bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1583The association of carotid atherosclerosis, protein-energy wasting and inflammation status with mortality in patients on haemodialysis
Authors: Ito R , Oshima S , Ishii H , Sakakibara T , Yamabe S , Umemoto N , Murohara T 
Published: October 2019

Abstract

Background
Carotid atherosclerosis such as increased intima-media thickness (IMT) is associated with poor cardiovascular outcome. On the other hand, protein-energy wasting (PEW) or malnutrition, currently considered to be due to inflammatory process rather than poor nutritional intake, is highly prevalent in in chronic kidney disease (CKD) patients, particularly those on haemodialysis (HD). We investigated the association of carotid atherosclerosis, PEW and inflammation, and their joint role with prediction of mortality in chronic HD patients.

Methods
Carotid ultra-sound was performed in a total of 774 CKD patients stably undergoing HD therapy. Carotid atherosclerosis is defined as IMT>0.8mm as median value with hyperechoic plaque. Geriatric nutritional risk index (GNRI) which calculated from serum albumin levels, body weight and height as a surrogate marker of the PEW, and C-reactive protein (CRP) were measured at the same point. Patients were followed-up for 7 years.

Results
Declined GNRI and elevated CRP levels were independently associated with carotid atherosclerosis [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93–0.98, p=0.0082 and OR 1.30, 95% CI 1.04–1.64, p=0.019, respectively] accompanied with age (OR 1.03, 95% CI 1.01–1.05, p=0.0024) and hypertension (OR 1.78, 95% CI 1.12–2.91, p=0.013). During follow-up period (median of 67 months), 180 patients (23.3%) died. Carotid atherosclerosis [62.7% vs. 79.3% for 7-year survival rate, hazard ratio (HR) 1.57, 95% CI 1.12–2.16, p=0.0078], GNRI<91.2 as an established cut-off value (58.8% vs. 83.7%, HR 1.87, 95% CI 1.35–2.59, p=0.0002) and CRP>1.1 mg/l as a median value (65.8% vs. 88.6%, HR 2.87, 95% CI 2.00–4.22, p<0.0001) were identified as independent predictors of mortality after adjustment for other confounders. When patients were divided into groups according to number of these three risk factors, 7-year Kaplan-Meier survival rate was 92.7%, 91.1%, 56.8% and 37.2% among groups with no risk factor, any 1 risk factor, any 2 risk factors and all risk factors, respectively (p<0.0001 for trend). After adjustment for other confounders, patients with any 1, any 2 and all risk factors had 2.21-fold (95% CI 1.26–4.14), 5.44-fold (95% CI 3.13–10.1) and 7.19-fold (95% CI 3.67–14.6) higher risk for mortality compared to those without any risk factor, respectively (p<0.0001 for trend).

Conclusions
Presence of carotid atherosclerosis was closely associated with both declined GNRI and elevated CRP levels in CKD patients on HD. Combination of these predictors was also additively associated with an increasing risk of mortality. These results clearly manifested the so-called malnutrition, inflammation and atherosclerosis (MIA) syndrome in this high-risk population.
P1584The prognostic significance of the blood pressure-pulse wave velocity association for cardiovascular outcomes and mortality in hemodialysis patients
Authors: Loutradis C , Sarafidis P , Mayer C , Karpetas A , Bikos A , Papadopoulos C E , Pagourelias E , Wassertheurer S , Vassilikos V , Schmaderer C , Papagianni A , London G 
Published: October 2019

Abstract

Introduction and purpose
Hemodialysis patients have premature arterial stiffness, and the relationship between pulse wave velocity (PWV) and blood pressure (BP) may be different than in other hypertensives. Previous studies showed that when BP decrease is accompanied by PWV decrease the survival is improved. The aim of this study is to examine the prognostic significance of BP sensitivity of PWV for major cardiovascular outcomes and all-cause mortality in hemodialysis patients.

Methods
This is a prospective cohort study including 242 hemodialysis patients [age, 62.6±14.2 years; female, 91 (37.6%); hemodialysis vintage, 41.53±43.46]. All subjects underwent 48-hour-ABPM with Mobil-O-Graph-NG and followed-up for 33.17±19.68 months. The within-individual MBP-PWV association (MBP, dependent and PWV independent variable) was evaluated using the beta-coefficient value from simple linear regression analysis for each patient. The primary end-point was first occurrence of all-cause death, non-fatal myocardial infarction or non-fatal stroke. Secondary end-points were: (i) all-cause mortality; (ii) cardiovascular mortality; (iii) a combination of cardiovascular events.

Results
Patients who experienced the primary end-point during follow-up had significantly lower beta-coefficient levels (primary end-point: 19.877±3.975 vs 18.483±3.550, p=0.008). Higher quartiles of beta-coefficients (indicating dependency of PWV on MBP) were associated with higher cumulative freedom from the primary end-point (50.8%, 60.0%, 70.0% and 80.3% for quartiles 1 to 4 respectively; logrank-p=0.001), higher overall survival (60.7%, 61.7%, 73.3%, 86.9%; logrank-p=0.002) and higher cardiovascular survival (78.7%, 75.0%, 81.7%, 91.8% for quartiles 1 to 4; logrank-p=0.044). The future risk for the primary end-point, all-cause and cardiovascular mortality and the combined outcome was progressively increasing for lower quartiles of beta-coefficients (HR for all-cause mortality 3.395; 95% CI: 1.524–7.563, p=0.003 for quartile 1 vs quartile 4). Age (OR: 1.046, 95% CI: 1.016–1.077 per year increase, p=0.003) and 48h heart rate (OR: 0.949, 95% CI: 0.916–0.982 per bpm increase, p=0.003) were independently associated with weaker relationship between 48h-MBP and 48h-PWV.

Conclusions
Lower within-individual MBP-PWV association, based on AMBP recordings, is associated with higher risk of death and cardiovascular events in hemodialysis. These findings support that BP-independent arterial stiffness may be the underlying factor for adverse outcomes in these individuals.
P1591Cardiovascular toxicity of ibrutinib: a pharmacovigilance study
Authors: Salem J E , Manouchehri A , arie Bretagne M , Lebrun Vignes B , Groarke J D , Johnson D B , Yang T , Reddy N M , Funck-Brentano C , Brown J R , Roden D M , Moslehi J J 
Published: October 2019

Abstract

Importance
Ibrutinib, a first in class Bruton tyrosine kinase inhibitor, has revolutionized treatment for several B-cell malignancies. However, early data suggested that ibrutinib was associated with supra-ventricular arrhythmias (SVA) and bleeding. Other types of cardiovascular adverse drug reactions (CV-ADR) induced by ibrutinib have been sporadically reported.

Objective
To determine the full spectrum of CV-ADR associated with ibrutinib and provide data concerning their clinical characteristics.

Design
An observational, retrospective, pharmacovigilance study

Setting
VigiBase, the World Health Organization's pharmacovigilance database.

Main outcomes and measures
A disproportionality analysis using reporting odds-ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and ADR using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) >0 is considered statistically significant.

Exposures
Exposure to ibrutinib versus entire database.

Results
Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVA; ROR: 23.1 [21.6–24.7]; IC025:3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7 [3.4–4.1]; IC025:1.63), heart failure (HF; ROR: 3.5 [3.1–3.8]; IC025:1.46), ventricular arrhythmias (VA; ROR: 4.7 [3.7–5.9]; IC025:0.96), conduction disorders (CD; ROR: 3.5 [2.7–4.6]; IC025:0.76), CNS ischemic events (ROR: 2.2 [2.0–2.5]; IC025:0.73) and hypertension (ROR: 1.7 [1.5–1.9]; IC025:0.4). CV-ADR occurred early after ibrutinib administration, as soon as after the first dose, with a shorter median time to onset of 27.5 days (IQR: 1–138.5 days) for CD (p<0.01, Kruskal-Wallis), as compared to CNS ischemic events (51 days; IQR: 17.5–160 days, p: 0.05 vs. CD), CNS hemorrhagic events (53.5 days; IQR: 20.3–183.3 days, p: 0.03 vs. CD), HF (54 days; IQR: 20–142.8 days, p: 0.05 vs. CD), VA (70 days; IQR: 28.5–152.5 days, p: 0.03 vs. CD), SVA (74 days; (IQR: 29.5–196.5 days, p: 0.0004 vs. CD) and hypertension (164 days; IQR: 20–274 days, p: 0.04 vs. CD). CV-ADR were associated with fatalities, with rates ranging from ∼10% (SVA and VA) to ∼20% (CNS events, HF and CD). More deaths occurred when SVA cases were associated with CNS hemorrhagic and/or ischemic events compared to their absence (15/52, 28.8% vs. 88/907, 9.7%, p<0.0001, respectively).

Conclusions
Severe and occasionally fatal cardiac events related to cardiac SVA, VA, CD, HF, hypertension, CNS hemorrhagic and ischemic events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs.
P1592A cardioprotective effect of dietary nitrate mediated by red blood cells
Authors: Jiao T , Yang J N , Sundqvist M , Tratsiakovich Y , Hellenius M L , Weitzberg E , Lundberg J , Pernow J 
Published: October 2019

Abstract

Background
Reduced bioavailability of nitric oxide (NO) is a key factor behind coronary artery disease and ischemic heart disease. Besides being produced from L-arginine by NO synthase, reduction of nitrate/nitrite to NO is also an important pathway for NO generation, especially during hypoxic/ischemic conditions. Existing evidences suggest that dietary nitrate improves endothelial function and ischemic tolerance via a NO-dependent mechanism. Recent data indicate that red blood cells (RBCs) are an important source of NO bioactivity that protects the heart from ischemia-reperfusion injury. It is unknown whether dietary nitrate exerts cardioprotection by increasing export of RBC NO bioactivity.

Purpose
To investigate whether dietary nitrate protects the heart against ischemia-reperfusion injury via a mechanism mediated by RBCs.

Methods
Patients with mild hypertension (systolic blood pressure >130, ≤159 mmHg) were randomly assigned to three groups after a 2-week run-in period on a diet low in nitrate: group 1 received nitrate-rich vegetables (green leafy, ∼150 g/day) plus capsules with placebo salt (KCl), group 2 received low nitrate vegetables (cherry tomato, sweet corn, capsicum, carrot, ∼150 g/day) and capsules with nitrate salt (KNO3, 300mg) and group 3 received low nitrate vegetables and placebo capsules for 5 weeks. The nitrate content of the pills and nitrate-rich vegetables were precisely matched. As a pre-specified substudy, RBCs were collected blindly from 48 subjects before (baseline) and after the 5-week treatment (follow-up). The RBCs were given to isolated Langendorff-perfused rat hearts at the onset of ischemia with and without the soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4] Oxadiazolo[4,3-a]quinoxalin-1-one, ODQ). The hearts were subjected to 25 min global ischemia following 60 min reperfusion. Left ventricular developed pressure (LVDP) was recorded as an indicator of cardiac function.

Results
The recovery in LVDP during reperfusion following global ischemia in hearts given RBCs collected at baseline was similar in the three groups (Fig. A). Of note, post-ischemic recovery of LVDP was significantly improved by administration of RBCs from patients randomized to high nitrate vegetables or nitrate capsule compared to the group randomized to low nitrate and placebo (Fig. B). There was no difference in LVDP recovery between the groups receiving high nitrate vegetables or nitrate capsule (Fig. B). The nitrate-induced improvement in post-ischemic cardiac recovery was totally abolished by the sGC inhibitor ODQ (Fig. C), indicating that the protective effect induced by RBCs from subjects given nitrate is NO-sGC dependent.

Conclusion
Dietary nitrate in the form of leafy vegetables induces protection against myocardial ischemia-reperfusion injury via a mechanism involving the NO-sGC signaling pathway in RBCs.
P1599Sodium channel gene therapy with dual adeno-associated viral vectors
Authors: Boink G J J , Wang J , Klerk M , Christoffels V M , Tan H L , Geerts D 
Published: October 2019

Abstract

Background
Sodium channel gene therapy carries significant potential for treatment of acquired and inherited arrhythmias. However, delivery is challenging to the length of the transgene that exceeds the packaging capacity of Adeno-Associated Virus (AAV), the most advanced long-term gene therapy vector to date. To overcome this issue, we have developed dual AAV vectors for the delivery of the skeletal muscle sodium channel 1 (SkM1).

Purpose
To achieve cardiac delivery of SkM1 and other large therapeutic genes using dual AAV vectors.

Methods
Dual AAV vectors were constructed, containing SkM1 gene fragments that allow reconstruction in the target cells by trans-splicing and recombination. An oversized single AAV vector containing SkM1 served as a control. HEK293T cells and neonatal rat ventricular cardiomyocytes (NRVMs) were transduced with dual AAV vectors or oversized single AAV vector at an MOI of 50,000 per vector. Etoposide and Teniposide were added 2h before transduction to improve the efficiency. SkM1 mRNA and protein were isolated 3 days post transduction and the expression was detected by RT-qPCR and Western blot.

Results
Robust full-length SkM1 protein expression was detected in both HEK cells and NRVMs transduced by dual AAV vectors while no expression was detected in the control. Transduction with dual AAV vectors also showed significantly higher SkM1 mRNA expression in both cell types (4 to 29-fold) comparing to oversized single AAV vector. Moreover, a relatively high level of SkM1 mRNA expression was achieved in NRVM; 22-fold higher than the native cardiac sodium channel.

Conclusion
Efficient delivery and expression of SkM1 was successfully achieved in vitro by hybrid dual AAV vectors. This approach supports the application of SkM1 and other sodium channel antiarrhythmic gene therapies. In vivo validation and functional testing are currently in on-going.
P1605Increased irregularity and spectral complexity of the intrinsic pacemaker beat-to-beat variability correlates with increased metabolic syndrome components
Authors: Calvo C J , Lozano W M , Arias-Mutis O J , Such-Miquel L , Genoves P , Chorro-Gasco F J , Alberola A , Pandit S V , Zarzoso M 
Published: October 2019

Abstract

Background
Metabolic syndrome (MetS) is becoming one of the future potential leading risk factors for heart and cardiovascular disease. MetS relates to a condition associated with at least three metabolic risk factors raising risk for health diseases concomitantly such as diabetes, stroke, hypertension, obesity and dyslipidemia. This can lead to chest pain, heart attack, heart damage and overall higher prevalence of cardiovascular disease, atrial fibrillation and sudden cardiac death. One of the underlying mechanisms of the progressive remodeling in presence of MetS components could be altered automaticity, which would reflect modifications of sinus node activity. These phenomena can be evaluated analyzing the components of heart rate variability (HRV).

Purpose
Our aim was to examine the modifications of sinus node variability in an isolated heart model of diet-induced obesity and MetS.

Methods
Male NZW rabbits were randomly assigned to high-fat (HF, n=8), control (HF-C, n=7), high-fat, high-sucrose (HFHS, n=9), and control (HFHS-C, n=9) groups, fed with their respective diets during 18/28 weeks. After euthanasia their hearts were isolated in a Langendorff system. We recorded 10–15 minutes of spontaneous activity. Short RR time series were analyzed, and standard HRV parameters were determined with special interest in the time-course of spectral, time-frequency and non-linear components. One-way ANOVA, Kruskal-Wallis test and bivariate correlations were used for statistical analysis (p<0.05).

Results
We did find an increase in the complexity and irregularity of intrinsic pacemaker activity as shown by modifications of entropy (ApEn: p=0.011 vs HF, p=0.002 vs HF-C, p=0.019 vs HFHS-C) and the complexity index (CI: p=0.006 vs HF, p=0.047 vs HF-C, p=0.027 vs HFHS-C) in HFHS animals (Figure). Higher dispersion on RR differences distributions was observed in the HFHS group. Time-frequency spectral heterogeneity increased in HFHS group (p=0.002 vs HF, p=0.050 vs HF-X, p=0.027 vs HFHS-C) even though no differences were found in standard time and frequency-domain analyses. High-band and low-band spectral concentration ratios showed decreased organization in HFHS when compared to HF (p=0.002) and controls HFHS-C (p=0.027) and HF-C (p=0.050). Interestingly, animal weight and glucose intolerance were highly correlated with the modifications of intrinsic pacemaker variability.
Modifications of intrinsic IHRV.

Conclusions
Modifications of intrinsic HRV seemed to be reliant on the number of components of MetS present, given that only HFHS group showed significant changes towards an increased complexity and irregularity of intrinsic pacemaker variability.

Acknowledgement/Funding
This work was partially supported by: GV2015-062, CB16/11/00486.
P1615HECT-Type Ubiquitin E3 Ligase ITCH attenuates cardiac hypertrophy by suppressing Wnt signaling pathway
Authors: Goto J , Otaki Y , Watanabe T , Aono T , Watanabe K , Toshima T , Kato S , Tamura H , Nishiyama S , Arimoto T , Takahashi H , Shishido T , Kubota I , Watanabe M 
Published: October 2019

Abstract

Background
The homologous to the E6-AP carboxyl terminus (HECT)–type ubiquitin E3 ligase ITCH is an enzyme that plays an important role in ubiquitin proteasomal protein degradation. Dishevelled proteins (Dvl1, Dvl2 and Dvl3), which are involved in canonical Wnt/β catenin signaling pathway, play a role in cardiac hypertrophy.

Purpose
The aim of this study was to examine whether ITCH interacts with Dvls and prevents cardiac hypertrophy induced by pressure overload.

Methods and results
We confirmed the protein interaction between ITCH and Dvls in cardiomyocytes. Overexpression of ITCH decreased protein expression levels of Dvls, phospho-GSK3β and β-catenin. Conversely, knockdown of ITCH using small interfering RNA augmented canonical Wnt/β catenin signaling pathway. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of ITCH (ITCH-Tg) and wild-type (WT) mice. The canonical Wnt/β catenin signaling pathway was inhibited and cardiac hypertrophy was attenuated in ITCH-Tg mice compared with WT mice after TAC.
Overexpression of ITCH in cardiomyocytes

Conclusion
We demonstrated that ITCH targets Dvls for ubiquitin-proteasome degradation in cardiomyocytes and ameliorates cardiac hypertrophy by suppressing canonical Wnt/β catenin signaling pathway.
P1624Blockade of protease activated receptor-1 signaling attenuates cardiac hypertrophy and fibrosis in renin-overexpressing hypertensive mice
Authors: Yokono Y , Narita M , Kawamura Y , Kato T , Kudo N , Tsushima M , Toyama Y , Hanada K , Shimada M , Makoto T , Osanai T , Tomita H 
Published: October 2019

Abstract

Introduction
Recent evidences have demonstrated that coagulation pathway is involved in cardiovascular remodeling induced by renin-angiotensin system (RAS), which finally leads to heart failure. Protease activated receptor-1 (PAR-1) is widely expressed in the vasculature and the heart, and plays important roles in pro-inflammatory process in the cardiovascular system. Recently, we demonstrated that the activity of factor Xa (FXa), which functions not only as a coagulation factor but as an agonist for PAR-1, was enhanced in renin-overexpressing hypertensive mice (Ren-Tg).

Purpose
The purpose of this study was to investigate whether inhibition of PAR-1 signaling has protective effects on the progression of heart failure induced by chronic RAS activation in Ren-Tg.

Methods and results
We treated 12–16 weeks-old male wild type mice (WT) and Ren-Tg with continuous subcutaneous infusion of PAR-1 antagonist SCH79797 (25mg/kg/day) or vehicle for 4 weeks. After treatment period, left ventricular (LV) wall thickness calculated as interventricular septum plus posterior wall thickness measured by echocardiography was greater in Ren-Tg than in WT (0.25±0.003 versus 0.18±0.002 mm), and SCH79797 attenuated the increase to 0.22±0.01 mm in Ren-Tg (both p<0.05, respectively). The ratio of heart weight to body weight was greater in Ren-Tg than in WT (6.1±0.4 versus 4.6±0.7 mg/g), and SCH79797 attenuated the increase to 5.2±0.1 mg/g (both p<0.05). The area of cardiac fibrosis evaluated by Masson-trichrome staining was greater in Ren-Tg than in WT (2.6±0.2 versus 1.4±0.3%), and SCH79797 attenuated it to 1.6±0.3% in Ren-Tg (both p<0.05). Cardiac mRNA expressions of tumor necrosis factor-α, transforming growth factor-β1, and β-myosin heavy chain were all greater in Ren-Tg than in WT, and SCH79797 attenuated the increases in Ren-Tg (all p<0.05).

Conclusions
Inhibition of PAR-1 signaling attenuates cardiac hypertrophy and fibrosis in Ren-Tg via inhibition of inflammatory cytokines production. These results support the involvement of PAR signaling in the development of heart failure induced by RAS, and may provide novel therapeutic insights for the treatment of hypertensive heart failure.