bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the sensitivity of commercial aPTT tests in measurement of the pharmacodynamic response of milvexian, a novel FXIa inhibitor
Authors: Bonilla F , Bunce M W , Alleman R , Kotha J , Jennings L K , Chintala M 
Published: October 2021

Abstract

Introduction
The activated partial thromboplastin time (aPTT) assay is a test routinely used to evaluate abnormalities or deficiencies in coagulation factors of the intrinsic and common pathways. The composition of the surface activator and phospholipids in the aPTT reagent is known to influence the response of heparin and direct FXa or thrombin inhibitors.
Milvexian (formerly referred to as BMS-986177/JNJ-70033093) is an investigational small-molecule Factor XIa (FXIa) inhibitor being studied for the prevention and treatment of major thrombotic conditions. Clinical pharmacology evaluation of milvexian includes aPTT as the primary pharmacodynamic assay, thus underscoring the need for a sensitive reagent to evaluate its anticoagulant activity.

Purpose
This study evaluated the sensitivity of six commercially available aPTT reagents in plasma from individual donors spiked with milvexian, at concentrations spanning the anticipated clinically relevant exposures.

Methods
Platelet-poor plasma (PPP) prepared from citrated whole blood collected from consenting, healthy adult volunteers (n=12) was spiked with vehicle (DMSO, 0.5% v/v) or 0.1–10 μM milvexian. The aPTT was measured using six commercially available aPTT reagent kits which included silica; kaolin, or ellagic acid as the contact activator, in combination with natural or synthetic phospholipids. The coagulation automated analysers used for testing were matched to the kit's manufacturer recommendations. All reagents and respective normal or abnormal controls were prepared as instructed by the manufacturer.

Results
Milvexian exhibited dose-dependent prolongation of aPTT with all reagents tested. Assays performed with aPTT reagents containing kaolin or ellagic acid demonstrated the highest sensitivity, as measured by the concentration that achieved a 2-fold aPTT prolongation (EC2x), and showed the widest dynamic range of response. Coefficient of variability of aPTT measurements in plasma from 12 individual donors was between 5.6–7.9% for Dade® Actin® FS, and 7.1–8% for STA®-C.K. Prest® 5.

Conclusions
Prolongation of aPTT in PPP spiked with milvexian exhibited a dose-dependent relationship, with statistically significant differences observed among reagents at milvexian concentrations above 0.3 μM. The highest sensitivity measured by changes in the ratio to baseline was obtained with aPTT reagents containing an activator/procoagulant phospholipid combination of ellagic acid + purified soy phosphatides or kaolin + cephalin, which performed similarly. Identification of the reagents with the best combination of sensitivity, precision, and dynamic range may help guide the selection of reagent for assessing milvexian activity.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Janssen Research & Development, LLC
Efficacy and safety of direct oral anticoagulants with diabetes and nonvalvular atrial fibrillation: a systematic review and meta-analysis
Authors: Costa G , Goncalves L , Teixeira R 
Published: October 2021

Abstract

Background
Diabetes Mellitus (DM) is an independent risk factor for stroke and atrial fibrillation (AF). Therefore, the risk/benefit profile of the direct oral anticoagulants (DOAC) is of clinical interest.

Purpose
To compare efficacy and safety outcomes of DOAC for nonvalvular AF in patients with DM versus without DM.

Methods
We systematically searched PubMed, Embase and Cochrane databases, in January 2020, for interventional studies comparing DOAC efficacy and safety in patients with AF and diabetes versus without diabetes.

Results
Four randomized clinical trials were included, providing a total of 63987 patients, 18860 with DM and 45127 without DM. In terms of efficacy, our meta-analysis revealed a similar rate of stroke/systemic embolism (pooled OR 1.02 [0.79, 1.31], P=0.87, I2=83%), stroke (pooled OR 1.98 [0.68, 1.40], P=0.90, I2=90%) and all-cause mortality (pooled OR 1.18 [0.97, 1.43], P=0.10, I2=87%), albeit with a significant heterogeneity. However, in direct factor Xa inhibitors sub analysis, diabetic patients had a lower trend of systemic embolism/stroke (pooled OR 0.90 [0.79, 1.02], P=0.09, I2=18%), significantly lower stroke rate (pooled OR 0.82 [0.73, 0.93], P&lt;0.01, I2=0%), but a higher all-cause mortality (pooled OR 1.08 [1.00, 1.16], P&lt;0.01, I2=0%). In terms of safety, the diabetic patients receiving DOAC had higher rates of major bleeding events (pooled OR 1.28 [1.14, 1.45], P&lt;0.01, I2=50%), although with significant heterogeneity. Direct factor Xa inhibitors sub analysis also revealed a higher rate of major bleeding events (pooled OR 1.22 [1.08, 1.38], P&lt;0.01, I2=24%), but a similar intracranial bleeding events (pooled OR 1.03 [0.86, 1.24], P=0.72, I2=0%).

Conclusion
Our pooled analysis suggests that diabetic patients on DOAC have an higher bleeding risk on DOAC, although with a superior embolic protection.

Funding Acknowledgement
Type of funding sources: None. Systemic Embolism/Stroke in DM vs. NonDM
Detection of myocardial ischemia by intracoronary ECG using convolutional neural networks
Authors: Bigler M R , Seiler C 
Published: October 2021

Abstract

Introduction
The electrocardiogram (ECG) is a valuable tool for the diagnosis of myocardial ischemia as it presents distinctive ischemic patterns. Deep learning methods such as convolutional neural networks (CNN) are employed to extract data-derived features and to recognize natural patterns. This study aimed to determine the optimal ischemic parameter as obtained from the highly susceptible intracoronary ECG (icECG) using pre-trained CNN.

Method
This was a retrospective observational study in 228 patients with chronic coronary syndrome. Each patient had participated in clinical trials with icECG recording and ST-segment shift measurement at the beginning (i.e.,non-ischemic) and the end (i.e.,ischemic) of a one-minute proximal coronary artery balloon occlusion establishing the reference. Using these data (893icECGs in total), two pre-trained, open-access CNN (GoogLeNet/ResNet101) were trained to recognize ischemia. The best performing CNN during training were compared with the icECG ST-segment shift for diagnostic accuracy in the detection of artificially induced myocardial ischemia.

Results
Using coronary patency or occlusion as reference for absent or present myocardial ischemia, receiver-operating-characteristics (ROC)-analysis of manually obtained icECG ST-segment shift (mV) showed an area under the ROC-curve (AUC) of 0.903±0.043 (p&lt;0.0001, sensitivity 80%, specificity 92% at a cut-off of 0.279mV). The best performing CNN showed an AUC of 0.924 (sensitivity 93%, specificity 92%). DeLong-Test of the ROC-curves showed no significant difference between the AUCs. The underlying morphology responsible for the network prediction differed between the trained networks but was focused on the ST-segment and the T-wave for myocardial ischemia detection.

Conclusions
When tested in an experimental setting with artificially induced coronary artery occlusion, quantitative icECG ST-segment shift and CNN using pathophysiologic prediction criteria detect myocardial ischemia with similarly high accuracy.

Funding Acknowledgement
Type of funding sources: None.
Triage-HF plus: 12-month study of remote monitoring pathway for triage of heart failure risk initiated during the Covid-19 pandemic
Authors: Bachtiger P , Park S , Letchford E , Scott F , Barton C , Ahmed F Z , Cole G , Keene D , Plymen C M , Peters N S 
Published: October 2021

Abstract

Background
The Covid-19 pandemic necessitated rapid adoption of remote monitoring across cardiovascular patient cohorts. Most patients with cardiac implantable electronic devices (CIEDs) are now able to be remotely monitored using either scheduled, patient- or threshold-triggered transmissions. The validated “Triage Heart Failure Risk Score” (Triage-HFRS) is a medical algorithm within company-specific CIEDs that can risk-stratify patients as low-, medium- or high-risk of worsening heart failure (WHF) in the next 30 days based on integrated monitoring of physiological parameters. Building on a previous proof-of-concept of the Triage-HF Plus pathway, we integrated remote data with simple 5-question telephone triage within a clinical pathway to identify WHF during the first year of the Covid-19 pandemic.

Purpose
Prospective evaluation of clinical remote monitoring pathway integrating Triage-HFRS with protocolised telephone triage (Triage-HF Plus pathway).

Methods
Prospective, real-world evaluation of clinical pathway serving a large urban region over a 12-month period, using data from April 2020 to April 2021 (initiated during the first wave of Covid-19 pandemic in the UK). From a population of 435 patients with CIEDs, 87 “high” Triage-HFRS alerts were received and patients contacted for telephone triage assessment. Screening questions were designed to identify episodes of WHF and non-HF events. Intervention was at discretion of the clinical practitioner and in line with guideline-directed practice. A consecutive sample of 115 “medium” risk scores received the same triage.

Results
Successful contact was made with 72 (82.8%) high-risk patients. Classification for high scoring patients confirmed on triage included isolated heart failure (18.3%), heart failure concurrent to medical problem (5.7%), alternative medical problem (10.3%), and recent hospital admission (8.0%); triage reassured absence of acute cause of high score in 40.2%. The sensitivity and specificity for detection of WHF was 87.9% (0.77–0.99) and 59.4% (0.50–0.69) respectively. Positive and negative predictive values were 40.3% and 94.0%, respectively. Overall accuracy was 66.2%.

Conclusions
The Triage-HF Plus pathway served as a useful remote monitoring tool for identifying patients with WHF whose care had been otherwise disrupted by the Covid-19 pandemic, allowing timely intervention and cementing the longer-term role for such models of care delivery. Crucially, in this multimorbid, high-cost population, relevant non-HF issues were also identified. The high negative predictive value further highlights the potential of proactive surveillance over conventional, periodic follow up.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Imperial Health Charity
Sex-related differential susceptibility to ponatinib-induced cardiotoxicity and its relationship to modulation of Notch signaling in a murine model
Authors: Madonna R , Pieragostino D , Cufaro M C , Del Boccio P , Pucci A , Mattii L , Doria V , Cadeddu Dessalvi C , Zucchi R , Mercuro G , De Caterina R 
Published: October 2021

Abstract

Background
Ponatinib (PON), a tyrosine kinase inhibitor approved in chronic myeloid leukemia, has proven cardiovascular toxicity. Although sex is a risk factor for PON-induced cardiotoxicity in humans, little is known about its mechanisms in general, and sex-related mechanisms in particular.

Objectives
To determine the mechanisms of sex-related PON-induced cardiotoxicity and identify potential rescue strategies in a murine model.

Methods
24-months-old male and female C57B5 mice were treated with 3 mg/kg/day of PON or vehicle via oral gavage for 28 days, with/without siRNA-Notch1 or siRNA-scrambled via tail vein every 3 days.

Results
PON + scrambled siRNA-treated male mice had a higher number of TUNEL-positive cells, a higher percentage of senescence-associated β-galactosidase positive senescent cardiac areas, as well as a lower reactivity degree for the survival marker Bmi1 than female counterparts. Proteomics analysis of cardiac tissue showed upstream activation of nitric oxide synthase (NOS) type 2, downstream activation of cell death and production of reactive oxygen species in PON + scrambled siRNA- compared to vehicle or PON + Notch1 siRNA-treated male mice. Upstream analysis showed beta-estradiol activation, while downstream analysis showed activation of cell survival and inhibition of cell death in PON + scrambled siRNA compared to vehicle-treated female mice. PON + scrambled siRNA-treated mice also showed a downregulation of cardiac actin, which was more marked in male; as well as vessel density, which was more marked in female mice. Female hearts showed a greater extent of cardiac fibrosis than male counterparts at baseline, with no significant changes after PON treatment. In contrast, PON + scrambled siRNA-treated mice had less fibrosis than vehicle or PON + Notch1-siRNA-treated mice. Left ventricular systolic dysfunction shown in PON + scrambled siRNA-treated male mice and - to a lesser extent - by female mice was similarly reversed in both PON + Notch1-siRNA-treated male and female mice (Table 1).

Conclusions
We found a sex-related differential susceptibility and Notch1 modulation in PON-induced cardiotoxicity. This can improve our understanding of sex-related differences and help identify biomarkers in PON cardiotoxicity.

Funding Acknowledgement
Type of funding sources: None.
Genome-wide association study of atrial fibrillation in 114,539 Finnish individuals reveals novel locus associated with cardiac remodelling
Authors: Paludan-Muller C , Vad O B , Svendsen J H , Olesen M S 
Published: October 2021

Abstract

Background/Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia and it is associated with serious complications, such as stroke, heart failure, and premature death. Previous genome-wide association studies (GWAS) have associated more than 140 genomic loci with AF; however, these studies predominantly include subjects of European ancestry. Although, the Finnish population is European, it is genetically considered different from other European populations as it has been isolated and developed through multiple bottlenecks followed by population growth. Therefore, pathogenic variants are more easily discovered and heritably diseases are more prevalent.

Methods
We accessed summary statistics on atrial fibrillation and flutter (I48) from the Finngen project. Loci were defined as 1 megabase regions around lead SNPs, and loci were considered novel when the SNPs had P-values &lt;5x10–8 after conditional analysis, and no previously reported SNPs were within the loci. FINEMAP was done with a Finnish LD reference panel, and colocalization of GWAS and eQTL signals were analysed with MetaXcan.

Results
A GWAS on 17,325 Finnish AF cases and 97,214 controls confirms 16 previous identified loci and reveals one novel locus on chromosome 19. The novel lead SNP, rs190065070 (odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.29–1.61, P-value = 5.96x10–11), is close to the gene EMC10, which encodes the endoplasmic reticulum membrane protein complex subunit 10. While the locus harbours other genes, our MetaXcan analysis could not provide conclusive evidence for other plausible genes. The EMC complex consists of 10 subunits and is a chaperone in endoplasmic reticulum-resident membrane proteins. Previous mouse studies have shown EMC10 to be important in angiogenesis after myocardial infarction, and it has recently been associated with a novel neurodevelopment syndrome. The EMC1 subunit has been associated with congenital heart disease.

Conclusion
We present a novel susceptibility locus associated with AF in the Finnish population. The locus is in proximity to the gene EMC10, which is involved in structural remodelling of the heart after myocardial infarction. These results propose a potentially novel pathophysiological pathway in AF.

Funding Acknowledgement
Type of funding sources: Public hospital(s). Main funding source(s): The Research Foundation RigshospitaletThe John and Birthe Meyer Foundation
Morphological features of mitral annular calcification leading to systolic anterior motion of the mitral valve
Authors: Friend E J , Wiener P C , Murthy K , Pressman G S 
Published: October 2021

Abstract

Background
Systolic anterior motion (SAM) of the mitral valve (MV) can develop after mitral valve repair with placement of an annuloplasty ring. It is occasionally seen in patients with mitral annular calcification (MAC) but mechanisms have not been carefully delineated. Using 2-dimensional echocardiography we explored morphologic parameters which may contribute to SAM in patients with MAC.

Hypothesis
We hypothesized that in cases of MAC where SAM is present there would be anterior displacement of the valve by the posterior annular calcification.

Methods
From our echocardiographic database we identified 20 patients with severe MAC who also had SAM with definite septal contact. Each subject was paired with 2 controls free of MAC and 1 control with severe MAC but no SAM. All controls were matched for age, sex, BSA, and septal wall thickness (±1.5 mm). 2-D echocardiographic measurements were taken from the parasternal long-axis (PLAX), apical 3-chamber and apical 4-chamber views.

Results
MAC+SAM vs MAC no-SAM. Three notable differences were observed: MAC+SAM patients, as compared with MAC no-SAM, had a smaller left ventricular outflow tract (LVOT), longer anterior mitral leaflet, and greater displacement of the MV coaptation point towards the interventricular septum (Figure 1). Median values for these 3 factors were determined using the no-MAC controls; each MAC subject was then scored for number of factors exceeding those values. MAC+SAM patients had a mean score of 2.7 vs 1.1 for MAC no-SAM patients. By combining anterior mitral leaflet length and coaptation point-septal distance as a ratio we could effectively separate MAC+SAM vs MAC no-SAM when &gt;0.9 with one exception (Figure 2). We also observed a smaller anteroposterior annular dimension in the MAC+SAM group.
MAC no-SAM vs no-MAC. Comparing these groups there were no differences in LVOT diameter or coaptation-septal distance; effective anterior mitral leaflet length was smaller in MAC no-SAM subjects vs no-MAC controls while anteroposterior dimension of the annulus was larger.

Conclusions
SAM develops in a subset of patients with severe calcification of the mitral annulus. These patients have a smaller anteroposterior annular dimension, possibly due to severe MAC. Other notable differences characterize MAC patients with SAM from those without. The LVOT is smaller, the effective anterior mitral leaflet length is longer, and the point of leaflet coaptation is displaced towards the septum. Using the ratio of anterior mitral leaflet length/coaptation point-septal distance in this study sample effectively separated those MAC patients with SAM from those without.

Funding Acknowledgement
Type of funding sources: None. Figure 1Figure 2
Epicardial adipose tissie-derived leptin induce MMPs/TIMPs imbalance and promotes myocardial remodeling in high fat diet-induced obese rats
Authors: Tian G , Liu L , Luo C D , Li M , Cao L F , Zhu D J 
Published: October 2021

Abstract

Background and aims
Epicardial adipose tissue (EAT)-derived leptin contributes to myocardial remodeling in metabolic syndrome. However, the precise mechanisms remain to be determined. The present study was designed to elucidate the adverse effects of EAT-derived leptin on obesity-related myocardial remodeling.

Methods and results
Eight-week-old male Wistar rats were divided into two groups that received either a normal diet (control, n=10) or a high-fat diet (obese, n=10) for 12 weeks. Obese rats exhibited abnormal myocardial structure, diastolic dysfunction and abundant collagen deposition. Local leptin expression in obese rats EAT upregulated along with adipocyte hypertrophy, accompanied by renin-angiotensin-aldosterone system (RAAS) activation and increased oxidative stress level. Leptin receptor (ObR) and angiotensin II type 1 receptor (AT1R) expression in obese EAT were significantly higher than that in control. In vitro, mature adipocytes treated with angiotensin II (Ang II) exhibited pronounced leptin synthesis and secretion by promoting AP-1 nuclear translocation via the AT1R-ROS-ERK1/2 pathway. Moreover, cardiac fibroblasts were incubated with obese rat EAT-conditioned medium (EAT-CM), plus various inhibitors. EAT-derived leptin promoted proliferation of cardiac fibroblasts associated with increased ERK1/2 phosphorylation and induced MMPs/TIMPs imbalance, stimulating upregulation of type I collagen via the JAK2/STAT3-TGF-β1/Smad3 pathway in cardiac fibroblasts of obese rats.

Conclusions
The paracrine effect of EAT-derived leptin on myocardial remodeling, inducing MMPs/TIMPs imbalance and promoting the proliferation of cardiac fibroblasts via activating ERK1/2 and JAK2/STAT3-TGF-β1/Smad3 pathway in obesity.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): the Nature Science Foundation of China (grant no. 81873513, 81600574, and 30871042)
Identification of miRNA-497 and miRNA-27b-5p as potential diagnostic markers of cardiac fibrosis
Authors: Tikhomirov R , Reilly-O'donnell B , Lucarelli C , Greco S , Zacagnini G , Maryam A , Menicanti L , Leszek P , Faggian G , Srivastava P , Emanueli C , Martelli F , Gorelik J 
Published: October 2021

Abstract

Background
Cardiac fibrosis is associated with inflammation and extracellular matrix (ECM) accumulation. A pro-fibrotic cytokine, IL11 induces cardiac fibroblasts conversion to myofibroblasts expressing α-smooth muscle actin (α-SMA) and ECM. MicroRNAs (miRNAs) are a class of small non-coding RNAs which participate in regulation of gene expression; Although mainly intracellular, miRNAs can be released into the blood stream where they can be readily detected.

Purpose
To screen miRNAs upregulated following IL11 triggered conversion of rat cardiac fibroblasts into myofibroblasts. To validate these miRNAs as potential diagnostic biomarkers of cardiac fibrosis by testing their level in blood plasma and septum of aortic valve stenosis (AVS) patients.

Methods and results
With a bioinformatical approach (Figure 1), we predicted miRNAs which can target proteins involved in TGFβ and IL-11 pathways of fibrosis progression. Of a vast number of miRNAs, we identified 7 strong candidates. After qPCR validation, we found miRNA-27b-5p and miRNA-497 to be significantly upregulated in rat cardiac fibroblasts treated by IL11 (5 ng/ul) but not TGFβ1 (100 ng/ul), values are 2–ΔΔCt: (3±1.5) and (5.2±2.2) (p-value &lt;0.05) for miRNA-27b-5p and miRNA-497 respectively. Next, we overexpressed these two miRNAs separately in rat cardiac fibroblasts. With immunostaining we observed a (18.3±6.8)% increase in the percentage of α-SMA positive cells for miR-27b-5p and a (38.0±8.3)% increase for miR-497. Moreover, we detected with qPCR a significant up-regulation of α-SMA expression (−ΔΔCt = 3.4±0.9 for miR-27b-5p; −ΔΔCt = 8.2±0.7 for miR-497) in cells overexpressing miRNA27b-5p and miRNA497. Furthermore, we found that levels of both miRNA-27b-5p and miRNA-497 were significantly higher in blood plasma (p=0.0002, p=0.04) of AVS patients compared to age and sex matched control group of healthy donors (Figure 2) and heart septum (p=0.0004, p=0.04) of AVS patients compared to septum of healthy donors that could not be used for transplantation. In addition, quantification of Sirius red staining and immunohistochemistry for Col1a1 displayed significant ECM accumulation in AVS patients (p=0.04).

Conclusions
We found miRNA-497 and miRNA-27b-5p to be pro-fibrotic in rat fibroblasts. Importantly, we found both miRNAs to be up-regulated in the peripheral blood of AVS patients.

Funding Acknowledgement
Type of funding sources: Other. Main funding source(s): Roman Tikhomirov PhD studentship is supported by a fellowship from the University of Verona, ItalyEEU-Cardiac RNA cost action CA17129