bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1588Beta-blocker therapy and risk of dementia: a population-based prospective study
Authors: Holm H , Ricci F , Di Martino G , Bachus E , Nilsson E D , Ballerini P , Melander O , Hansson O , Nagga K , Magnusson M , Fedorowski A 
Published: October 2019

Abstract

Introduction
Cerebral side effects have long been recognized as complications to beta-blocker treatment. However, evidence of a longitudinal relationship between the use of beta-blockers and incident dementiais still controversial.

Objective
To evaluate the longitudinal relationship between use of beta-blockers, as a class, and incident risk of all-cause dementia, vascular dementia, Alzheimer and mixed dementia.

Methods
From the prospective, population-based, Malmö Preventive Project, 18,063 individuals (mean age 68.2, males 63.4%) were included at baseline and followed for 84,506 person-years. Patients with prevalent cerebrovascular disease and dementia were excluded. In order to weight the risk of incident dementia associated with beta-blocker consumption, we performed propensity score matching analysis, resulting in 3,720 matched pairs of beta-blocker users and non-users at baseline, and multivariable Cox proportional-hazardsregression.

Results
Overall, 122 study participants (1.6%) were diagnosed with dementia over the course of follow-up. Use of beta-blockers was independently associated with increased risk of developing vascular dementia, regardless of confounding factors (HR: 1.72, 95% CI 1.01–3.78; p=0.048). Conversely, treatment with BB was not associated with increased risk of all-cause, Alzheimer and mixed dementia (HR: 1.15; 95% CI 0.80–1.66; p=0.44; HR: 0.85; 95% CI 0.48–1.54; P=0.59 and HR: 1.35; 95% CI 0.56–3.27; p=0.50, respectively).

Conclusions and relevance
We observed that use of beta-blockers, as a class, is associated with increased longitudinal risk of vascular dementia in the general elderly population, regardless of cardiovascular risk factors, prevalent or incident history of atrial fibrillation, stroke, coronary events and heart failure. Further studies are needed to confirm our findings in the general population and to explore the mechanisms underlying the relationship between use of beta-blockers and increased risk of vascular dementia.
P1601N-glycosylation of TREK-1/hK2P2.1 two-pore-domain (K2P) potassium channels
Authors: Wiedmann F , Schlund D , Ratte A , Katus H A , Kraft M , Thomas D , Schmidt C 
Published: October 2019

Abstract

Background and purpose
Mechanosensitive hTREK-1 (hK2P2.1) two-pore-domain potassium channels give rise to background currents that control resting membrane potential in excitable tissue. Recently TREK-1 currents have been linked to regulation of cardiac rhythm as well as hypertrophy and fibrosis. Even though pharmacological and biophysical characteristics of hTREK-1 channels have been widely studied, less is known about its posttranslational modifications. This study aims to evaluate whether hTREK-1 channels are N-glycosylated and whether glycosylation may affect channel functionality.

Experimental approach
Following pharmacological inhibition of N glycosylation, enzymatic digestion or mutagenesis, immunoblots of Xenopus laevis oocytes and HEK-233T cell lysates were used to assess electrophoretic mobility. Two-electrode voltage clamp measurements were employed to study channel function.

Key results
TREK-1 channels subunits undergo N-glycosylation at asparagine residues 110 and 134. The presence of sugar moieties at these two sites increases channel function. Detection of glycosylation-deficient mutant channels in surface fractions and recordings of macroscopic potassium currents mediated by these subunits demonstrate that non-glycosylated hTREK-1 channels subunits are able to reach the cell surface in general, but seemingly with reduced efficiency.

Conclusion and implications
hTREK-1 are glycoproteins and N glycosylation at positions 110 and 134 is involved in channel surface trafficking. These findings extend our view on regulation of hTREK-1 currents by posttranslational modifications and provide novel insights into how glycosylation deficiency disorders may promote arrhythmogenesis.
P1623Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates doxorubicin-induced cardiotoxicity in mice
Authors: Obata Y , Ishimori N , Saito A , Kinugawa S , Nakano I , Kakutani N , Yamanashi K , Anzai T 
Published: October 2019

Abstract

Objective
Doxorubicin (DOX) is an effective antineoplastic agent commonly used to treat many types of cancer but its clinical use is limited because of cardiotoxicity, which might proceed to irreversible cardiac dysfunction in a dose-dependent manner. The precise mechanism of DOX-induced cardiotoxicity is still not fully elucidated but it has been reported that cardiac inflammation is involved in the cardiotoxicity. Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens and secrete a large amount of Th1 and Th2 cytokines on activation, have been shown to play crucial roles in the regulation of immune responses. However, it remains unclear whether iNKT cells are involved in DOX-induced cardiotoxicity.

Methods and results
Male C57BL/6J mice were administered DOX (20mg/kg body weight single intraperitoneal injection; n=28) or vehicle (Vehicle; n=6). DOX-administered mice were further divided into 2 groups; α-galactosylceramide (αGC, 0.1μg/g body weight twice intraperitoneal injection; DOX-αGC; n=14), which specifically activates iNKT cells, or phosphate-buffered saline alone (PBS; DOX-PBS; n=14) 4 days before and 3 days after DOX administration. Survival rate at 14 days after DOX/Vehicle administration was significantly lower in DOX-PBS than in Vehicle (71% vs. 100%, P<0.05), and this decrease was completely attenuated in DOX-αGC (100%, P<0.05 vs. DOX-PBS). Echocardiography at 14 days after DOX/Vehicle administration revealed that left ventricular (LV) fractional shortening was significantly reduced in DOX-PBS compared to Vehicle (49.3±0.8% vs. 59.2±1.7%, P<0.05), and this decrease was completely attenuated in DOX-αGC (57.7±1.3%, P<0.05 vs. DOX-PBS) without affecting LV end-diastolic diameter. Picro-sirius red staining revealed that the ratio of fibrosis area to the cardiac tissue was markedly higher in DOX-PBS than in Vehicle (4.3±0.5% vs. 2.2±0.1%, P<0.05), and this increase was completely attenuated in DOX-αGC (2.8±0.1%, P<0.05 vs. DOX-PBS). Real-time PCR analysis revealed that mRNA expression of anti-inflammatory Th2 cytokine IL-4 was enhanced by 7.9-folds in DOX-αGC compared to DOX-PBS, though the difference did not reach statistically significance (P=0.09).

Conclusions
Activation of iNKT cells by αGC ameliorates DOX-induced cardiotoxicity in mice via up-regulation of anti-inflammatory IL-4 and reducing cardiac fibrosis. iNKT cell activation may be a novel therapeutic strategy against DOX-induced cardiotoxicity.

Acknowledgement/Funding
Japan Agency for Medical Research and Development (18lm0203001j0002) and JSPS KAKENHI (18K15834)
P1626MicroRNA-21 deteriorates left ventricular reverse remodeling by promoting cardiac fibrosis in non-ischemic cardiomyopathy
Authors: Watanabe K , Narumi T , Watanabe T , Aono T , Goto J , Sugai T , Toshima T , Kato S , Tamura H , Nishiyama S , Takahashi H , Arimoto T , Shishido T , Watanabe M 
Published: October 2019

Abstract

Background
Left ventricular reverse remodeling (LVRR) contributes to better outcomes in patients with non-ischemic cardiomyopathy (NICM). It is reported that LVRR is associated with progression of cardiac fibrosis. MicroRNAs (miRs) have emerged as powerful regulators of post-transcriptional gene expression. We focused on miR-21, which plays a key role in pathogenesis of fibrosis in multiple organs. The aim of this study was to clarify the effect of miR-21 on cardiac fibrosis and LVRR in patients with NICM.

Methods
We measured plasma miR-21 levels in 16 patients with NICM. LVRR was defined as increased LVEF by ≥10% and decreased LV end-diastolic diameter index by ≥10% from baseline data after optimal medication treatment at 1-year of follow-up. Further, we examined miR-21 expression and its potential role in cardiac fibrosis induced by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes (NRCMs).

Results
There were 12 patients without LVRR and 4 patients with LVRR. Plasma miR-21 levels were significantly higher in patients without LVRR compared with those with LVRR. In TAC mice heart, miR-21 levels were significantly increased and programmed cell death 4 (PDCD4), a main target of miR-21, was decreased. In vitro, miR-21 levels were significantly increased and its upstream transcriptional factor, activator protein 1 (AP-1), was activated by Ang II stimulation in NRCMs. After transfection of miR-21 specific inhibitor, PDCD4 levels were upregulated. Furthermore, AP-1 activity, expression of collagen type I, and α-smooth muscle actin levels were significantly decreased after miR-21 inhibition.

Conclusions
These findings suggested that miR-21/PDCD4/AP-1 feedback loop pathway was involved in LVRR in patients with NICM by promoting cardiac fibrosis. MiR-21 can be the therapeutic target in NICM.
P1631Machine-learning defined predictors of mortality in ischemic and non-ischemic heart failure patients undergoing CRT-P or CRT-D implantation
Authors: Kosztin A , Schwertner W R , Tokodi M , Toser Z S , Kovacs A , Veres B , Zima E , Geller L , Merkely B 
Published: October 2019

Abstract

Background
Both Cardiac Resynchronization Therapy Pacemakers (CRT-P) and CRT Defibrillators (CRT-D) improve mortality in heart failure patients with reduced ejection fraction and wide QRS complex. However, not every patient benefits equally from each type of treatment and determinants of mortality may vary across the subgroups of patients with different etiologies and devices.

Purpose
Our aim was to investigate the differences in the predictors of long-term mortality in heart failure patients with different etiologies undergoing CRT-P or CRT-D implantation using machine learning.

Methods
We created 4 separate random forest models to predict 5-year all-cause mortality (models for ischemic and non-ischemic etiology in both CRT-P and CRT-D subgroups). A registry of 1650 patients (66±10 years, 1258 [76%] males, 751 [46%] CRT-D) was used as the training cohort for the prediction models. Forty-seven pre-implant parameters including cardiovascular risk factors and clinical variables were utilized to train our models. For each clinical parameter, we calculated the mean decrease in Gini impurity (dG). Based on the extent of decline, the 10 most important features were selected for each model. To keep the data comparable between the different models, we took the union of these features and plotted the results on radar charts.

Results
There were 879 (53%) deaths during the follow-up period. The mortality benefit of adding an Implantable Cardioverter Defibrillator could be observed only in ischemic patients (Hazard Ratio = 0.83, 95% Confidence Interval: 0.72–0.97, p<0.005), but not in the entire cohort or in patients with non-ischemic etiology. In patients with non-ischemic etiology, the pattern of mortality predictors were almost similar: in CRT-P patients the most important predictors were age, serum urea levels and left ventricular ejection fraction (LVEF) (dG: 0.114, 0.054 and 0.053, respectively) whereas in the CRT-D subgroup these factors were age, LVEF and serum sodium (dG: 0.116, 0.060 and 0.052, respectively). In CRT-P patients with non-ischemic etiology, the most relevant variables were age serum urea and LVEF in decreasing order (dG: 0.085, 0.060 and 0.050, respectively). The strongest predictors of mortality were age, hemoglobin and serum creatinine in ischemic patients with CRT-D (dG: 0.088, 0.060 and 0.052, respectively).
CRT-P vs. CRT-D by ischemic etiology

Conclusions
In patients with ischemic heart failure, CRT-D was associated with a mortality benefit compared to CRT-P. Our results also suggest that machine-learning may identify distinct patterns in clinical characteristics for a better mortality prediction. Taking these factors into consideration during the management of heart failure patients with CRT, risk stratification and outcomes could be improved.
P1642High-sensitivity cardiac troponin I and NT-proBNP and their relationship to heart failure in the European BiomarCaRE population
Authors: Yan I , Boerschel C , Neumann J , Spruenker N , Kontto J , Kuulasmaa K , Salomaa V , Iacoviello L , Di Castelnuovo A , Costanzo S , Linneberg A , Soederberg S , Zeller T , Blankenberg S , Westermann D 
Published: October 2019

Abstract

Aims
Heart failure (HF) is an increasingly important contributor to the overall burden of cardiovascular disease in the population. We aimed to determine the distribution of the cardiac biomarkers high-sensitivity cardiac troponin I (hs-cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations across the European population to characterize the association with incident HF.

Methods and results
Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 48,455 individuals from four prospective population-based cohort studies (DanMONICA, FINRISK, Moli-Sani, Northern Sweden MONICA study) across Europe with a maximum follow-up of 27 years. The median age of the participants was 50.7 years (25th percentile: 40.0 years, 75th percentile: 61.7 years) and 49.1% (25,146) were men. Considered endpoints were incident HF and all-cause mortality. The median follow-up time for occurrence of HF was 6.61 (6.55; 6.66) years. We found that cardiovascular risk factors (CVRFs), especially diabetes with HR of 2.11 (95% CI 1.8, 2.5) and smoking status with HR of 1.79 (95% CI 1.59, 2.1) (Figure 1) were associated with incident HF. Furthermore, beyond the CVRFs, elevated hs-cTnI and NT-proBNP concentrations contributed to risk of HF in the general population with HR of 1.49 (95% CI 1.21, 1.9) and HR of 2.37 (95% CI 1.97, 3.0) respectively. As a cut-off value to select individuals, who would benefit most from preventive strategies, a hs-cTnI concentration of 2.8 ng/L was calculated using the optimal cut-off methodology by Contal and O'Quigley in CSDA 1999.
Hazard ratio for incident HF

Conclusion
In our large population-based cohort, hs-cTnI and NT-proBNP were independently associated with incident HF. Use of biomarkers for HF screening thus may help to select those individuals in the general population who would benefit most from preventive strategies. Based on the cut-off value future studies are needed to evaluate therapeutic options.
P1643An exploratory analysis for the optimal monitoring interval of N-terminal pro-B-type natriuretic peptide in patients with stable heart failure
Authors: Dai Z , Asano T , Ohde S , Komiyama N 
Published: October 2019

Abstract

Background
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a potential biomarker for monitoring the status of heart failure. However, the optimal monitoring interval is unknown. This study aims to investigate minimal informative monitoring interval of NT-proBNP in patients with stable chronic heart failure.

Methods
In this retrospective open cohort study, adult patients followed up at a tertiary hospital for chronic heart failure with NT-proBNP measurements were included if they had been previously admitted due to acute heart failure and were free from readmission over 6 months after discharge. We analyzed NT-proBNP measured between 6 months after discharge and the timepoint of an alteration of medication regimen or readmission due to worsening of heart failure. To distinguish actual progression of the disease from biological variability and measurement error, the signal-to-noise ratio method was applied with a random-effects model. Stratified analysis was performed according to underlying risks.

Results
In this analysis, 368 patients were included with NT-proBNP measured between July 2009 and December 2017. The patients had 6.0 times of NT-proBNP measurements in median (interquartile range [IQR] 4.0–10.0) during the follow-up period (median 12.0 months [IQR 6.0–27.0]). In the estimates of the random-effects model, signal (i.e. actual progression of the disease) exceeded noise (i.e. biological variability and measurement error) at 8.1 months (95% confidence interval [CI]: 5.7–10.1) after the index measurement. In a subgroup analysis according to the AHEAD risk score, the minimal informative monitoring interval was shortened as the risk score increased (0–1 point: 12.3 months [95% CI: 10.3–14.5]; 2–3 points: 8.0 months [95% CI: 6.8–9.7]; 4–5 points: 3.3 months [95% CI: 3.0–3.8]; Figure).
Informative intervals stratified by risk

Conclusion
In patients with stable chronic heart failure, the overall minimal informative monitoring interval of NT-proBNP measurement was 8.1 months, which varies by underlying risk. The optimal monitoring interval could be lengthened especially for patients at lower risk.
P1651Pulmonary artery pressure could predict closed aortic valve in patients managed by veno-arterial extracorporeal membrane oxygenation
Authors: Yamaguchi S , Sawamura A , Arao Y , Ooishi H , Kato H , Kuwayama T , Haga T , Hiraiwa H , Yokoi T , Kondo T , Morimoto R , Okumura T , Murohara T 
Published: October 2019

Abstract

Background
Although veno-arterial extracorporeal oxygenation (VA-ECMO) is widely used as mechanical circulatory support, it reduces native left ventricular (LV) stroke volume through the cardiac preload decrease and afterload increase. Therefore some patients with severe cardiac dysfunction present persistently closed aortic valve (AV). The closed AV is considered to increase the risk of pulmonary edema or intracardiac thrombosis. However, little is known about the variables that contribute to persistently closed AV under the management of VA-ECMO.

Purpose
We investigated the factors that could predict persistently closed AV at the time of VA-ECMO initiation.

Methods
This was a retrospective chart review. We investigated the patients who received the management of VA-ECMO due to cardiogenic shock from April 2011 to December 2018, and analyzed 18 patients (43±16 years, 50% female) who presented closed AV immediately after the introduction of VA-ECMO. We obtained the hemodynamic data at the time of VA-ECMO initiation (baseline) and 24h after. The patients who presented persistently closed AV during 24h were defined as Close-group (n=8). The patients whose AV was opened within 24h were defined as Open-group (n=10). The status of AV was investigated by the echocardiogram.

Results
All patients were managed by concomitant use of intra-aortic balloon pumping. The etiologies were myocarditis (56%), cardiomyopathy (33%), and acute myocardial infarction (11%). Nine patients experienced in-hospital death (6 were Close-group and 3 were Open-group, p=0.15). At baseline, there were no significant differences between mean arterial blood pressure (mABP) (p=0.07), central venous pressure (CVP) (p=0.71), and left ventricular ejection fraction (p=0.44). However, Close-group had significantly lower mean pulmonary artery pressure (MPAP) and pulmonary artery pulse pressure (PAPP) than Open-group (Close-group versus Open-group; MPAP, 15±6 mmHg versus 27±11 mmHg, p=0.01; PAPP, 3±2 mmHg versus 8±3 mmHg, p=0.01). Logistic regression analyses revealed the lower MPAP and PAPP had the predictive value of closed AV within 24-h after VA-ECMO initiation [MPAP: odds ratio (OR) 0.78, 95% confidence interval (95% CI) 0.62–0.99, P=0.003; PAPP: OR 0.18, 95% CI 0.02–1.13, P<0.001]. In the following 24h, no significant change was found in MPAP and PAPP.

Conclusion
At the time of VA-ECMO initiation, lower MPAP and PAPP had the predictive value for persistently closed AV. LV preload derived from right heart function would have major impact on AV status.
P1704The impact of electrocardiographic changes upon resuscitation from out-of-hospital cardiac arrest on mortality
Authors: Iiya M , Kimura S , Shimizu M , Fujii H , Suzuki M 
Published: October 2019

Abstract

Background
The serial electrocardiographic changes in patients following out-of-hospital cardiac arrest (OHCA) are unclear.

Purpose
To evaluate serial electrocardiographic changes and to predict all-cause mortality in patients following OHCA.

Methods
We retrospectively studied 101 OHCA patients (70±16 years, 49 male) who achieved a return of spontaneous circulation (ROSC) and survived for ≥3hours. Twelve-lead electrocardiograms (ECGs) were evaluated twice in each patient: initial-ECG, after achieving ROSC; and 2nd-ECG, after receiving the initial evaluation in the emergency room. Patients were divided into two groups: S-group, those surviving for 28 days, and D-group, those dying within 28 days. Multivariate Cox regression analyses were performed to predict the 28-day survival following OHCA. A Kaplan-Meier curve analysis for the 28 day mortality stratified by the QRS morphology and rhythm of initial-ECG was performed.

Results
Among variables of initial-ECG, there were significant differences between the group-S and group-D (table). Multivariate analysis with a step-wise regression demonstrated that age, lactate, and QRS duration of the initial-ECG were significant predictors of all-cause mortality (Odds ratio (OR): 1.04, 1.21, 1.02, p: 0.002, 0.001, 0.001, respectively). Kaplan-Meier analysis revealed that a complete right bundle branch block (CRBBB) of initial-ECG and presence of atrial fibrillation were associated with an increased risk of all-cause mortality (Picture).
Serial change of ECG variables Initial-ECG 2nd-ECG Group S Group D p Group S Group D p Heart Rate [/min] 109±23 105±31 0.527 88±21 94±23 0.341 Af [N,%] 10 (25%) 27 (52%) 0.018* 3 (9%) 6 (26%) 0.134 QRS duration [ms] 111±18 139±33 0.001* 107±29 111±30 0.623 Morphology 0.001* 0.284 – Normal [N,%] 30 (75%) 10 (19%) 29 (81%) 14 (61%) – CRBBB [N,%] 5 (13%) 30 (57%) 5 (14%) 5 (22%) – CLBBB [N,%] 1 (2%) 0 0 1 (4%) – IVCD [N,%] 4 (10%) 13 (24%) 2 (6%) 3 (13%) Comparing variables between group S and group D stratified by initial ECG and delayed ECG. QRS morphology were examined, normal, complete right bundle branch block (CRBBB), complete left bundle branch block (CLBBB), and unspecific interventricular conduction delay (IVCD).
Study flow diagram, KM curve analysis

Conclusions
The QRS duration and morphology upon resuscitation were associated with an increased risk of all-cause mortality following OHCA.