bluuebunny/crossref_metadata_2025_split huggingface dataset:
A macrophage migration inhibitory factor as a predictor of reperfusion myocardial injury in patients with st-segment elevation myocardial infarction
Authors: Vishnevskaya I , Storozhenko T.Y.E , Kopytsya M.P 
Published: November 2020

Abstract

Introduction
Major adverse cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI) are still common despite the modern treatment approaches. It may be caused by the “no-reflow” phenomenon. One of the promising biomarkers for the coronary “no-reflow” phenomenon prediction is proinflammatory cytokine macrophage migration inhibitory factor (MIF).

Purpose
To estimate the role of MIF in the prediction of early reperfusion myocardial injury in patients with STEMI.

Methods
The study involved 341 STEMI patients (78.6% male and 21.4% female) with an average age of 59.08±9.65 years. Control group of 12 healthy volunteers included. All patients were made to undergo a baseline investigation. In addition, the level of MIF determined twice during the first 12 hours of STEMI, before the percutaneous coronary intervention (PCI) and after the procedure. Coronary blood flow evaluated using TIMI flow grade and myocardial blush grade (MBG). All patients had epicardial blood flow TIMI 3. The criteria for “no-reflow” diagnosis were myocardial perfusion at MBG 0 or MBG 1 level with complete recovery of epicardial blood flow or ST-segment resolution (rST) of less than 70% from baseline within 2 hours after PCI. All patients were divided into two groups according to MBG and rST after PCI more and less than 70%: 147 patients in the first group with MBG stage 0–1, 182 patients with MBG stage 2–3

Results
64% of STEMI patients had elevated MIF levels above the highest value in healthy controls (2778±217 ng/ml; 225±6,7 ng/ml; p=0,0003). The level of MIF biomarker, determined before PCI was significantly higher in the group of patients with MBG 0–1 in comparison to MBG 2–3. (4708±471 ng/ml vs 2914±347ng/ml; p=0,004). Using the multivariate regression analysis, the dependencies of the biomarker MIF on the parameters of the reperfusion myocardial injuries were obtained. MIF measured before revascularization as well as the patient's gender, was an independent predictor of MBG 0–1 and rST less than 70% (coefficients Beta 0,1; odd ratio 1,1; 95%confidential interval (CI) 1,0–1,2; p=0,037 and coefficient Beta 2,9; odd ratio 17.7; 95% CI 0,96–32; p=0,05, respectively).

Conclusions
The study revealed that MIF predicts reperfusion myocardial injury in patients with STEMI. Future investigations of the MIF biological effects are the perspective direction in the field of modern cardiology.

Funding Acknowledgement
Type of funding source: None
Obstructive respiratory events transiently impair electromechanical coupling and increase premature ventricular contraction rate in a drug-induced Long-QT-2 pig model
Authors: Linz B , Flethoj Madsen M , Hotbjerg Hansen M , Melis Hesselkilde E , Saljic A , Hohl M , Wirth K , Linz D , Sattler M , Tfelt-Hansen J , Jespersen T 
Published: November 2020

Abstract

Background
Obstructive sleep apnea (OSA) is characterized by intermittent negative thoracic pressure fluctuations and intermittent hypoxemic events. Recent findings associate OSA with impaired ventricular repolarization during sleep and increased risk of sudden cardiac death, which may have special implications for Long-QT-2-syndrome patients. Therefore, we elucidated changes in ventricular repolarization and electromechanical coupling (electromechanical window; EMW) during either obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) or hypoxemic events simulated by intermittent hypoxia (IH) in vehicle (VEH) and dofetilide (DOF) treated pigs, as a simulation of drug induced Long-QT-2 syndrome.

Methods
In sedated spontaneously breathing pigs, either VEH or DOF (50 μg/kg) was perfused and INAP was applied by a negative pressure device connected to the intubation tube. For IH-application the device was connected and left turned off. INAP or IH was maintained for 75 seconds followed by a ten-minute resting period. In order to evaluate the electromechanical window, the time difference between electrical (QT-duration) and mechanical systole (Q-wave to the end of left ventricular pressure signal, QLVPend) was measured before (pre-INAP/-IH), during and 60 seconds after INAP/IH (post-INAP/-IH). Incidence rates of premature ventricular contractions (PVC) and ventricular tachycardia were compared pre- to post-INAP/-IH.

Results
In VEH-pigs, EMW shortened throughout INAP and post-INAP periods steadily (VEH: pre-INAP: 81.69±2.31ms; INAP: 55.65±6.13ms; post-INAP: 38±8.89ms. p=0.008). EMW shortening during post-INAP was associated with an increase in PVCs (VEH: pre-INAP 5.41±1.87 vs. post-INAP 26.5±8.15; p=0.04). In DOF-pigs, INAP-associated EMW-shortening was further potentiated (DOF: pre-INAP: 61.16±7.18ms; INAP: 38.09±9.84ms; post-INAP: 14.93±9.24ms. p=0.016), which was associated with an increase in PVCs (DOF: pre-INAP 4.75±2.36 vs. post-INAP 36.58±10.92; p=0.017). Administration of Atenolol could prevent post-INAP shortening of the EMW and decrease counts of premature ventricular contractions. While desaturations were comparable in INAP and IH, IH did not result in EMW-shortening or increased arrhythmia risk.

Conclusion
Transient dissociation of the ventricular electromechanical coupling during a simulated obstructive apnea, but not during IH, creates a dynamic and sympathetically driven arrhythmogenic substrate. Apnea associated ventricular electromechanical uncoupling was aggravated in a drug-induced Long-QT-2 simulation. Whether OSA represents a modifiable arrhythmogenic risk factor in Long-QT-2-patients warrants further studies.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Novo nordisk fonden
Genetic variants in calcium regulatory cardiac genes and their contribution to Takotsubo syndrome
Authors: Treu F , Dybkova N , Jung P , Li Y , Huebscher D , Maurer W , Hasenfuss G , Voigt N , Sossalla S , Wollnik B , Streckfuss-Boemeke K 
Published: November 2020

Abstract

Background and purpose
Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction similar to a myocardial infarction (MI) in the absence of coronary artery stenosis. Patients show symptoms similar to the acute MI with increased biomarkers and blood serum catecholamines. Recently, we developed a patient-specific TTS stem cell model and identified a higher sensitivity to catecholamine-induced stress. Furthermore, familial TTS cases and genetic studies point to a genetic predisposition. The purpose of this study was to analyze a genetic predisposition by characterizing genetic variants in genes associated with cardiac pathologies and their impact on calcium homoeostasis in TTS.

Methods and results
Whole exome sequencing analysis of a TTS patient discovered 2 missense AHNAK variants in its C-terminal domain and in addition the missense variant F189L in the calcium buffering calsequestrin 2 gene (CASQ2). AHNAK is a 700kDa big nucleoprotein and is involved in the β-adrenergic regulation of the cardiac calcium channel Cav1.2. 3-month old TTS-iPSC-derived cardiomyocytes (CM) were generated and the variants were confirmed by sequencing. We found AHNAK higher expressed in TTS-iPSC-CMs compared to control, whereas no expression alteration was observed for Cav1.2. Since AHNAK is described to act as a repressor towards Cav1.2, which is relieved under β-adrenergic stimulation, we analyzed the effect of AHNAK variants on a potential co-localization and interaction between both proteins. AHNAK and Cav1.2 were shown to co-localize in the cytoplasm as well as the membranes and co-immunoprecipitation experiments confirmed an interaction of AHNAK and Cav1.2 in all tested control- and TTS-iPSC-CMs. On a functional level, we were able to show by patch clamp analysis that Cav1.2 calcium currents are significantly increased in TTS-iPSC-CMs compared to control. The influence of CASQ2-F189L on sarcomeric reticulum (SR) calcium load was analyzed by epifluorescence microscopy using FURA4 and caffeine-applications. We found significantly decreased SR calcium content with an increased fractional release during systole in TTS-iPSC-CMs. To test, whether these variants are the main reason for altered interaction of AHNAK and Cav1.2, calcium currents or SR calcium load in TTS need to be proven in the future by using CRISPR/Cas9-rescued AHNAK/CASQ2 lines.

Conclusion
Here we show the cardiac functional consequences of AHNAK and CASQ2 missense mutations in TTS-iPSC-CMs with regard to calcium currents and SR calcium load. These results show that AHNAK and CASQ2 variants may predispose to TTS and enable a new therapeutic option for TTS.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Else Kröner-Fresenius Foundation
Cyclin dependent kinase 1 (CDK1) positively regulates cardiac hypertrophy and fibrosis via TGF-beta pathway
Authors: Yamamoto T , Matsushima S , Okabe K , Ikeda S , Ishikita A , Enzan N , Sada M , Tsutsui Y , Miyake R , Tsutsui H 
Published: November 2020

Abstract

Background
Transforming growth factor beta (TGF-β) critically mediates cardiac fibrosis by transforming fibroblasts to myofibroblasts in pathological conditions. Cyclin dependent kinases (CDKs), cell cycle-regulating proteins, are known to be intimately involved in cardiac fibrosis. Among CDK isoforms, CDK1 is essential for cell cycle progression and cell division. It is reported some interphase CDKs such as CDK4 or CDK6 were involved in cardiac fibrosis, however, detailed mechanisms of cardiac fibrosis through CDK1 and its interactions with TGF-β in cardiac fibrotic process haven't been elucidated. We hypothesize that CDK1 is involved in cardiac fibrotic process via TGF-β pathway and its suppression decreases TGF-β expression and transformation to myofibroblasts from fibroblasts presenting antifibrotic effect.

Methods and results
Isolated neonatal rat cardiac fibroblasts were treated with angiotensin II (ANG II, 1 μM, 24 h) or phosphate-buffered saline (PBS). ANG II increased CDK1 and TGF-β in cardiac fibroblasts, by 97% and 292%, respectively (p&lt;0.05). Administration of Ro-3306, a specific CDK1 inhibitor (1 μM, 24 h), suppressed TGF-β protein levels in ANG II-treated cardiac fibroblasts by 58% (p&lt;0.05). Similarly, knockdown of CDK1 by RNA silencing also inhibited ANG II-induced increases in TGF-β in cardiac fibroblasts by 39% (p&lt;0.05). ANG II increased alpha-smooth muscle actin (α-SMA), which is a marker of myofibroblasts, and knockdown of CDK1 significantly suppressed it by 49% (p&lt;0.05). In vivo study, 11-week-old male C57BL/6J mice were administered ANG II continuously with infusion pump, at a dose of 1000 ng/kg/min, for a week. Also, Ro-3306 was intraperitoneally injected at a dose of 2 mg/kg/day, every other day, for a week. First, Ro-3306 attenuated ANG II-mediated cardiac hypertrophy indicated by heart weight and echocardiographic parameter as to left ventricular wall thickness. Second, CDK1 and TGF-β expression were significantly augmented in ANG II-infused mice by 404% and 113%, respectively (p&lt;0.05). Injection of Ro-3306 suppressed TGF-β protein levels by 48%, although the difference wasn't statistically significant (p=0.09). Finally, histopathological examination (Masson's trichrome stain) demonstrated remarkable repression of ANG II-induced cardiac fibrosis by Ro-3306.

Conclusions
CDK1 positively controls cardiac fibrotic process by regulating transformation to cardiac myofibroblasts from fibroblasts via TGF-β pathway. It also presents an antihypertrophic effect on ANG II stimulation. CDK1 is a potential therapeutic target of cardiac fibrosis and hypertrophy.

Funding Acknowledgement
Type of funding source: Other. Main funding source(s): KAKENHI
Distinct dietary alpha-linolenic acid-dependent shifts in the fecal microbiome composition suppresses aging-associated inflammatory responses and thrombus formation
Authors: Saeedi Saravi S.S , Bonetti N.R , Camici G.G , Luscher T.F , Beer J.H 
Published: November 2020

Abstract

Background
Aging is associated with alterations in the fecal microbiome composition. The microbiota-derived trimethylamine-N-oxide (TMAO) correlates with arterial thrombotic events, e.g. myocardial infarction and stroke, the leading causes of mortality worldwide. The omega-3 fatty acid (n-3 FA) α-linolenic acid (ALA) has been shown to be protective against thrombosis and associated pathologies. Therefore, we hypothesized that long-term dietary ALA supplementation protects against the aging-associated microbiome dysbiosis, and reduces inflammatory and thrombotic responses.

Methods
24 week-old male C57BL/6 mice were fed either a high ALA (7.3g%) or low ALA (0.03g%) diet for 12 months. We examined the compositional changes of fecal microbiota of the animals treated with high vs. low ALA via 16S rRNA gene sequencing. The plasma levels of TMAO and its precursors choline and betaine, and LPS were measured by ELISA. Additionally, the platelet aggregation in response to thrombin, and thrombus formation on collagen under high-shear flow conditions of 3000/sec (to mimic blood flow in stenosed arteries) were investigated.

Results
Genomic analyses showed that the abundance of Phylum Proteobacteria and the family of desulfovibrio were reduced 71.72% and 51.73% in the aged high ALA-treated mice (p&lt;0.01 and p&lt;0.001, resp.) that may result in decrease in TAMO production and the subsequent inflammatory responses. However, microbial diversity of Bacteroidetes or Fermicutes and Bacteroidetes/Fermicutes ratio did not demonstrate a significant change between high vs. low ALA groups. Interestingly, the dietary intake of high ALA increased the abundance of Lachnospiraceae (p&lt;0.01) that may exert anti-inflammatory effects. Importantly, high ALA significantly decreased the plasma levels of TMAO (p&lt;0.01) and its precursor choline (P&lt;0.05), but not betaine. The pro-inflammatory cytokine TNF-α showed a significant reduction (p&lt;0.05), whereas plasma IL-1β did not change significantly following high ALA supplementation. An increased thrombus formation on collagen under high-shear flow (36.34%, p&lt;0.01) and thrombin-induced platelet aggregation (31.31%, p&lt;0.05) were found in the aged mice.

Conclusion
These studies demonstrate that an ALA-rich diet induces beneficial bacterial shifts in the aging-associated fecal microbiome that may lead to the suppression of inflammatory and thrombotic responses. Hence, long-term dietary ALA supplementation may be exploited as a nutritional antithrombotic strategy in the aging.
Microbiome-Thrombosis-Aging

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Swiss National Science Foundation (SNSF)
Impact of hypoxia on immune cells in human atherosclerotic plaques
Authors: Vorobyeva D , Lebedeva A , Elizarova A , Maryukhnich E , Gontarenko V , Shpektor A , Margolis L.B , Vasilieva E 
Published: November 2020

Abstract

Background
Inflammation plays a major role in atherosclerotic plaques' progression and was shown to be associated with the formation of hypoxic areas within the plaques. However, the data about the impact of hypoxia on atherosclerosis are contradictory, in part due to inadequacy of in vitro and animal models to reproduce faithfully the complexity of human atherosclerotic plaques.

Purpose
The aim of this study was to investigate the effect of hypoxia on immune status in the ex vivo system of human atherosclerotic plaques.

Methods
We collected 25 atherosclerotic plaques from patients undergoing carotid endarterectomy, cut plaques into ring-shaped slices and cultured them for 24 hours at the liquid/air interface on collagen sponges under hypoxic (2% O2) and normoxic (12% O2) conditions. After 24 hours we evaluated T-cell activation status within plaques according to the presence of membrane activation markers by means of multiparametric flow cytometry and the activity of cytokine production using xMAP technology.

Results
We found that CD8 T cells from human atherosclerotic plaques cultured under hypoxic conditions compared to normoxic conditions have a decreased expression of CD69 activation marker (42.7 [34.3; 50.9]% vs 53.8 [33.3; 63.3]%, n=10, p=0.047) and lower level of CD69 and HLA-DR coexpression (16.0 [10.5; 22.3] vs 22.6 [11.3; 28.2], n=10, p=0.02). CD4 T cells did not show any significant changes in expression of activation markers under hypoxia. Hypoxic conditions also resulted in a reduced IL-10 production (104.2 [53.8; 170.9] vs 235.2 [158.5; 335.3] pg/100 mg of tissue, n=20, p=0.0001) and increased VEGF production (116.1 [79.8; 253.5] vs 89.9 [71.1; 148.8] pg/100 mg of tissue, n=20, p=0.033).

Conclusions
Our results indicate that hypoxia causes a decrease in the activity of cytotoxic T cells and increases stimuli for angiogenesis within the human atherosclerotic plaques. The established ex vivo model of human atherosclerotic plaques culture under hypoxia enables further studies of the hypoxia impact on atherosclerosis.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Russian Science Foundation grant
Identification of mRNA and microRNA profiles in right ventricular dysfunction induced type II cardiorenal syndrome
Authors: Chen K.T , Liao Y.L 
Published: November 2020

Abstract

Background
Type II Cardiorenal syndrome (CRS) induced by right ventricular (RV) dysfunction is a disease with high mortality but little attention. Its unique pathophysiology and molecular characteristics remains puzzled. This study is aimed to investigate the transcriptomic expression profile of circRNAs, miRNAs and mRNAs, and identify the potential therapeutic targets that regulate molecular signaling networks in RV dysfunction-induced type II CRS.

Methods
Male C57BL/6 mice receiving pulmonary artery constriction were used to establish RV dysfunction model. The expression profiles of mRNAs, miRNAs and circRNAs in RV and kidney tissues were obtained by whole transcriptome sequencing. Bioinformatics analyses were performed, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and co-expression network analysis. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to confirm the results of transcriptome sequencing.

Findings
A total of 741 and 86 differentially expressed (DE) mRNAs, 159 and 29 DEmiRNAs and 233 and 104 DEcircRNAs were found in RV and kidney tissue, respectively. Pairs of miRNA-mRNA were established. GO and KEGG analysis displayed a significant correlation with proliferation signaling pathways and metabolic pathways. Then the circRNA-miRNA-mRNA network related to proliferation and metabolic pathways were established. We identified hub circRNA-miRNA-mRNA pairs affected the fibrotic, proliferative and metabolic pathways significantly.

Interpretation
These findings indicate that the function of ceRNA networks play an important role in RV dysfunction induced type II CRS. Therefore, these circRNA-miRNA-mRNA pairs should be potential targets for treatment of this disease.
Figure 1

Funding Acknowledgement
Type of funding source: None
Clot formation, lysis and ultrastructure in patients with acute phase myocardial infarction
Authors: Siniarski A , Baker S.R , Duval C , Gajos G , Nessler J , Ariens R.A.S 
Published: November 2020

Abstract

Background/Introduction
Patients with established coronary artery disease have impaired clot structure and lysis. Prior research has compared patients with myocardial infarction to those with stable coronary artery disease (without a healthy reference), or patients after myocardial ischemia. The role of clot structure in the acute phase of the disease is unknown.

Purpose
Investigate clot structure in the acute phase of myocardial infarction (AMI) compared to healthy controls.

Methods
Plasma clots from AMI patients (within 12 hours of symptoms onset) or healthy controls were analyzed by turbidity and lysis. Clot pore size was determined by permeation. Clot ultrastructure was determined by confocal and scanning electron microscopy. Average fiber radius and protofibril packing were investigated by turbidimetry.

Results
Analysis on clot formation, using turbidity, showed increased lag time (24%, p&lt;0.05), suggesting changes in protofibril packing and increased fiber size for AMI patients compared to controls. Additionally, AMI clots formed more quickly as evidenced by average rate of clotting (2.9-fold increase, p&lt;0.001) and time to maximum absorbance (38% decrease, p&lt;0.0001). Decreased plasminogen in AMI patients (23%, p&lt;0.05) had strong effects on clot lysis, including increased time to half lysis (1.72-fold, p&lt;0.0001) and increased time to maximum lysis rate (7.96-fold, p&lt;0.0001). Taken together, these results suggest that AMI patients form less porous clots made from densely packed fibers with decreased numbers of protofibrils, which was confirmed using permeation (1.05-fold decrease, p&lt;0.0001), confocal (Figure 1) and scanning electron microscopy (46% increase, p&lt;0.0001), and turbidimetry (16% decrease, p&lt;0.05) respectively.

Conclusions
Plasma from patients with AMI form denser and less permeable clots that lyse more slowly than healthy controls. These data show marked abnormalities in clot ultrastructure that contribute to the high risk of thrombosis during the acute phase of myocardial infarction, which has not shown in previous investigations.
Figure 1. Confocal microscopy of AMI vs. controls

Funding Acknowledgement
Type of funding source: Public Institution(s). Main funding source(s): Jagiellonian University Medical College to G.G. (N41/DBS/000096) and BHF Programme Grant to S.R.B. and R.A.S.A. (RG/18/11/34036).
Deep learning and the electrocardiogram: review of the current state-of-the-art
Authors: Somani Sulaiman , Russak Adam J , Richter Felix , Zhao Shan , Vaid Akhil , Chaudhry Fayzan , De Freitas Jessica K , Naik Nidhi , Miotto Riccardo , Nadkarni Girish N , Narula Jagat , Argulian Edgar , Glicksberg Benjamin S 
Published: November 2020

Abstract
In the recent decade, deep learning, a subset of artificial intelligence and machine learning, has been used to identify patterns in big healthcare datasets for disease phenotyping, event predictions, and complex decision making. Public datasets for electrocardiograms (ECGs) have existed since the 1980s and have been used for very specific tasks in cardiology, such as arrhythmia, ischemia, and cardiomyopathy detection. Recently, private institutions have begun curating large ECG databases that are orders of magnitude larger than the public databases for ingestion by deep learning models. These efforts have demonstrated not only improved performance and generalizability in these aforementioned tasks but also application to novel clinical scenarios. This review focuses on orienting the clinician towards fundamental tenets of deep learning, state-of-the-art prior to its use for ECG analysis, and current applications of deep learning on ECGs, as well as their limitations and future areas of improvement.