bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient Selection for Routine Troponin Monitoring After Noncardiac Surgery
Authors: Weersink Corien S. A. , van Waes Judith A. R. , Grobben Remco B. , Nathoe Hendrik M. , van Klei Wilton A. 
Published: July 2021

Background
Myocardial infarction is an important complication after noncardiac surgery. Therefore, perioperative troponin surveillance is recommended for patients at risk. The aim of this study was to identify patients at high risk of perioperative myocardial infarction (POMI), in order to aid appropriate selection and to omit redundant laboratory measurements in patients at low risk.

Methods and Results
This observational cohort study included patients ≥60 years of age who underwent intermediate to high risk noncardiac surgery. Routine postoperative troponin I monitoring was performed. The primary outcome was POMI. Classification and regression tree analysis was used to identify patient groups with varying risks of POMI. In each subgroup, the number needed to screen to identify 1 patient with POMI was calculated. POMI occurred in 216 (4%) patients and other myocardial injury in 842 (15%) of the 5590 included patients. Classification and regression tree analysis divided patients into 14 subgroups in which the risk of POMI ranged from 1.7% to 42%. Using a risk of POMI ≥2% to select patients for routine troponin I monitoring, this monitoring would be advocated in patients ≥60 years of age undergoing emergency surgery, or those undergoing elective surgery with a Revised Cardiac Risk Index class >2 (ie >1 risk factor). The number needed to screen to detect a patient with POMI would be 14 (95% CI 14–14) and 26% of patients with POMI would be missed.

Conclusions
To improve selection of high‐risk patients ≥60 years of age, routine postoperative troponin I monitoring could be considered in patients undergoing emergency surgery, or in patients undergoing elective surgery classified as having a revised cardiac risk index class >2.
Targeting Hypertension Screening in Low‐ and Middle‐Income Countries: A Cross‐Sectional Analysis of 1.2 Million Adults in 56 Countries
Authors: Kirschbaum Tabea K. , Theilmann Michaela , Sudharsanan Nikkil , Manne‐Goehler Jennifer , Lemp Julia M. , De Neve Jan‐Walter , Marcus Maja E. , Ebert Cara , Chen Simiao , Aryal Krishna K. , Bahendeka Silver K. , Norov Bolormaa , Damasceno Albertino , Dorobantu Maria , Farzadfar Farshad , Fattahi Nima , Gurung Mongal S. , Guwatudde David , Labadarios Demetre , Lunet Nuno , Rayzan Elham , Saeedi Moghaddam Sahar , Webster Jacqui , Davies Justine I. , Atun Rifat , Vollmer Sebastian , Bärnighausen Till , Jaacks Lindsay M. , Geldsetzer Pascal 
Published: July 2021

Background
As screening programs in low‐ and middle‐income countries (LMICs) often do not have the resources to screen the entire population, there is frequently a need to target such efforts to easily identifiable priority groups. This study aimed to determine (1) how hypertension prevalence in LMICs varies by age, sex, body mass index, and smoking status, and (2) the ability of different combinations of these variables to accurately predict hypertension.

Methods and Results
We analyzed individual‐level, nationally representative data from 1 170 629 participants in 56 LMICs, of whom 220 636 (18.8%) had hypertension. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or reporting to be taking blood pressure–lowering medication. The shape of the positive association of hypertension with age and body mass index varied across world regions. We used logistic regression and random forest models to compute the area under the receiver operating characteristic curve in each country for different combinations of age, body mass index, sex, and smoking status. The area under the receiver operating characteristic curve for the model with all 4 predictors ranged from 0.64 to 0.85 between countries, with a country‐level mean of 0.76 across LMICs globally. The mean absolute increase in the area under the receiver operating characteristic curve from the model including only age to the model including all 4 predictors was 0.05.

Conclusions
Adding body mass index, sex, and smoking status to age led to only a minor increase in the ability to distinguish between adults with and without hypertension compared with using age alone. Hypertension screening programs in LMICs could use age as the primary variable to target their efforts.
Association of Socioeconomic Disadvantage With Mortality and Readmissions Among Older Adults Hospitalized for Pulmonary Embolism in the United States
Authors: Wadhera Rishi K. , Secemsky Eric A. , Wang Yun , Yeh Robert W. , Goldhaber Samuel Z. 
Published: July 2021

Background
In the United States, hospitalizations for pulmonary embolism (PE) are increasing among older adults insured by Medicare. Although efforts to reduce health disparities have intensified, it remains unclear whether clinical outcomes differ between socioeconomically disadvantaged and nondisadvantaged Medicare beneficiaries hospitalized with PE.

Methods and Results
In this study, there were 53 386 Medicare fee‐for‐service beneficiaries age ≥65 years hospitalized for PE between October 2015 and January 2017. Of these, 5494 (10.3%) were socioeconomically disadvantaged and 47 892 (89.7%) were nondisadvantaged. Socioeconomically disadvantaged adults were of similar age as nondisadvantaged adults (77.1 versus 77.0), more likely to be female (68.5% versus 54.2%), and less likely to receive advanced therapies (11.0% versus 12.1%). After adjustment for demographics, 90‐day all‐cause mortality rates were similar between disadvantaged and nondisadvantaged adults. In contrast, 1‐year mortality rates were higher among socioeconomically disadvantaged adults (hazard ratio [HR], 1.16; 95% CI, 1.10–1.22), although these differences were partially attenuated after additional adjustments for comorbidities and PE severity (HR, 1.09; 95% CI, 1.02–1.16). Risk‐adjusted 30‐day and 90‐day all‐cause readmission rates were substantially higher among socioeconomically disadvantaged patients (30‐day HR, 1.14 [95% CI, 1.06–1.22]; 90‐day HR, 1.18 [95% CI, 1.12–1.25]). In addition, 90‐day readmissions attributed to PE, deep vein thrombosis, and/or bleeding were higher among socioeconomically disadvantaged patients (HR, 1.16; 95% CI, 1.02–1.32).

Conclusions
Socioeconomically disadvantaged older adults hospitalized with PE have higher 1‐year mortality rates compared with their nondisadvantaged counterparts. Nearly 1 in 3 socioeconomically disadvantaged older adults was readmitted within 90 days of a hospitalization for PE. Targeted strategies are needed to improve transitional and ambulatory care for this vulnerable population.
Cardiovascular Development and Congenital Heart Disease Modeling in the Pig
Authors: Gabriel George C. , Devine William , Redel Bethany K. , Whitworth Kristin M. , Samuel Melissa , Spate Lee D. , Cecil Raissa F. , Prather Randall S. , Wu Yijen , Wells Kevin D. , Lo Cecilia W. 
Published: July 2021

Background
Modeling cardiovascular diseases in mice has provided invaluable insights into the cause of congenital heart disease. However, the small size of the mouse heart has precluded translational studies. Given current high‐efficiency gene editing, congenital heart disease modeling in other species is possible. The pig is advantageous given its cardiac anatomy, physiology, and size are similar to human infants. We profiled pig cardiovascular development and generated genetically edited pigs with congenital heart defects.

Methods and Results

Pig conceptuses and fetuses were collected spanning 7 stages (day 20 to birth at day 115), with at least 3 embryos analyzed per stage. A combination of magnetic resonance imaging and 3‐dimensional histological reconstructions with episcopic confocal microscopy were conducted. Gross dissections were performed in late‐stage or term fetuses by using sequential segmental analysis of the atrial, ventricular, and arterial segments. At day 20, the heart has looped, forming a common atria and ventricle and an undivided outflow tract. Cardiac morphogenesis progressed rapidly, with atrial and outflow septation evident by day 26 and ventricular septation completed by day 30. The outflow and atrioventricular cushions seen at day 20 undergo remodeling to form mature valves, a process continuing beyond day 42. Genetically edited pigs generated with mutation in chromatin modifier
SAP130
exhibited tricuspid dysplasia, with tricuspid atresia associated with early embryonic lethality.

Conclusions
The major events in pig cardiac morphogenesis are largely complete by day 30. The developmental profile is similar to human and mouse, indicating gene edited pigs may provide new opportunities for preclinical studies focused on outcome improvements for congenital heart disease.
Abstract 114: Allogeneic Cardiosphere-Derived Cells Are Safe and Effective in a Pig Model of Myocardial Infarction
Authors: Smith Rachel R , Kreke Michelle , Malliaras Konstantinos , Kanazawa Hideaki , Huang Christene A , Valle Ileana , Blusztajn Agnieszka , Yee Kristine , Sachs David H , Terrovitis John , Marban Linda 
Published: July 2021

Allogeneic cardiosphere-derived cells (CDCs) have proven safe and effective in a small animal model of myocardial infarction (MI), and have been shown to act primarily via paracrine mechanisms to stimulate endogenous regeneration. The present translational study tested allogeneic CDCs in a large animal model (mini-pigs).
To establish a robust allogeneic model, all pigs were swine leukocyte antigen (SLA) typed by PCR. A male donor and female recipients with full SLA I, II mismatch were used. Pigs underwent balloon occlusion of the LAD for 2.5 hours, followed by reperfusion. Two weeks later, 12.5 million CDCs (n=8) or vehicle (n=6) were infused. Animals were sacrificed 2 weeks or 2 months post-infusion to assess the cellular (histology using a clinical rejection scale) and humoral (donor-specific antibodies, complement-dependent cytotoxicity) immune responses, as well as cardiac function (left ventriculography, hemodynamics, morphometry). Numerous in-life assessments for safety were performed and CDC engraftment was assessed by FISH for Y chromosome.
All immunological assays indicated an undetectable response to CDCs. Cardiac enzymes and systemic inflammation showed no differences between groups. There were no systemic histological findings related to CDCs. CDCs did not permanently engraft, with <0.1% persisting 2 weeks post-infusion and none evident 2 months post. Despite evanescent engraftment, functional benefits were seen following infusion of CDCs. Ejection fraction (EF) and infarct size (IS) were significantly improved in CDC-treated animals compared to vehicle-treated 2 weeks post-infusion (EF: 48.6±2.1% vs 38.2±2.6%, p<0.05; IS: 9±2 vs 14±2%, p<0.05). At 2 months, EF still trended higher in CDC-treated animals (42±5 vs 32±10%, p=0.09), and IS still trended lower (14±4 vs 16±7%, p=0.60). Pressure-volume relationships revealed a trend for enhanced contractility in CDC-treated animals (Emax: 3.2±2.2 vs 1.0±1.1 mmHg/mL, p=0.26). The magnitude of the functional benefits was similar to that seen in a prior pig study using autologous CDCs.
Overall, results of the present study demonstrate that allogeneic CDCs are largely equivalent to autologous in terms of efficacy, and elicit no detectable immunological response or safety concern.
Abstract 183: A Genomewide Screen to Identify Novel NFAT Regulators
Authors: Maillet Majorie , Blair N Scott , Molkentin Jeffery D 
Published: July 2021

NFAT (Nuclear Factor of Activated T cells) transcriptions factors are directly activated by the Ca2+	activated serine-threonine protein phosphatase calcineurin. Following dephosphorylation, NFAT factors translocate to the nucleus. They share a Rel/NFkB homology DNA binding domain that functions in concert with other transcription factors such as AP-1, GATA4, NFkB, MEF2, CREB, Myc, and IRF-1 to alter the expression of genes involved in tissue and cellular differentiation as well as adaptation to extracellular stimuli. Although the fundamental aspects of how NFAT factors are regulated by phosphorylation and dephosphorylation, as well as some interacting factors, have been described; much remains to be understood about the function of these factors in cardiac myocytes and other cell types. To identify potential new NFAT regulators that could influence nuclear shuttling or its trans-activating properties, we performed a genome wide screen with a NFAT-dependent luciferase reporter and a library of cDNA expression plasmids. Roughly 20,000 cDNA expression plasmids from the Mammalian Genome Collection were individually co-transfected with a NFAT-luciferase reporter in a human immortalized cell line in 384-well plates. Approximately 2% of the genes of the library gave a positive result, including well-known NFAT partners, calcium sensitive genes and transcriptions factors. Among them, twenty potential NFAT activators were selected and NFAT-Luciferase activation was validated in a secondary screen which normalized for transfection efficiency and cell number. The results of the screen will be presented along with functional characterization of the more interesting interacting NFAT co-activators.
Abstract 273: P2Y2 Receptor-Mediated Lymphotoxin-α Secretion Regulates ICAM-1 Expression in Smooth Muscle Cells
Authors: Seye Cheikh , Derbigny Wilbert , Qian Shaomin 
Published: July 2021

Rationale: Single nucleotide polymorphism (SNP) in the LGASL2 galectin-2 (Gal-2) gene leads to altered secretion of lymphotoxin-α (LT-α) and is associated with coronary artery disease.
Objective:Our aim was to determine whether factors other than genetic variations in LGASL2 regulate LT-α release and to define the role of this pro-inflammatory in vascular smooth muscle cells (SMC).

Methods and results: The proinflammatory cytokine lymphotoxin-alpha (LTA) is thought to contribute to the pathogenesis of atherosclerosis. However, the mechanisms that regulate its expression in VSMC are poorly understood. The ability of exogenous nucleotides to stimulate LTA production was evaluated in VSMC by ELISA. The P2Y
2
nucleotide receptor (P2Y
2
R) agonist UTP stimulates a strong and sustained release of LTA from wild-type but not P2Y
2
R
-/-
SMC. Assessment of LTA gene transcription by LTA promoter-luciferase construct indicated that LTA levels are controlled at the level of transcription. We show using RNAi techniques that knockdown of the actin-binding protein filamin-A (FLNa) severely impaired nucleotide-induced Rho activation and consequent Rho-mediated LTA secretion. Re-introduction of FLNa in FLNa RNAi SMC rescued UTP-induced LTA expression. In addition, we found UTP-stimulated LTA secretion is not sensitive to brefeldin A (BFA), which blocks the formation of vesicles involved in protein transport from the ER to the Golgi apparatus, suggesting that P2Y
2
R/filamin-mediated secretion of LTA is independent of the ER/Golgi secretory vesicle route. Furthermore, UTP selectively induces ICAM-1 expression in WT but not SMC expressing a truncated P2Y
2
R deficient in LTA secretion.

Conclusion: These data suggest that P2Y
2
R recruits FLNa to provide a cytoskeletal scaffold necessary for Rho signaling pathway upstream of LTA release and subsequent stimulation of ICAM-1 expression on VSMC.
Abstract 277: Development of Anxiety- and Depression-Like Behavior in Mice After Myocardial Infarction
Authors: Frey Anna , Popp Sandy , Post Antonia , Lehmann Marc , Sirén Anna-Leena , Ertl Georg , Lesch Klaus-Peter , Frantz Stefan 
Published: July 2021

Objective: Anxiety and depression are common and independently predict mortality in patients with heart failure. The mechanisms of these interrelations are still unclear. Consequently, we developed a model in C57BL/6 mice with experimental myocardial infarction (MI) and heart failure to study anxiety- or depression-like behavior.
Methods: Heart failure was achieved after coronary artery ligation in 13 mice; 16 sham operated mice acted as controls. Left ventricular (LV) remodeling was assessed by echocardiography, infarct size by histology. Sucrose preference test was performed over a period of 8 weeks to assess depression-like behavior. The elevated plus maze (EPM), the light-dark box (LDB) and the open field (OF) tests were subsequently applied to determine general disinterest and anxiety-like behavior. Finally, the histological and immunohistochemical evaluation of the brain was performed.
Results: Mice with MI size of at least 30% of LV (averaged 50±3%; increase in diastolic LV diameter from 0.40±0.02 cm to 0.62±0.03 cm) showed diminished intake (p=0.029) and preference (p=0.029) for sucrose solution. Besides, MI mice exhibited reduced exploratory behavior and markedly lower interest in unfamiliar environments, indicated by an increase in center time (p=0.016) and a reduced number of vertical rears (p=0.037) in the EPM. An increased latency to the first rear (p=0.018), covered shorter distances (p=0.048) and spent less time moving (p=0.028) in the OF were found in MI mice. MI did not affect anxiety-related measures in all three tests (all p>0.05). MI mice showed normal brain morphology with normal neuronal morphology and neuropil structure, also confirmed by normal expression of selected neuronal markers. Markers for neurodegeneration, apoptosis or inflammation showed no abnormalities in MI mice.
Conclusions: Mice with MI exhibited anhedonia-like behavior, which was accompanied by other characteristics of depression-like behavior, such as decreased exploratory activity and interest in novelty. Hence, MI caused distinct behavioral changes in mice comparable to symptoms observed in humans with heart failure and comorbid depression, but did not affect anxiety-like behavior. The model is suitable for further mechanistic studies.
Abstract 28: In Vivo Knockdown of Mirna-15b Results in Increased Cardiac Hypertrophy and Fibrosis in Response to Pressure Overload of the Mouse Heart
Authors: Tijsen Anke J , van der Made Ingeborg , van Deel Elza D , Hiller Monika , Reckman Yolan J , Duncker Dirk J , Pinto Yigal M , Creemers Esther E 
Published: July 2021

MiRNAs play an important role in the control of diverse aspects of cardiac function. MiR-15b is highly expressed in the heart and is found consistently upregulated in hypertrophic and failing hearts. To investigate the function of miR-15b in the heart we set out two experiments. In the first experiment we generated two independent transgenic mouse lines that drive miR-15b expression under the αMHC-promotor and show a three and four fold overexpression of miR-15b. Strikingly, both lines show a decrease in heart weight/tibia length of 20% in adult and aged mice when compared to littermate controls. We investigated the response of these transgenic mice to thoracic aorta constriction (TAC) and found no differences in the hypertrophic response or in cardiac function measured by echocardiography between wild-type and transgenic mice. In a second experiment, we inhibited miR-15b using LNA-based antimiRs. In these mice, TAC resulted in an increased hypertrophic response and increased cardiac fibrosis when compared to a negative control antimiR.
A wide range of predicted targets of miR-15 belong to the pathways of the TGFβ-superfamily and using a smad-dependent reporter we show that miR-15b inhibits TGFβ-induced Smad activity in HepG2 cells. One of the predicted targets in the TGFβ pathway is TGFβ receptor 1 (TGFβR1), of which the 3’UTR contains six predicted miR-15 binding sites. This suggests that the phenotype in the transgenic mice and after knockdown of miR-15b may be (partly) mediated by repression of TGFβR1. Indeed, in the adult miR-15b transgenic hearts we found a downregulation of TGFβR1 mRNA and protein and we confirmed binding of miR-15 to the TGFβR1 3’UTR by luciferase assays.
In conclusion, miR-15b causes a cardiac hypotrophic phenotype at baseline in transgenic mice and inhibition of miR-15b leads to a stronger hypertrophic and fibrotic response after TAC. Furthermore miR-15b inhibits the TGFβ pathway by targeting the TGFβR1 and possibly other targets in this pathway.
This research is funded by the Dutch Heart Foundation (NHF grant #2007B077).
Abstract 283: The Coupling of Tumor Endothelial Marker-8 and Capillary Morphogenesis Gene-2 Receptors to Contractile-Related Signaling Pathway in Cardiac Myocytes
Authors: Nizamutdinov Damir , Golden Honey B , Feng Hao , Gerilechaogetu Fnu , Foster Donald M , Tong Carl W , Glaser Shannon S , Dostal David E 
Published: July 2021

Recent molecular and pharmacological studies performed on non-cardiac tissues suggest that tumor endothelial marker-8 (TEM-8), also known as anthrax toxin receptor 1 (ANTXR1) and capillary morphogenesis gene-2 (CMG-2), known as anthrax toxin receptor 2 (ANTXR2) regulate survival, proliferation, cell shape, as well as polarity, adhesion, migration and differentiation. However, downstream signaling mechanisms and function of these molecules have not been studied. Recent studies indicate that activation of protein kinase B (Akt) and c-Jun N-terminal kinases (JNK) have been associated with hypertrophic growth, as well as regulation of contractility in cardiac myocytes (CM).
In this study we’ve investigated the role of ANTXR1 and ANTXR2 receptors in intracellular pathways of contractility regulation in neonatal rat ventricular myocytes (NRVM).

Primary culture of NRVM was used to determine the effects of ANTXR1/ANTXR2 activation on Akt and JNK phosphorylation by Western blot analysis. Flow cytometry and immunostaining of alive CM were used to determine expression levels and distribution of anthrax receptors throughout the cells. Furin-activated form of anthrax protective antigen (PA
63
) was used in order to selectively stimulate ANTXR1/ANTXR2 receptors and get understanding of downstream signaling mechanisms coupled to them. The treatments with angiotensin II, type1 receptor (AT
1
) inhibitors were used in order to separate responses of distinct regulatory pathways of contractility. All treatments were done at variable time courses started in seconds and finished in half of hour to determine a sequence of phosphorylation reactions going from cellular membrane to deep inside of cell. As a result, abundant expression of both receptors was observed in cardiac myocytes. Activation of one phospho-site of focal adhesion kinase (FAK
861
) was started in 15 sec with subsequent phosphorylation of JNK and Akt
473
in 5 and 10 minutes. Involvement of new molecules was observed in cascade chain reaction of contractility regulation.

In conclusion, ANTXR1/ANTXR2 were demonstrated to couple to mechano-sensor molecules: FAK, Akt and JNK, as well as interact with the AT
1
receptors to mediate downstream signaling events responsible for regulation of contractility.