bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is “one size fits all” anti-aggregation really effective? Variability in the response to P2Y12 receptor inhibitors in obese patients
Authors: Playan Escribano J , Vivas Balcones D , Lugo Gavidia L.M , Gomez Polo J.C , Marcano Fernandez A.L , Bernardo E , Ortega M.A , De La Hera Galarza J.M , Tello-Montoliu A , Besteiro Vazquez A , Silva I , Marin F , Roldan I , Gomez-Hospital J.A , Ferreiro J.L 
Published: November 2020

Abstract

Background
Different “ex vivo” studies have shown both a greater platelet activation and higher rates of resistance to clopidogrel in obese patients. Although there is less evidence, less prasugrel activity has also been observed in these patients. Our aim was to study the variability of the response to clopidogrel, ticagrelor and prasugrel in obese patients, defined as a body mass index ≥30.

Methods
Prospective, multicenter, observational, pharmacodynamic study, conducted in a Spanish population of patients with an acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI) and double anti-aggregation with acetylsalicylic acid and a P2Y12 receptor inhibitor. Platelet function tests were performed the morning after the ICP and 30 days after it, including: 1) VerifyNow P2Y12 assay; 2) multiple electrode aggreometry (Multiplate); and 3) VASP analysis.

Results
Of the total patients included (988), 300 were obese (30.3%). The obese group was younger (62.8±12 years vs 64.9±12), had a higher incidence of arterial hypertension (76.3% vs. 56.7%), diabetes mellitus (35% vs. 27.5%); and lower incidence of chronic kidney disease (7.7% vs. 17%). There were no differences in the acute phase (day 1 after PCI) in the pharmacodynamic response to any of the P2Y12 inhibitors used. After 30 days, greater platelet aggregation (decreased response) was documented in obese patients treated with prasugrel according to VASP tests (PRI in non-obese 23.9±13% vs. 30.4±14.7% in obese, p 0.035) and MEA (area under the aggregation units curve in non-obese 251.7±104.1 vs 320±166.7 in obese, p 0.007) and a numerical trend with VerifyNow. A trend in the same direction was also observed in patients treated with clopidogrel that did not reach statistical significance with all the platelet function tests used. No differences were observed in the ticagrelor group.

Conclusion
Obese patients with an ACS treated with PCI have a worse response to thienopyridines than non-obese patients in the maintenance phase of antiaggregant treatment, while the response to ticagrelor is not affected by obesity. Completing the clinical follow-up proposed by the registry is necessary to know if these differences have an implication in cardiovascular events.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciones Sanitarias (FIS)
Prospective external validation of PRECISE-DAPT score for prediction of bleeding and thrombosis after coronary stent implantation
Authors: Jaspattananon A , Wongpraparut N , Naowapanich S , Satsue S , Seesung S 
Published: November 2020

Abstract

Background
Optimal duration of dual antiplatelet therapy (DAPT) after coronary stent implantation depends on bleeding and thrombotic risk in an individual patient. The PRECISE-DAPT score is recommended for adjusting of optimal DAPT duration.

Purpose
To assess external validation of PRECISE-DAPT score for prediction of out-of-hospital bleeding and thrombosis after coronary stent implantation in prospective manner.

Methods
We prospectively enrolled patients who underwent coronary stent implantation and received DAPT in our institution during June 2018 through December 2019. Out-of-hospital bleeding and thrombotic events were assessed for validation of PRECISE-DAPT score.

Results
Six hundred and two patients were enrolled. The mean age was 65.0±11.7 years and 28.2% were female. STEMI, NSTEMI/UA and chronic coronary syndrome were 24.4%, 22.6%, 53% respectively. Prevalence of prior bleeding was 6.3%. Mean follow-up period was 312±72 days. Bleeding events were 5.1%. High PRECISE-DAPT score (score ≥25) had significantly higher bleeding events (9.4% vs 2.4%, P-value &lt;0.001), which were divided into major TIMI bleeding (3.4% vs 0.3%, P-valve 0.003) and minor TIMI bleeding (6.0% vs 2.2%, P-valve 0.014). MACE (CV death, MI, stroke) were 7% and significantly higher in high PRECISE-DAPT score (10.7% vs 4.6%, P-valve 0.004), compared with low PRECISE-DAPT score.

Conclusions
In real-world prospective study, high PRECISE DAPT score (score ≥25) is associated with high bleeding and thrombotic events. Because of increased both events in high PRECEISE-DAPT score, shortening DAPT duration requires physician final decision-making to balance future bleeding and thrombosis.

Funding Acknowledgement
Type of funding source: Public hospital(s). Main funding source(s): Siriraj grants for medical research and education, Faculty of Medicine Siriraj Hospital, Mahidol University
A web-based tool for the early identification and real time assessment of drug-induced proarrhythmic and torsade de pointes safety risk
Authors: Baretta A , Bisotti M.A , Palazzin A , Cano J , Gomis-Tena J , Romero L , Saiz J , Bursi R 
Published: November 2020

Abstract

Introduction
It is well recognized that early identification of drug-induced proarrhythmic safety risks is crucial to drug development for ethical, animal sparing and costs reduction considerations. The availability, however, of easily accessible, user-friendly tools for real time assessments of the proarrhythmic potential of chemical compounds has been lacking. The novel Tx index, implemented in the presented web-based tool, was applied to a dataset of 84 compounds.

Materials and methods
The tool is based on 206,766 cellular simulations of compound-induced effects on Action Potential Duration (APD) in isolated endocardial, midmyocardial, and epicardial cells and on 7,072 tissue simulations on QT prolongation in a virtual tissue. Simulations were performed by blocking the slow and the fast components of the delayed rectifier current (IKs and IKr, respectively) and the L-type calcium current (ICaL) at different levels. Based on these simulations, four Tx indices were defined as the ratio of drug concentration leading to a 10% prolongation of the APDendo, APDmid, APDepi or QT over the maximum Effective Free Therapeutic Plasma Concentration (EFTPC), respectively. A dataset of 44 non-torsadogenic and 40 torsadogenic drug compounds was used to validate the performance of the tool. The workflow of the web-based tool was built on the cloud environment, in compliance with the highest standards of security and privacy.
hERG test (positive response: hERG pIC50 &gt;6) was applied to the 84 compounds to compare performances.

Results
Receiver operating characteristic (ROC) curves were constructed on the four estimated Tx indices for each compound in the dataset to enable the identification of torsadogenic potential cut-off values2. These were identified as 8, 8, and 6.4 for Tx-APDendo, Tx-APDmid, Tx-APDepi and as 9.2 for Tx-QT, respectively.
The classification of the 84 compounds resulted in an accuracy ranging between 87% and 88% for the four Tx indices Tx-APDendo, Tx-APDmid, Tx-APDepi and Tx-QT.

Discussion and conclusion
hERG block exhibits poor performance. When applying the hERG test to the 84 compounds, it exhibited a TPR of 55%, a TNR of 89%, and an A of 73%, in close agreement with previous studies. In comparison, the in silico Tx tests described in this study yield TPRs of 85%, TNRs of 86–89% and As of 86–87%.
This method does not include drug effects on Na+ channels, which is related to the misclassification of 3 compounds (quetiapine, ranolazine, and lamotrigine – significant Na+ channels blockers at EFTPC). Future work will include this channel.
The presented web-based tool is a highly innovative method for an accurate torsadogenic risk assessment. Each assessment required only a few seconds of computational time.
Illustration workflow of the web tool

Funding Acknowledgement
Type of funding source: None
Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity in mice
Authors: Tanaka Y , Nagoshi T , Yoshii A , Oi Y , Takahashi H , Kimura H , Kashiwagi Y , Tanaka T.D , Yoshimura M 
Published: November 2020

Abstract

Background
Accumulating evidence suggests that high serum uric acid (UA) is associated with left ventricular (LV) dysfunction. Although xanthine oxidase (XO) activation is a critical regulatory mechanism of the terminal step in ATP and purine degradation, the pathophysiological role of cardiac tissue XO in LV dysfunction remains unclear.

Objectives
We hypothesized that cardiac XO is activated in doxorubicin-induced LV dysfunction, and XO inhibitors ameliorate LV function by inhibiting cell death signals as well as by modifying cardiac purine metabolism.

Methods
Either doxorubicin (10 mg/kg) or vehicle was intraperitonially administered in a single injection to ICR mice. Mice were treated with or without oral XO inhibitors (febuxostat 3 mg/kg/day or topiroxostat 5 mg/kg/day) for 8 days starting 24 hours before doxorubicin-injection. The LV function was assessed by echocardiography at day 6 and by ex vivo heart perfusion at day 7.

Results
Cardiac tissue XO activity measured by a highly sensitive assay with liquid chromatography/mass spectrometry (n=8 each) and cardiac UA content (n=3–6) were significantly increased in doxorubicin-treated mice at day 7 and dramatically reduced by XO inhibitors. Accordingly, XO inhibitors substantially improved LV ejection fraction (n=8 each) and LV developed pressure (n=9 each) that had been impaired by doxorubicin administration. Intriguingly, the expression of GPX4, a negative regulator of ferroptosis, was decreased in doxorubicin-treated hearts but improved by XO inhibitors (n=6 each). Furthermore, metabolome analyses revealed an enhanced purine metabolism in doxorubicin-treated hearts, and XO inhibitors suppressed the serial metabolic reaction of hypoxanthine–xanthine–UA.

Conclusions
Doxorubicin administration induces cardiac tissue XO activation associated with an impaired LV function. XO inhibition attenuates the doxorubicin-induced cardiotoxicity partly through an anti-ferroptotic effect and the conservation of tissue ATP levels by modulating purine metabolism. The present study suggests that pharmacological XO inhibition represents a potential therapeutic strategy for the treatment of doxorubicin-induced cardiotoxicity.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported in part by grants-in-aid for Ministry of Education Culture, Sports, Science and Technology.
Electrocardiographic evaluation of depolarization and repolarization abnormalities in breast cancer patients with HER2-inhibitor related cardiac dysfunction
Authors: Kinoshita T , Yuzawa H , Wada R , Yano K , Yao S , Akitsu K , Koike H , Shinohara M , Abe A , Fujino T , Ogata H , Ikeda T 
Published: November 2020

Abstract

Background
The arrhythmic substrates of the myocardium such as depolarization and repolarization abnormalities are thought to reflect cardiac dysfunction prior to the morphologic left ventricular dysfunction. Activation time (AT), recovery time (RT) and T wave peek-end interval dispersion (Tpe-dispersion) are useful indicators of the arrhythmic substrate. We examined the appearance of depolarization and repolarization abnormalities in patients with cancer therapeutics-related cardiac dysfunction (CTRCD) using AT, RT and Tpe-dispersion.

Methods
We conducted a standardized case-control study of CTRCD with 40 patients who developed breast cancer and treated with trastuzumab (13 cases and 27 controls). We assessed the relation between electrocardiographic indexes, including AT, RT and corrected Tpe-dispersion, and CTRCD. QT intervals were measured by Fridericia method, and QT observer 3 software were used for the measurement of all electrocardiographic indexes.

Results
LVEF in case and control group were 45.7±8% and 69.2±6%, respectively. AT in aVR lead was significantly higher in case group compared with control (28.8±7ms vs 22.8±5ms, P=0.02). corrected Tpe-dispersion tended to be higher in case group than that of control group (43.2±19ms vs 31.9±10ms, P=0.06). QT dispersion and RT dispersion were not different between case and control group.

Conclusions
Our study demonstrated that AT in aVR may predict cardiac dysfunction in breast cancer patients with HER2-inhibitor related cardiac dysfunction. More detailed studies using other modalities which can detect depolarization and repolarization abnormalities, including ventricular late potentials and T wave alternans, are needed.

Funding Acknowledgement
Type of funding source: None
Prevalence of drug to drug interactions in critical cardiac patients
Authors: Mohamed Ariff A.M , Abd Hadi H , Win N.T , Thoulath M.I , Aktifanus A.T.J , Mutaya S.M , Nalliah S , Mohamed Yusof A.K 
Published: November 2020

Abstract

Background
Pharmacotherapy in the management of cardiovascular disease patients with multiple co-morbidities has been challenging due to polypharmacy (five or more drugs). They have been attributed with potential drug – drug interactions (DDI). Detecting the clinically significant drug interactions allows the opportunity for prevention through clinical drug decision support system (CDDSS) and clinical management.

Purpose
To identify significant potential DDI in critical cardiac patients

Method
We prospectively observed patients admitted at CCCU received multiple medications leading to potential DDI from Feb 2018 to July 2018 using two commercially available CDDSS along clinical management and pharmacovigilance algorithm.

Results
Patients admitted at CCCU co-administered with two or more drugs were analyzed. The mean age was 61.1 years. Total 649 patients were screened, resulting 87.7% (569/649) patients took more than five drugs. Of the 4249 potential DDI 543 were unique interacting drug pairs. On average, CCU patients were prescribed with 12.1 drugs, potentiating 14.1 potential DDI. Older patients (&gt;60 years) received more medications than younger ones (mean 18.7 vs 15.1 drugs). 82.1% patients had one or more potential DDI with major and moderate severity detected by one or both CDDSS. Common potential clinical adverse was bleeding, QTc prolongation and CYP3A4 inhibition. Both CDDSS agreed on the severity ratings in 36.9%. There were significant association of potential DDI with specific risk factors (geriatric, female, Indian and heart failure patients)

Conclusions
Rate of potential DDI adversely influenced by polypharmacy, antiarrhythmic drugs, comorbidities and LOS. Significant potential DDI occur in the CCU, highlighting the need for CDDSS potentially prevent patient harm. Identified risk factors (geriatrics population, female sex, Indian ethnicity and heart failure patients) can be used in mitigating adverse DDI.

Funding Acknowledgement
Type of funding source: Private hospital(s). Main funding source(s): NATIONAL HEART INSTITUTE
Daily intra-individual variability of positive but not negative affect impacts moderate to vigorous physical activity
Authors: Wierenga K , Moore S.E , Fresco D.M 
Published: November 2020

Abstract

Introduction
The World Health Organization recommends moderate to vigorous physical activity (MVPA) for 150 minutes per week to reduce the risk of primary or secondary cardiovascular diseases (CVD). Adherence to these recommendations is only around 30% in the US. Identifying reliable barriers or facilitators of time spent in MVPA is a critical component to primary and secondary CVD prevention. Negative affect, including feelings such as being sad, nervous, and restless, is known to diminish time spent in MVPA, whereas positive affect, which includes feelings such as being calm, happy, or full of life is associated with MVPA increases. Relatedly, variability in positive but not negative affect is associated with poorer physical health. What is unclear is how intra-individual variability of positive and negative affect may influence MVPA.

Research question
What is the influence of variations (i.e. intra-individual day-to-day) in positive and negative affect on variations in MVPA? Method. Guided by the individual and self-management theory, a secondary analysis was conducted of data from a nationwide US sample of participants. Using data from the Midlife in the United States (MIDUS) Refresh Wave Study Daily Diary Project, we analyzed eight consecutive days of affect and MVPA assessments in a sample of 553 healthy participants (54% women, 86% white, mean age = 48.7 years). Latent trajectory models were computed to determine the influence of daily positive and negative affect on daily MVPA.

Results
Affect variability, calculated as the standard deviation of daily positive and negative affect, was positively correlated with MVPA variability. An autoregressive cross-lagged latent trajectory model provided the best fit to examine relationships between positive affect, negative affect, and MVPA (χ2=946.54, df=379, p&lt;0.001; CFI=0.95; RMSEA=0.05, SRMR = 0.06). Positive, but not negative affect, intercepts were significantly correlated with MVPA trajectories (r=0.19, p&lt;0.05). Individuals who initially begin the eight day time span with a higher reported positive affect show a modest increase in MVPA over the same time period (r=0.19, p&lt;0.001). By contrast, individuals evidencing increases in positive affect over the time span showed a decreased rate of change in MVPA over that same time (r=−0.32, p&lt;0.001).

Conclusion
The association of positive affect to MVPA necessitates a complex analysis to more fully understand intra-individual-level interactions. Relatively higher positive affect with fewer fluctuations was associated with greater MVPA. These intriguing preliminary findings must be considered in light of important limitations (e.g., only eight days of data; affect and MVPA do not necessarily follow diurnal patterns). Still, findings support the view that beginning with positive affect may lead to stability in time spent in MVPA.

Funding Acknowledgement
Type of funding source: None
Exercise motivation in patients with heart failure
Authors: Klompstra L , Jaarsma T , Stromberg A , Van Der Wal M.H.L 
Published: November 2020

Abstract

Background
Being physically active is important for patients with heart failure (HF) to improve clinical outcome, however, adherence to exercise is low (&lt;50%). To tailor intervention that increase physical activity, it is important to know what motivates HF patients to exercise. Therefore, the aim of the study is to describe motivations of HF patients to exercise and describe variables that are related to their exercise motivation.

Methods
This is a cross-sectional analysis of baseline data of 605 patients with HF (mean age 67±12, 71% male, 60%NYHA I/II) who were included in the HF-Wii study. Stepwise regression modelling was used with exercise motivation as dependent variable. Exercise motivation was measured with the Exercise Motivation Index, including 15 statements with answers ranging from 0 (not important) to 4 (extremely important), with 3 subscales (physical, psychological and social motivation).
Based on previous research the following predictors were included in the model: quality of life (MLwHFQ), self-efficacy (Exercise self-efficacy scale), cognition (MoCA), depression (HADs), sleeping difficulties (MISS), HF symptoms (fatigue, shortness of breath), age, gender, NYHA-class, comorbidity and educational level.

Results
Mean total motivation to exercise was 2.3±0.9 and physical and psychological motivation were rated as the more important (2.7±0.9 and 2.5±0.9) than social motivation (1.8±1.1). Motivation statements that were considered extremely important were being healthier (55% rated 4), slow down the ageing process (38% rated 4) and increasing well-being (31% rated 4). From the multiple linear regression model lower quality of life (β=−0.31, P&lt;0.0001), lower self-efficacy (β=0.16, P&lt;0.0001), experiencing shortness of breath (β=−0.28, P&lt;0.0001), having COPD (β=−0.14, P=0.001) and low educational level (β=−0.09, P&lt;0.028) were predictors related to lower motivation. This model explained 17% of the exercise motivation variability (p&lt;0.0001). Cognition, sleeping difficulties, age, gender, NYHA-class and experiencing fatigue were not significantly related to motivation.

Conclusion
Lower quality of life, lower self-efficacy, experiencing shortness of breath, having COPD and lower educational level, decreases the motivation to exercise and may therefore be considered as barriers for exercise. These barriers should be assessed and considered when motivating patients to become more physically active.

Funding Acknowledgement
Type of funding source: None
Frailty is associated with vascular thrombosis events in chronic hemodialysis patients
Authors: Wu C.C , Cheng J.H , Yang H.J , Ps L.I.N , Liu S.J , Huang S.C , Lo C.M 
Published: November 2020

Abstract

Background
Frailty is common in chronic hemodialysis patients and is associated with increased risk of mortality. In hemodialysis patients, cardiovascular disease is the most cause of mortality but the impact of frailty on cardiovascular disease remained unknown.

Purpose
To access if there was an association between frailty and vascular thrombotic events among chronic hemodialysis patients.

Methods
This is a multi-center cohort study of chronic hemodialysis patients conducted since Jan, 2018 (last follow-up in December, 2020). Baseline data were collected from medical records and hemodialysis records. Frailty was defined by the Fried's criteria, a composite construct that incorporated poor physical functioning, exhaustion/fatigue, low physical activity, and undernutrition using a self-reported questionnaire. The primary outcome was vascular thrombosis events, defined as myocardial infarction, ischemic stroke, acute or critical limb ischemia, and dialysis vascular access thrombosis. The outcomes were assessed from a prospectively-collected nationwide registration system which was updated every 3 months and verified after review of medical records or discussion with caring physicians.

Results
During the study period, 571 chronic hemodialysis patients were enrolled. The mean age of study participants was 66 years old (SD, 13) and 55% of them were male. A total of 247 patients (43%) were categorized as frail. At baseline, logistic regression analysis revealed that older age, female sex, diabetes, low albumin and history of stroke were independently associated with frailty. During the follow-up period (median, 18 months), 57 patients (10%) died and 182 patients (31.9%) had vascular thrombosis events, including 101 arterial thrombosis (17.7%) and 105 dialysis access thrombosis (18.4%). In the primary outcome analysis, Cox proportional hazards modeling indicated that frailty was independently associated with vascular thrombosis events (Hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.132–2.597). In the secondary analysis, frailty was associated death (HR 2.25, CI 1.16–4.37), arterial thrombosis events (HR 1.92, CI 1.16–3.18), and dialysis vascular access thrombosis events (HR 1.90, CI 1.24–2.91).

Conclusion
Frailty phenotype is extremely common in hemodialysis patients. It is associated with mortality and vascular thrombosis events among chronic hemodialysis patients. Given its prevalence and consequence, research focus on interventions aimed to prevent or attenuate frailty in hemodialysis patients should be warranted.

Funding Acknowledgement
Type of funding source: Public hospital(s). Main funding source(s): Grants from National Taiwan University Hospital, Hsinchu Branch.