bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4423Extreme bradycardia in athletes is due to intrinsic changes within the heart
Authors: Flannery M D , Sully F , Janssens K , Morris G , Kalman J , La Gerche A 
Published: October 2019

Abstract

Background
It is well known that athletes and in particular endurance athletes have lower resting heart rates than non-athletes. This has generally been considered a healthy adaptation. Traditionally this was thought be due to increased vagal tone. Several studies have shown that endurance athletes continue to have lower heart rates in the absence of autonomic influence suggesting bradycardia is due to intrinsic changes within the heart. A subset of endurance athletes have very low heart rates with Tour de France cyclists having described heart rates in the 30s. It is unclear whether in these elite athletes with very low heart rates the profound bradycardia is due to autonomic influence or intrinsic changes within the heart.

Aim
The aim of this study was to determine if extreme bradycardia in athletes is due to excess vagal tone or more profound intrinsic changes within the heart.

Methods
We recruited three cohorts for this study: non-athlete controls (NA), endurance athletes with a documented resting heart rate >40 (EA) and endurance athletes with a resting heart rate <40 (BA). All participants underwent baseline testing including ECG, echocardiography and VO2 max testing. All participants came back on a second occasion for treatment with dual autonomic blockade (DAB) to determine intrinsic heart rate in the following manner. After resting supine for five minutes resting heart rate was measured. Participants were then administered 0.04mg/kg of intravenous atropine. After five minutes participants were then administered 0.05mg/kg of intravenous metoprolol. This was repeated every five minutes until there was no further drop in heart rate or 0.2mg/kg had been administered. The resting heart rate at this stage was recorded as the intrinsic heart rate. Parasympathetic blockade was confirmed by lack of response to Valsalva manoeuvre and sympathetic blockade was confirmed by lack of response to metoprolol. VO2 max testing was then performed to determine maximum heart rate.

Results
9 NA (7 male), 10 EA (8 male) and 5 BA (4 male) participated in this study. The average age was similar in all groups (NA 32.9y, EA 32.4y, BA 31.4y). The average resting heart rate was 71.7 in the NA group, 48.3 in the EA group and 41.6 in the BA group (p<0.05 for comparisons between all three groups). Following dual autonomic blockade resting heart rate was 86.0 in the NA group, 76.9 in the EA group and 64.4 in the BA group (p<0.05 for comparisons between all three groups). Maximum heart rate under DAB was 140.1 in the NA group, 138.0 in the EA group and 140.4 in the BA group. These differences were not significant.

Conclusion
In athletes with very low heart rates, bradycardia is due to more profound intrinsic changes within the heart.

Acknowledgement/Funding
NHMRC Project Grant
P4443Elevated levels of D-dimer are associated with inflammation and disease activity rather than risk of venous thromboembolism in patients with granulomatosis with polyangiitis
Authors: Borowiec A , Kowalik I , Hadzik-Blaszczyk M , Rusinowicz T , Krupa R , Zycinska K 
Published: October 2019

Abstract

Background
Granulomatosis with polyangiitis (GPA) is one of antineutrophil cytoplasmic autoantibody (ANCA) – associated vasculitis. The disease is characterized by necrotising inflammation of small vessels causing tissue ischemia in a variety of organs with a wide range of clinical presentations. It has been established that active GPA is associated with a very high risk of venous thromboembolic events (VTEs).

Purpose
The aim of the present study was an evaluation of inflammation, coagulation and fibrinolysis markers, and their association with various clinical and laboratory parameters in GPA patients.

Methods
The group of 100 consecutive patients with GPA was prospectively followed in the study. In all patients echocardiography and laboratory tests were performed.

Results
The patients were followed up for an average of 4.0±1.9 years. In this group, D-dimer was elevated in majority (56%) of patients. The circulating levels of D-dimer were significantly higher in GPA patients in active stage of disease compared with those in remission (652 vs. 405 ng/ml, p=0.0002). In 23 patients venous thromboembolism was diagnosed during observation. However, there was no difference in D-dimer concentration between patients with and without VTE either in active stage or in remission. Among the 100 GPA patients higher D-dimer levels were observed in patients with coronary artery disease (p=0.04), atherosclerosis (p=0.01), hypertension (p=0.0049), diabetes (p=0.0065) and hypercholesterolemia (p=0.03). Moreover, correlation analysis showed that the levels of D-dimer correlated with hs-CRP (r=0.42; p<0.0001) and creatinine (r=0.58; p<0.0001). In patients with VTE, D-dimer levels correlated positively with age (r=0.5, p=0.02), right ventricle diameter (r=0.63, p=0.0017), right ventricle systolic pressure (r=0.44, p=0.04), and negatively with pulmonary artery acceleration time (r=−0.43, p=0.05).
D-dimer – normal D-dimer – elevated p Inclusion – active stage n=44 (44%) n=56 (56%) Elevated creatinine 1 (2.27%) 25 (44.6%) <0.0001 Elevated CRP 5 (11.3%) 22 (39.2%) 0.0015 Venous thromboembolism 7 (15.9%) 16 (28.6%) 0.0712 CRP: C-reactive proteine.

Conclusion
In patients with Granulomatosis with polyangiitis elevated levels of D-dimer are associated with disease activity and inflammation, rather than with risk of venous thromboembolism. D-dimer is not a useful marker of venous thromboembolism episodes in patients with small vessel vasculitis.
P4444Hypertension, autoimmune inflammation and salt sensitivity in women with rheumatoid arthritis
Authors: Osipova I V , Starodubova J 
Published: October 2019

Abstract

Introduction
Hypertension (HTN) takes the first place among cardiovascular diseases in patients with rheumatoid arthritis (RA). Currently, the main risk factors for hypertension are known, but eating habits are often not considered in patients with RA. The salt taste sensitivity threshold (STST) in women with autoimmune inflammation and the effect of salt sensitivity to hypertension in RA have not been practically studied which was the novelty of our study.

Purpose
Purpose is to determine the salt taste sensitivity threshold in women with RA and assess the correlation between salt sensitivity, autoimmune inflammation and the development of hypertension in women with RA.

Methods
STST was studied in all patients with RA (n=202). Then, to assess the risk factors for hypertension in RA, the patients were divided into 2 groups: group 1 – patients with hypertension (n=141), group 2 – patients without hypertension (n=61). The patients' examination was carried out using the standards of the Association of Rheumatologists of Russia and the Russian Society of Cardiology. Salt taste sensitivity threshold was determined with R.J. Henkin's method. The patients with middle and high STST were considered salt-sensitive. Statistical data were obtained with Statistica 10.0. Regression analysis was used to identify the correlation between risk factors and the development of hypertension.

Results
The following results based on STST testing were obtained in patients with RA (n=202): high STST was in 129 patients (64.3%), middle - in 20 patients (10.7%), low - in 53 patients (25.0%). The activity of the inflammatory process was significantly higher in salt-sensitive patients (p=0.01). According to regression analysis, the predictors for hypertension in women with RA, in order of importance were age >55 years (p=0.001), early menopause (p=0.001), increased total cholesterol (p=0.001), taking prednisolone >10 mg/day (p=0.001), early family history of cardiovascular diseases (p=0.01), reduced glomerular filtration rate <60 ml/min 1.73 m2 (p=0.01), high STST (p=0.01), pregnancy pathology (p=0.01), high activity of the inflammatory process (p=0.01), psychosocial factors (stress, anxiety, depression) (p=0.01), obesity (p=0.01), RA duration >10 years (p=0.01). There were twice as many salt-sensitive patients with RA and HTN as with RA and without HTN (87% and 48%, respectively). Excessive fluid in the body was observed with decreased natriuresis that assumes the presence of volume-dependent hypertension.

Conclusion
The results of the study showed the importance to determine STST associated with a set of factors and autoimmune inflammation was significant among them. The widespread application of the method determining the salt sensitivity will make it possible to increase the effectiveness of hypertension treatment based on individual recommendations for women with RA.
P4460microRNA-17-5p and microRNA-20a-5p downregulation by atorvastatin in Hepg2 cells: a new mechanism involved in the lipid-lowering therapy
Authors: Saavedra K , Leal K , Zapata D , Sagardia S , Ortega F , Zambrano T , Saavedra N , Salazar L A 
Published: October 2019

Abstract

Background
Hypercholesterolemia increases the risk of coronary artery disease and its pharmacological treatment has demonstrated, besides reducing cholesterol levels, a decrease in the incidence and mortality from coronary events. The treatment of hypercholesterolemia is mainly driven by using statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in a variable effect in both lipid lowering and risk reduction. Thus, a better understanding of lipid-lowering mechanism and response variability at molecular level is required. Previously, we demonstrated a deregulation of microRNA (miR) profile in HepG2 cells after atorvastatin treatment, including the downregulation of miR-17-5p and miR-20a-5p which potentially targets the LDL receptor gene (LDLR), suggesting that it might be involved in allowing the LDLR overexpression on the surface of hepatic cells to subsequently capture circulating LDL and to reach the expected lipid-lowering effect.

Purpose
To determine the role of miR-17-5p and miR-20a-5p on the regulation of LDLR gene expression in HepG2 cells.

Methods
Cells HepG2 were treated with atorvastatin 10μM for 24 hours. RNA extraction and enrichment of smallRNAs were performed. The gene expression of miR-17-5p, miR-20a-5p, miR-24-3p, miR-93-5p, miR-106a-5p and LDLR were evaluated. To evaluate the effect of miR-17-5p and miR-20a-5p on LDLR gene expression, both miRs were overexpressed or repressed by transfection of mimics or inhibitors respectively into HepG2 cells for 24, 48 and 72 Hours. The gene expression of LDLR was quantified by real time PCR using RPL27 gene as reference gene. The protein expression of LDLR and beta actin were evaluated using western blot and quantified using the ImageJ software.

Results
Our data showed that atorvastatin significantly repressed the expression of miR-17-5p (P<0.0001) and miR-20a-5p (P=0.0456) in HepG2 cells. In silico studies showed that miR-17-5p interact with the 3'-UTR region of the LDLR. Consistently, when miR-17-5p or miR-20a-5p were overexpressed by using mimics, we observed that gene and protein expression of LDLR decreased significantly (P<0.0001 and P<0.05 respectively). Consistently, when miR-17-5p or miR-20a-5p were repressed by the use inhibitors, we observed that the gene and protein expression of LDLR increases significantly (P<0.005).

Conclusions
In conclusion, we demonstrate that atorvastatin induces a significant down-regulation of the miR-17-5p and miR-20a-5p in HepG2 cells. The overexpression or repression regulate the gene and protein expression of LDLR.

Acknowledgement/Funding
FONDECYT N°3160567, FONDECYT N°1171765 and DIUFRO DI19-0094
P4475Vasodilation- and blood pressure normalization-independent cardioprotective effects of endogenous, physical activity-induced alpha calcitonin gene-related peptide in chronic hypertension
Authors: Skaria T , Mitchell K , Fischer J A , Born W , Gassmann M , Vogel J 
Published: October 2019

Abstract

Background
Alpha calcitonin gene-related peptide (αCGRP) is one of the strongest vasodilators and, as such, is cardioprotective in chronic hypertension when reducing the associated elevated blood pressure. However, we hypothesize that endogenous, physical activity-induced αCGRP has blood pressure independent cardioprotective effects in chronic hypertension.

Methods
Chronic hypertension was induced in WT and αCGRP−/− mice by one-kidney one-clip surgery. Chronic hypertensive WT and αCGRP−/− mice lived sedentarily or performed voluntary wheel running and were treated simultaneously with either vehicle, αCGRP or αCGRP receptor antagonist CGRP8–37. Cardiac function and tissue phenotype were evaluated echocardiographically and by ddPCR, Western blotting and histology, respectively.

Results
Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological cardiac remodeling and symptomatic heart failure already in sedentary, chronic hypertensive WT mice. In these mice, voluntary wheel running significantly improved cardiac tissue phenotype and function, that was abolished by CGRP8–37 treatment. In αCGRP−/− mice, αCGRP treatment, in contrast to voluntary wheel running, improved cardiac tissue phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-mediated blunting of pathological cardiac remodeling.

Conclusion
Endogenous, physical activity-induced αCGRP has blood pressure independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, permanently inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger hypertensive patients.

Acknowledgement/Funding
Swiss National Science Foundation, Novartis Foundation for Medical-biological Research
P4483Transforming growth factor-beta and arrhythmias in mitral valve prolapse patients
Authors: Malev E , Omelchenko M , Mitrofanova L , Vasina L , Pankova I , Gordeev M , Bondarenko B , Zemtsovsky E 
Published: October 2019

Abstract

Transforming growth factor-β (TGF-β) is a multifunctional cytokine with fibrogenic properties. Also increased TGF-β signaling contributes to the development of myxomatous changes of the mitral valve (MV). Recent data suggests that TGF-β may play a potentially important role in the heart arrhythmogenesis. Our aim was to evaluate the possible proarrhythmic effects of TGF-β in patients with mitral valve prolapse (MVP) and severe mitral regurgitation (MR) undergoing MV repair.

Methods
30 consecutive patients (mean age 53.1±9.4, 47% male) undergoing MV repair for severe MR due to MVP were enrolled in our observational, prospective, single-center study. Immunohistochemical characterization of mitral valve sections was performed with TGF-β1 and TGF-β2 primary antibodies. The levels of TGF-β1 and TGF-β2 in serum were determined by enzyme-linked immunosorbent assay Human Platinum ELISA.Transthoracic echocardiography and 24-hour Holter monitoring were performed pre- and postoperatively annually. Atrial fibrillation, PVCs and nonsustained ventricular tachycardia (VT) runs were reviewed.

Results
Resected MV leaflets showed the increase ofTGF-β1 and TGF-β2 positive cell count (33% and 38%, respectively). High level of TGF-β1 (>14.75 ng/ml) and/or TGF-β2 (>2.0 ng/ml) was detected in majority (77%) of patients and associated with thickening of posterior leaflet (r=0.67; p=0.016), residual valve prolapse (r=0.68; p=0.007) and recurrent MR (r=0.56; p=0.01), pre- and postoperative left atrial (p<0.001) and end-systolic LV diameter (p<0.001), and negatively with LV ejection fraction (p<0.001).
Atrial fibrillation was documented in 20% patients before repair. Postoperative AF occurred in 17% and associates with postoperative left atrial diameter (rs=0.60; p=0.008) and MR degree (rs=0.51; p=0.01). Total number of PVCs and non-sustained ventricular tachycardia runs dropped significantly in 1st (p=0.04, Wilcoxon matched pairs test) and 2nd (p=0.03), years of postoperative follow-up. Postoperative incidence of PVCs and VT associates strongly with postoperative end-diastolic LV diameter (rs=0.70; p=0.005), moderate negatively with LV ejection fraction (rs=−0.55; p=0.01).
TGF-β2 (but not TGF-β1) serum level were associated with postoperative incidence of atrial fibrillation (p<0.001), but not PVCs or VT. In univariate analysis, postoperative left atrial diameter (p=0.001), residual MR (p=0.003), myxomatous degeneration (p=0.008) and the serum level of TGF-β2 (p=0.001) were identified as risk factors of persistent atrial fibrillation after surgery.

Conclusions
High level of TGF-β2 is associated with persistent atrial (but not ventricular) arrhythmias in MVP patients after mitral valve repair, possibly through 1) progression of valve myxomatous after reconstructive surgery (via recurrent MR and LA enlargement) and 2) previously shown alteration of the electrophysiological phenotype of cardiac myofibroblasts.
P4484Notch-dependent endothelial dysfunction in patients with aortic valve calcification
Authors: Kostina A S , Semenova D , Kiselev A , Urtyuga O , Shcherbinin T , Ibragimov A , Gordeev M , Uspenskiy V , Kostareva A , Malashicheva A 
Published: October 2019

Abstract

Background
Aortic valve calcification associated with either bicuspid or tricuspid aortic valve remains among the most dangerous cardiovascular diseases but cellular and molecular reasons of this pathology are not fully understood. It has been shown that NOTCH1 haploinsufficiency in endothelial cells derived from iPS and also inhibition of NOTCH1 in aortic valve endothelial cells gives rise to the activation of proosteogenic pathways. Endothelial cells regulate underlying interstitial cells and govern them to differentiation. Thus, elucidation of molecular mechanisms of endothelial dysfunction could shed light on valve calcification pathogenesis.

Purpose
To elucidate key genes responsible for valve endothelial dysfunction in aortic valve calcification.

Methods
Primary human aortic valve endothelial cells (VEC) were isolated from 45 patients (BAV, n=21; TAV, n=26) with calcific aortic valve disease and from 8 healthy donors. Expression of corresponding genes was estimated by qPCR.

Results
We checked expression of about 30 genes related to Notch/Wnt/Bmp pathways and shear stress response. Endothelial cells of patients with calcification had significantly lower mRNA levels of Notch component genes NOTCH2, NOTCH3, DLL4 and JAG1 as well as of Notch target genes HEY1, SNAIL and SLUG. Expression of Wnt-related genes such as DKK1, GREM1 and TCF4 was altered in VEC from calcified valves. Interestingly, mRNA level of ROBO4, recently suggested to be involved in endothelial dysfunctions, was significantly higher in VEC of patients with calcification. Moreover, endothelium from calcified valves had impaired expression of matrix gla protein (MGP), which is known to sequester calcium and inhibit soft tissue calcification in the vasculature and aortic valve.

Conclusions
Our data show that Notch pathway genes are downregulated in valve endothelial cells of the patients with aortic valve calcification. Our results suggest also implication of shear stress responsive genes and genes of endothelial performance in changing the properties of valve endothelial population of calcified valves and thus presumably to the pathogenesis of aortic valve calcification.

Acknowledgement/Funding
Russian Foundation For Basic Research 18-34-00277
P4487Inhibition of aortic valve calcification by SNF472 in vitro
Authors: Zabirnyk A , Bogdanova M , Ferrer M , Perez M , Kaljusto M , Stenslokken K , Salcedo C , Fiane A , Vaage J 
Published: October 2019

Abstract

Background
Calcific aortic valve disease is the 2nd most frequent cause of open heart surgery. The valve interstitial cells (VIC) are crucial for calcification. SNF472 (a derivative of phytic acid) is a calcification inhibitor currently in clinical development for the treatment of cardiovascular calcification (Phase 2 CaLIPSO trial, EudraCT 2016–002834–59). SNF472 has been shown to inhibit vascular calcification in several preclinical models.

Purpose
1. Establish a new model of calcification in cultured human VIC; 2. Investigate whether SNF472 would inhibit calcification in this model, and 3. Study if SNF472 might inhibit ongoing calcification processes.

Methods
Healthy and calcified aortic valves were obtained from heart transplant recipients and patients undergoing aortic valve replacement due to calcific valve disease, respectively. VIC were isolated and seeded in basic growth medium, osteogenic differentiation medium (Osteodiff) alone, and with addition of different concentrations of SNF472. The following series of studies were performed: 1. VIC from healthy and calcified valves were cultured for three weeks with Osteodiff; 2. VIC from calcified valves were cultured for 3 weeks in Osteodiff media with 0, 1, 3, 10, 30, or 100 μM SNF472; 3. VIC from calcified valves were cultured for 3 weeks in Osteodiff media in total, but after 1 or 2 weeks 30 or 100 μM SNF472 was added to the cultures (n=8). Calcification was visualized by Alzarin Red staining and quantified by spectrophotometry. Statistics analysis was performed nonparametric One-Way ANOVA (Friedman and Kruskal–Wallis tests) with Dunn's post-test.

Results
Calcification was found to be 30% stronger in cultures of VIC from calcified valves as compared to cultured VIC from healthy valves (p=0.03). SNF472 successfully inhibited VIC calcification in a dose-dependent manner. SNF472 concentrations of 1, and 3 μM inhibited calcification by 7% (not significant) and 66% (p=0.08) respectively. Concentrations of 10, 30, and 100 μM completely inhibited calcification. 30 and 100 μM of SNF472 added after 1 week reduced ongoing calcification by 84% (p<0.01) and 100% (p<0.01) respectively. When given after 2 weeks of ongoing calcification non-significant inhibition was still observed (21 and 30%, respectively).

Conclusions
VIC from calcified valves have a more pro-calcification phenotype than VIC from healthy valves. SNF472 is able to inhibit the development VIC calcification in vitro. By early intervention SNF472 is also able to stop the progression of ongoing calcification. SNF472 shows to be a promising therapy to treat heart valve calcification.

Acknowledgement/Funding
EC FP7 (GA 609020), Balearic Islands Government grant (ES01/TCAI/41_2017), FEDER 2014-2020, Laboratoris Sanifit, Palma, Spain; University of Oslo