bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4435Effects of interleukin 6 inhibitor tocilizumab on endothelial glycocalyx, vascular and myocardial function compared to prednisolone
Authors: Ikonomidis I , Pavlidis G , Katsimbri P , Andreadou I , Triantafyllidi H , Tsoumani M , Varoudi M , Thymis I , Triantafyllou C , Kostelli G , Frogoudaki A , Vrettou A R , Boumpas D , Alexopoulos D , Iliodromitis E 
Published: October 2019

Abstract

Background/Introduction
Tocilizumab, a humanised monoclonal antibody against the human interleukin-6 receptor, is used for the treatment of rheumatoid arthritis (RA).

Purpose
We investigated the effects of tocilizumab on arterial function, LV myocardial deformation and endothelial glycocalyx in RA patients.

Methods
80 patients with rheumatoid arthritis were randomized to tocilizumab (n=40) or prednisolone (n=40) for 3 months. At baseline and after 3-month treatment we assessed: a) carotid-femoral pulse wave velocity (PWV-Complior SP ALAM), b) LV longitudinal strain (GLS), systolic (LongSr) and diastolic (LongSrE) strain rate using speckle tracking echocardiography, c) perfused boundary region (PBR) of the sublingual arterial microvessels (ranged from 5–25μm) using Sideview Darkfield imaging (Microscan, Glycocheck). Increased PBR is considered an accurate index of reduced endothelial glucocalyx thickness, d) flow mediated dilatation (FMD) of the brachial artery after and percentage difference of FMD (FMD%) after hyperemia, e) coronary flow reserve (CFR) of the LAD using Doppler echocardiography, and f) malondialdehyde (MDA), protein carbonyls (PCs) and C-reactive protein (CRP) plasma levels.

Results
At baseline, all patients had similar disease activity score and markers of vascular and myocardial function. Compared to baseline, all patients had reduced CRP post treatment, while MDA and PCs levels were reduced only after tocilizumab treatment (p<0.05). The percent decrease of MDA was correlated with percent increase of GLS (p<0.001). Compared to baseline, tocilizumab-treated patients reduced PWV (11±3% vs. 10.3±2m/sec) and PBR (2.11±0.2 vs. 1.95±0.18μm) (Figure 1) and increased GLS (−16.1±2.9 vs. −17.6±2.5%), CFR (2.73±0.8 vs. 3.06±1), and FMD% (5.9±2.9 vs. 11.6±3.6) (p<0.05 for all comparisons). No significant changes were observed among prednisolone-treated patients.
Figure 1

Conclusions
IL-6 inhibition improves endothelial function and oxidative stress resulting to improved vascular function and LV myocardial deformation.
P4467PCSK9 and Lp(a) levels of children born after assisted reproduction technologies: results from a pilot study
Authors: Koutagiar I , Vlachopoulos C , Terentes-Printzios D , Kosteria I , Sakka S , Gkourogianni A , Skoumas I , Miliou A , Papassotioriou I , Gardikioti V , Solomou E , Rigatou A , Chrousos G , Kanaka-Gantenbein C , Tousoulis D 
Published: October 2019

Abstract

Background
Since the introduction of Assisted Reproduction Technologies (ART) in clinical practice several studies have addressed concerns regarding the long-term health of the offspring and have revealed indications of an adverse cardiovascular/cardiometabolic outcome. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipoprotein (a) (Lp[a]) levels have been associated with cardiovascular risk.

Purpose
To investigate PCSK9 and Lp(a) levels of children born after ART compared with naturally conceived (NC) controls.

Methods
In this case-control study, 73 sex- and age-matched children (mean age 98±35 months) of ART (intracytoplasmic sperm injection [ICSI]: n=33, classic in vitro fertilization [IVF]: n=40) and 73 NC children were assessed. Blood lipid profile, including PCSK9 and Lp(a) levels, was measured. Children were grouped according to age (<8 years, 8–10 years, ≥10 years).

Results
In the univariate model of the overall population, circulating PCSK9 levels were related to total cholesterol (r=0.186, P=0.025), LDL-C (r=0.180, P=0.029) and SBP (r=0.199, P=0.021). Similarly, circulating Lp(a) levels were related to age (r=0.269, P=0.001), apoB (r=0.214, P=0.01), birth weight (r=−0.183, P=0.037), height (r=0.263, P=0.001), waist-to-hip ratio (r=−0.350, P<0.001), HOMA-IR (r=0.319, P<0.001), insulin (r=0.316, P<0.001), and hsCRP (ρ=0.241, P=0.018). No significant differences were observed regarding lipid biomarkers between ART and NC children. (p=0.515 for PCSK9 and p=0.277 for Lp(a) values). It is noteworthy that a significant interaction was found between age groups and conception method (P<0.001) showing that PCSK9 levels increase with age in ART children, while they decline with age in NC offspring (Figure 1). IVF children showed higher levels of adjusted mean Lp(a) than ICSI (13.5 vs. 6.8 mg/dl, P=0.010) and NC children (12.3 vs. 8.3 mg/dl, P=0.048).
Mean LogPCSK9 concentrations with the st

Conclusions
PCSK9 and Lp(a) levels did not differ between ART and NC children. Nonetheless, PCSK9 levels increase with age in ART children indicating a gradual deterioration of lipidemic profile that could lead to increased cardiovascular risk. Moreover, our results imply that ART method may be of importance given that classic IVF is associated with higher levels of Lp(a). The impact of the method of conception on PCSK9 and Lp(a) values should be validated in larger patient series.
P4468Dietary plant derived omega-3 fatty acid alpha linolenic acid prevents age-dependent arterial stiffness and improves outcome after stroke in mice
Authors: Bonetti N R , Diaz-Canestro C , Pasterk L , Liberale L , Vdovenko D , Gobbato S , Luescher T F , Camici G G , Beer J H 
Published: October 2019

Abstract

Background
A fundamental determinant of cardio- and cerebrovascular diseases is vascular aging, characterized by arterial stiffness. Arterial stiffness is an independent predictor of adverse cardio- and cerebrovascular events and mortality.
Fish-derived omega-3 fatty acids (n3-FA) have been described to decrease cardiovascular events in high risk populations. Little is known on the effects of the plant-derived n3 FA alpha-linolenic acid (ALA). More insight is urgently needed, because of the low costs and abundant global supply of ALA. Thus, we aimed to investigate the effects of a long-term dietary intervention with ALA on age-dependent arterial stiffness and the magnitude of these effects on a specific vascular endpoint – ischemic stroke – in a mouse model of aging.

Methods
C57BL/6 wildtype males were either fed an ALA-rich (high ALA, 7.3 g%) or a respective control (0.3 g%) diet for 12 months, starting from 6 months of age.
At 9, 15 and 18 months, arterial stiffness was assessed by measuring pulse wave velocity (PWV) in the right common carotid artery using a Vevo 3100 system (VisualSonics, Fig. 1A).
At 18 months, ischemic stroke was induced by transient middle cerebral artery occlusion (30 mins/48 h). Stroke size was assessed by triphenyl tetrazolium chloride staining and neurological function by a Bederson based score.

Results
Arterial stiffness steadily and significantly increased in controls over time, while ALA clearly and effectively prevented it (PWV at 9 vs. 18 months: controls + 95%; p<0,0001 vs. High ALA + 15%; ns) (Fig 1A).
Stroke size at 18 months was significantly decreased in ALA-fed animals compared to controls (28.39 mm3 vs. 51.77 mm3 p=0.0017) (Fig. 1B). In line with the morphological changes, controls performed significantly worse neurologically (Fig. 1C). Additionally, post-stroke survival at 48 h was improved in ALA-fed animals compared to controls, with 85% survival compared to 57% (Fig. 1D).
Figure 1

Conclusion
We demonstrate that long-term dietary supplementation with the plant-derived ALA fully prevents the development of age-dependent arterial stiffness.
The magnitude of this effect is clearly reflected in biologically relevant decreased stroke size, improved neurological performance and even post-stroke survival.
This study not only demonstrates vasoprotective effects of ALA, but also links them to improved outcome of a specific clinical endpoint. Future analyses will aim at delineating the molecular basis of the observed benefits. This will result in a better understanding of some ambiguous results from clinical trials and likely define the population which benefits from ALA.
P4469Reduced myocardial perfusion reserve in type 2 diabetes is caused by increased rest perfusion as well as decreased maximal perfusion during stress
Authors: Soerensen M H , Bojer A S , Madsen P L , Gaede P 
Published: October 2019

Abstract

Background
Reduced myocardial perfusion reserve is a well-known complication in patients with type 2 diabetes mellitus (T2DM). Furthermore, reduced myocardial perfusion reserve has been linked to the development of diastolic dysfunction, a key characteristic in diabetic cardiomyopathy. However, it is not fully explored whether a decrease in perfusion during stress or an increase in perfusion during rest is responsible for this reduction in myocardial perfusion reserve, nor is it clear what causes these changes.

Purpose
The purpose of this study was to examine differences in myocardial perfusion in rest and during stress in patients with T2DM compared to healthy control subjects, and to identify potential predictors for changes in perfusion during rest and stress among patients with T2DM.

Methods
200 patients with T2DM and 25 healthy volunteers matched for age and sex underwent a comprehensive cardiac MRI protocol including gadolinium first-pass perfusion during rest and stress (adenosine infusion 140 mg/min–1/kg–1). Perfusion was measured on a per-segment basis based on the AHA model and averaged to calculate global perfusion index both during rest and stress. Any areas with infarctions and/or significant perfusion defects were excluded from the analysis. Backwards stepwise multiple linear regression was performed to identify predictors for perfusion changes during rest and stress in patients with T2DM. Variables with P<0.1 in a univariate analysis were included into the models.

Results
Patients with T2DM had significantly higher rest perfusion index (0.135±0.024 vs. 0.120±0.016; P=0.001) and significantly lower stress perfusion index (0.174±0.041 vs. 0.225±0.027; P<0.001) compared to healthy volunteers. In a multiple linear regression model among patients with T2DM female sex (P<0.001) was associated with increased rest perfusion. In a similar analysis for stress perfusion, diabetes duration (P=0.01), albuminuria (P<0.001) and the presence of ischaemic heart disease (P<0.001) were associated with reduced myocardial stress perfusion index in patients with T2DM.

Conclusion
In patients with T2DM reductions in myocardial perfusion reserve is caused by a combination of increased basal myocardial blood flow and a decrease in maximal blood flow during stress. Decreased stress perfusion is associated with coronary vascular disease and the diabetic complication albuminuria related to renal microvascular disease. Stress perfusion also decreased with increasing duration of T2DM. This suggest that the coronary microcirculation is gradually damaged in patients with T2DM and that the mechanism responsible is similar to that causing renal microvascular damage.

Acknowledgement/Funding
Local science committee of Region Zealand, Regional science committee of Region Zealand, The Danish Heart Association
P4485The number of lipoprotein(a) kringle IV-type 2 repeats is associated with the osteogenic profile of aortic valvular interstitial cells induced by plasma from patients with calcific aortic stenosis
Authors: Arangalage D A , Simon T S , Varret M V , Croyal M C , Arsenault B A , Cattan-Levy L C L , Sayah N S , Deschildre C D , Boutten A B , Michel J B M , Mathieu P M , Nicoletti A N , Messika-Zeitoun D M Z , Caligiuri G C , Laschet J L 
Published: October 2019

Abstract

Background
Considerable progresses have been made in the invasive treatment of calcific aortic stenosis (AS), but there is still no pharmacological treatment available because the exact mechanism leading to the initiation of valvular calcification remains unknown. An increasing number of evidences, including large-scale genetic studies, have linked Lipoprotein(a) (Lp(a)) to AS but its pathogenic role in the osteoblastic transition of valvular interstitial cells (VIC) has remained undeciphered.

Objective
We sought to study the mechanistic link between the transition of VICs towards an osteoblastic phenotype leading to intraleaflet calcium deposition and the type of Lp(a) isoform, defined by the number of kringle IV-type 2 (KIV 2) repeats, in the plasma of patients with AS compared with healthy controls.

Methods
VICs isolated from healthy aortic valves were cultured in the presence of plasma samples deriving from 100 patients with severe AS included in the prospective cohort GENERAC and 50 matched control patients exempt from any aortic valve disease. We evaluated the number of Lp(a) KIV 2 repeats of each plasma preparation by liquid chromatography-mass spectrometry. The phenotypic changes of VICs towards an osteoblastic phenotype were assessed by immunofluorescence microscopy (osteocalcin expression) and Alizarin red staining (calcium deposition).

Results
Incubation of VICs with the plasma of AS patients triggered their transformation towards an osteoblastic phenotype, evidenced by the production of osteocalcin, and calcium deposition. There was no association between the plasma levels of Lp(a) and the extent of calcium deposition in the study population. However, a negative and significant correlation was found between calcium deposition and the number of KIV-2 repeats in the Lp(a) of the different plasma preparations (r=−0.20, p=0.038). A direct, causal role of Lp(a) isoforms containing a low number of KIV-2 repeats (5 to 6) in the transition of VICs towards an osteoblastic phenotype was supported by experiments performed with preparations of these isoforms, isolated from the plasma of blood donors.

Conclusion
A low number of KIV–2 repeats in plasma Lp(a) triggers the acquisition of an osteoblastic phenotype by VICs. The isoform, rather than the concentration of Lp(a) may play a pathogenic role in AS. Determining the number of KIV-2 repeats in the Lp(a) of patients may allow to identify subgroups of patients with an increased risk of developing AS.

Acknowledgement/Funding
ANR-16-RHUS-0003_STOP-AS. PHRC National 2005 and 2010, and PHRC regional 2007.
P4497Serum ceramides and type 2 diabetes are mutually independent predictors of cardiovascular events in patients with peripheral artery disease
Authors: Leiherer A , Muendlein A , Saely C H , Laaksonen R , Laaperi M , Vonbank A , Larcher B , Mader A , Fraunberger P , Dopheide J F , Baumgartner I , Drexel H 
Published: October 2019

Abstract

Background
Ceramides are enriched in atherosclerotic plaques, and a set of circulating ceramides including Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0) has recently emerged as predictors of cardiovascular outcomes in coronary artery disease patients.

Purpose
The purpose of this study was to investigate their power to predict cardiovascular events in patients with peripheral artery disease (PAD).

Methods
We measured the serum concentrations of the above mentioned ceramides in a cohort of 380 patients with sonographically proven PAD, of whom 107 had type 2 diabetes (T2DM). Prospectively, we recorded 221 cardiovascular events over a mean follow-up time of 6.3±2.3 years.

Results
Cardiovascular event risk was higher in T2DM patients than in those who did not have diabetes (69 vs. 52%, p=0.001). The ceramides Cer(18:1/16:0) and Cer(18:1/24:1) and the respective ratios Cer(18:1/16:0) / Cer(18:1/24:0) and Cer(18:1/24:1) / Cer(18:1/24:0) were significant predictors of cardiovascular events both univariately and after multivariate adjustment including the presence of T2DM (figure). Conversely, T2DM predicted cardiovascular events independently from the investigated ceramides (adjusted HR 1.76 [1.31–2.35], p<0.001).

Conclusion
We conclude that the investigated ceramides and T2DM are mutually independent predictors of cardiovascular events in PAD patients.
P4498Subcellular anti-atherosclerotic therapy: an approach to elimination of dysfunctional mithohondria by photodynamic therapy
Authors: Ryabova A V , Romanishkin I D , Skobeltsin A S , Moskalev A S , Makarov V I , Loschenov V B , Nikiforov N G , Orekhov A N , Orekhova V A , Sukhorukov V N , Sobenin I A 
Published: October 2019

Abstract

Photo-theranostics is a therapeutic and diagnostic approach that uses photosensibilization. This approach makes part of the medicine of the future – subcellular therapy. Photo-theranostics targets cells and tissues that are affected by pathological changes inducing apoptotic cell death. However, the approach allows targeting cellular organelles, if the photo-sensitizing agent is accumulated selectively. Such selectivity can result from the organelle's functional state, as in the case of mitochondria affected by mitochondrial genome abnormalities. For instance, some pro-atherogenic mitochondrial DNA (mtDNA) mutations can lead to mitochondrial dysfunction
Some photo-sensitizing agents accumulate selectively in mitochondria making the photodynamic targeting efficient enough. For instance, protoporfyrine IX (PpIX), which is widely used in clinical practice, is produced from a prodrug 5-aminolevulinic acid (5-ALC) in course of heme synthesis cascade in the mitochondria. Exogenous 5-ALC causes excessive formation of PpIX, which cannot be efficiently processed by ferrochelatase and accumulates in the cells. PpIX accumulation directly depends on the cell's metabolic activity.
We studied 5-ALC-induced PpIX accumulation on cybrid lines derived from thrombocytes with mutation-bearing mitochondria and THP-1 monocytes devoid of mitochondria. We used 3 cybrid lines and 2 THP-1 monocyte cultures cultured independently by different research groups. The mitochondrial functional state was assessed by fluorescence intensity of mitochondrial dye MitoTracker™ Orange CMTMRos (Thermo Fisher Scientific). Measurement of fluorescence was performed by laser scanning microscopy with spectral unmixing. MitoTracker and PpIX dyes were excited with a 561 nm laser, and fluorescence was measured at 570–750 nm wavelength. The signal was spectrally unmixed to obtain separate MitoTracker and PpIX signals. Individual cells areas were traced on microscopic images taken under identical conditions, and mean values of PpIX and MitoTracker fluorescence intensity were obtained for each cell.
We found that PpIX accumulation varied significantly from cell to cell within cell populations. Cybrid lines had increased PpIX accumulation in comparison with original THP-1 monocyte lines. A positive correlation between PpIX amount and mitochondrial membrane potential was observed (Figure 1).

Therefore, selective elimination of dysfunctional (mutated) mitochondria can be achieved by adjusting laser intensity sufficient to induce photodynamic destruction of the organelles, while normal mitochondria and the cells as a whole should be preserved at the used light intensities. This work was supported by the Russian Science Foundation (Grant #19-15-00010).

Acknowledgement/Funding
Russian Science Foundation (Grant # 19-15-00010)
P4506New indices of arterial stiffness correlates with disease severity and mid-term prognosis in acute decompensated heart failure
Authors: Zhou J T , Wang Y S , Kang Y , Feng Y Z , Chen X J , Zhang Q 
Published: October 2019

Abstract

Background
Arterial stiffness has been implicated in pathophysiology of heart failure (HF) since it is involved in the ventricular-vascular coupling. Recently, new indices obtained by a cuff oscillometric technique, the arterial velocity-pulse index (AVI) for the stiffness of central arteries and the arterial pressure-volume index (API) for the stiffness of peripheral arteries have been developed and validated. However, the AVI and API measurement has not been attempted in HF population.

Purpose
This study aimed to investigate the relationship between the AVI, API and clinical outcomes in HF patients.

Methods
A prospective cohort of patients with acute decompensated HF were enrolled within 6 months, who were admitted to a tertiary referral hospital in China. Measurement of the AVI and API (AVE-1500, Shisei Datum, Tokyo, Japan) was performed on the day of admission and discharge. Patients were followed up to 6 months for the composite endpoint of all-cause death and HF rehospitalization.

Results
A Total of 127 patients were recruited for analysis (60±15 years, 70% male). 80% of the patients were in New York Heart Association (NYHA) Class III or above at admission, who presented a mean left ventricular ejection fraction (LVEF) of 34±9%. During hospitalization, all patients received guideline directed medical therapy if not contraindicated. The AVI (27.3±5.2 vs. 28.6±6.7, p=0.002) and API (24.9±4.9 vs. 26.0±6.5, p=0.05) were lower at discharge than at admission. By dividing the patients into tertiles according to the amino-terminal pro-brain natriuretic peptide (NT-proBNP), LVEF, transmitral E velocity over mitral annular e' velocity (E/e' ratio) and systolic blood pressure (SBP) at admission, it was observed that the AVI increased with a higher level of NT-proBNP (p for trend <0.001), a larger E/e' (p<0.001) and a lower LVEF (p=0.001), while the API increased as the SBP became higher (p=0.005).The improvement in AVI at discharge was correlated with that in LVEF (R=-0.3024, p<0.05) and NT-proBNP (R=0.3118, p<0.05), while the change in API was positively correlated with that in SBP (R=0.3897, p<0.001). In 6 months after discharge, there were 52 predefined events including 15 deaths and 44 HF rehospitalization. Apart from the level of NT-proBNP, the AVI at discharge of ≥26 showed a trend of being associated with the composite outcome (2.747, 1.411–5.349, p<0.001 for univariate analysis; 1.8648, 0.8928–3.8949, p=0.0973 for multivariate analysis).

Conclusions
New noninvasive arterial stiffness indices as the AVI and API reflected severity of illness and mid-term prognosis in admitted HF patients. Further studies are warranted for understanding its mechanisms and developing clinical applications.
P4528Feasibility and safety of left bundle branch area pacing by transvenous approach through the interventricular septum in patients with left bundle branch block
Authors: Huang W J , Wu S J , Su L , Chen X Y , Cai B N , Zhou J G , Lan R F , Fu G S , Xu L , Xiao F Y , Wang S J , Mao G Y , Vijayaraman P , Ellenbogen K 
Published: October 2019

Abstract

Background
His bundle pacing (HBP) has been shown to correct left bundle branch block (LBBB), however it often requires high pacing output and the success rate is variable.

Objective
To assess the feasibility and safety of left bundle branch area pacing (LBBAP) in patients with LBBB.

Methods
From Apr 2014 to Aug 2018, patients with LBBB from multicenters indicated for CRT or pacing therapy were included. LBBAP was performed by advancing the MDT 3830 lead deep into the septum about 1 cm distal to the His bundle region (Figure 1F). Pacing characteristics, success rate, threshold and R-wave amplitude were assessed.

Results
A total of 94 patients aged 68.3±10.7 y with the native QRS duration of 167.2±17.2 ms were included. In 92 patients, LBBAP was successfully achieved and demonstrated RBBB pattern during unipolar tip pacing (UTP), with the paced QRS duration of 116.4±12.6ms (Figure 1C). Fusion of LBBAP and native conduction via the RBB eliminated RBBB and resulted in an average QRS duration of 103.2±10.1 ms (Figure 1D). LBB potential could be recorded from the LBB lead during correction of LBBB by HBP in 21 patients who used two leads method (His lead and LBB lead, Figure 1B). Output dependent selective and non-selective LBBAP were demonstrated in 48 patients (Figure 1C, D). The LBB capture threshold by UTP was 0.53±0.18V/0.5ms at acute and 0.62±0.17V/0.5ms at 6 months and 0.65±0.2V/0.5ms at 1 year. The R-wave amplitude were 11.4±5.2mV, 12.4±5.8mV and 12.0±5.8mV at acute, 6 month and 1 year. During follow-up, only one patient had an increase in LBB capture threshold to 2.5V/0.5ms at 3 months and there were no other complications such as dislodgment, infections, embolism or stroke associated with the implantation.

Conclusion
Permanent LBBAP is feasible and safe in patients with LBBB.