome and thus offers both preventive and therapeutic value.

Purpose
To determine the specific effects of age on the outcome after stroke in mice and delineate culprit molecular pathways with a focus on inflammatory mediators and to assess the efficacy of specific anti-inflammatory treatment with the TNF-α antibody Infliximab in this setting.

Methods
Old (18–20 months) C57BL/6 wildtype mice were compared to young (12 weeks) controls. Baseline levels of inflammatory cytokines were assayed in plasma and brain homogenates by ELISA. Ischemic stroke was induced by transient middle cerebral artery occlusion (30 minutes/48 h). Neurological function was assessed by a Bederson based score and the RotaRod test. Anti-inflammatory treatment with Infliximab was administered to a subset of old mice via weekly intraperitoneal injections (10 mg/kg) for 4 weeks prior to stroke induction. Young and old control animals received vehicle.

Results
At baseline (prior to stroke), old animals showed significantly higher plasma levels of TNF-α compared to young (Fig. 1A), while IL-6 and IL-1β remained below detection level in both groups. In brain homogenates of healthy old and young animals, TNF-α and IL-1β did not differ, while IL-6 was below detection level.
Old mice showed significantly larger stroke sizes (Fig.1B), performed worse neurologically (Fig. 1C) and suffered from higher post-stroke mortality compared to young (Fig. 1D). Pre-treatment with the TNF-α inhibitor Infliximab significantly decreased stroke size, neurological impairment and mortality in old animals (Fig1B-D).
Figure 1

Conclusions
In a model lacking additional confounding factors, we demonstrate a direct adverse effect of age per se on stroke outcome and mortality. Elevated TNF-α plasma levels in old mice outline the mechanism of “inflamm-aging” as a possible culprit. This concept is strongly supported by the beneficial effect of Infliximab on stroke outcome in old animals. Further investigation of the downstream mediators of the observed effect could help in tailoring treatments to the particularly vulnerable and growing elderly population.
P6291Post-myocardial infarction activation of P2X7 dependent inflammasome is crucial to develop an appropriate scar integrity
Authors: Merz J , Van Garlen S , Ahmed I , Dimanski D , Rofa K , Hoppe N , Bode C , Zirlik A , Stachon P 
Published: October 2019

Abstract

Introduction
Cardiovascular diseases are the main cause of death worldwide. Acute ischemia results in cell death of cardiomyocytes accompanied with the release of so called damage associated molecular patterns (DAMPs) such as nucleotides. High concentration of ATP in the extracellular fluid leads to the opening of the ionotropic purinergic receptor P2X7. The following transmembranous ion flux triggers the assembly of the NLRP-3 inflammasome and proteolytic caspase-1 activation which cleaves pro-IL-1β and provokes the release of fully active pro-inflammatory IL-1β. Myocardial scar formation can be divided into an early remodelling IL-1β-dependent and a late scar forming TGFβ phase. Both phases negatively regulate each other. The current stuy aimed to investigate the role of this master regulator of NLRP3 inflammasome assembly P2Y7 in myocardial remodeling during prolonged ischemic conditions.

Methods
10 weeks old P2X7 knock-out and C57Bl6/J mice received a full ligation of the left anterior descending (LAD) artery. Mice three and seven days post-infarction underwent echocardiography. Myocardial scar formation was assessed by histological staining and flow cytometry. Furthermore caspase-1 activity was measured using FLICA in histology. Gene expression was assessed using TaqMan realtime PCR.

Results
Macrophages in the myocardial infarct area showed high P2X7 expression by Co-staining with fluorescent antibodies against F4/80, CD68 and P2X7. Intriguingyl P2X7 deficient animals showed a significantly worse survival rate in a Kaplan-Meier survival analysis compared to wt littermated with LAD ligation (Mortality after 21 days P2X7+/+ 50%; P2X7−/− 100%, p<0.05). Cause of death assessed by autopsy was myocardial rupture in P2X7−/− mice. Accordingly histological analysis revealed a less compact infarct area in P2X7 knock-out animals with abundant coagulation necrosis. In agreement with that we observed a thickened infarcted anterior wall by echocardiography in P2X7 animals. Furthermore whereas the infarcted area of P2X7 competent mice showed high signals for active caspase-1 in histology, we were not able to detect any signal of caspase-1 activity in P2X7 deficient mice. In coherence with this observation we detected a premature increased TGFβ gene transcript upregulation in infarct tissue of P2X7 deficient animals.

Conclusion
The knockout of the NLRP3 inflammasome activating P2X7 receptor impairs the outcome after myocardial infarction by reduced monocyte infiltration and deranged scar formation. Disruption of the fine-tuned IL-1β/TGFβ sequence with an early block of IL-1β signaling and premature TGFβ activation could explain the missing clean-up of necrotic debris and impaired scar formation. Taken together these findings highlight the importance of an early inflammasome phase during myocardial scar formation.
P6302GALNT4 enhances monocyte adherence and chemotaxis by regulating PSGL1 O-glycosylation in patients with acute coronary syndrome
Authors: Ye Z X , Huang H 
Published: October 2019

Abstract

Background
GalNAc-T4 (GALNT4), a member of N-acetylgalactosaminyltransferases family, which transfers GalNAc to Serine and Threonine residues in the initial step of O-linked protein glycosylation. Genome wide association studies (GWAS) have predicted that GALNT4 gene play a causal role in the susceptibility to cardiovascular diseases, whereas the precise mechanisms of it in acute coronary disease (ACS) is unknown.

Purpose
In this study, we sought to determine the role of GALNT4 in regulating monocytes with ACS and the underlying mechanisms.

Methods and results
The expression of GALNT4 mRNA was significantly elevated in patience with STEMI (n=50) compare with stable coronary heart disease (SCHD) (n=50) and controls (n=50) (Clinicaltrial.gov: NCT 03335514). Moreover, GALNT4 siRNA knockdown suppressed monocytes adherence under static and flow condition with P-selectin stimulation, as well as chemotaxis triggered by monocyte chemotactic protein-1 (MCP-1). In contrast, adenovirus mediated GALNT4 overexpression enhanced monocytes adherence and chemotaxis. Furthermore, vicia villosa lectin (VVL) pull down and PSGL1 immunoprecipitation assays showed that GALNT4 overexpression increased VVL binding to PSGL-1 and P-selectin induce phosphorylation of Akt and mTOR. Conversely, knockdown of GALNT4 decreased VVL binding and attenuated the activity of Akt /mTOR. Additionally, mTOR inhibitor rapamycin blocked these effects of GALNT4 overexpression on monocytes.

Conclusion
Expression of GALNT4 was increased in patience with ACS, GALNT4 overexpression enhances the adherence and chemotaxis of monocytes via modifying O-glycosylation of PSGL-1 and activity Akt/mTOR pathway. These findings suggest that GALNT4 may be a potential therapeutic target for ACS.

Acknowledgement/Funding
The National Natural Science Foundation of China (No. 81100220 and No. 81770340)
P6305Activation of invariant natural killer T cells ameliorates doxorubicin-induced cardiomyopathy
Authors: Sada M , Matsushima S , Ikeda S , Okabe K , Ishikita A , Tadokoro T , Enzan N , Yamamoto T , Deguchi Y , Ikeda M , Ide T , Tsutsui H 
Published: October 2019

Abstract

Background
Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions, especially strongly upregulating interferon (IFN)-γ. Activation of iNKT cells have been previously reported to exert protective effects against post-infarcted cardiac remodeling and cardiac ischemia/reperfusion injury. However, the role of iNKT cells has not been determined in doxorubicin (DOX)-induced cardiomyopathy.

Purpose
The purpose of this study was to examine whether the activation of iNKT cells by α-galactosylceramide (αGC), which specifically activates iNKT cells, could affect DOX-induced cardiomyopathy, and if so, to elucidate its downstream target.

Methods
C57BL/6J mice were received the intraperitoneal injection of either αGC (0.1μg/g, n=11) or vehicle (n=13). After 1 week, these mice were treated with a low dose of DOX (18mg/kg via intravenous 3 injections over 1 week), and were followed during 14 days.

Results
DOX mice (DOX+vehicle) showed left ventricular (LV) dysfunction and dilatation, which were significantly ameliorated in DOX mice receiving αGC (DOX+αGC) (LV fractional shortening: 27.4±4.31 vs. 31.5±4.62%, p<0.05, LV end-diastolic diameter: 3.70±0.16 vs. 3.32±0.23mm, p<0.05), with no significant changes in arterial pressure, body weight, and food consumption, 14 days after DOX injection. DOX+vehicle demonstrated a significant decrease in myocardial gene expression of Vα14Jα18, a specific marker of iNKT cells, and IFN-γ compared with control mice. Vα14Jα18 expression levels were higher in DOX+αGC than DOX+vehicle by 9.2 folds (p<0.05). Consistent with this change, IFN-γ was higher in DOX+αGC than DOX+vehicle by 4.4 folds (p<0.05), whereas interleukin (IL)-1, IL-4, IL-6, IL-10, IL-17, IL-23, and tumor necrosis factor (TNF)-α were not altered in both groups. Phosphorylation of Akt, its active form, in the heart was significantly increased in DOX+αGC compared with DOX+vehicle by 1.8 folds (p<0.05).

Conclusions
Activation of iNKT cells by αGC play a protective role against DOX-induced cardiac dysfunction, which was associated with enhancing expression of IFN-γ and activating Akt. Therapies designed to activate iNKT cells might be beneficial to protect the heart from DOX injury.