bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hospital volumes and the likelihood of stent implantation among patients undergoing catheterization of the left heart: more is more?
Authors: Oettinger V , Zehender M , Von Zur Muehlen C , Bode C , Kaier K , Stachon P 
Published: November 2020

Abstract

Background
Percutaneous coronary intervention (PCI) is an established procedure, but recent studies analyzing the indication for stenting are going to change clinical practice. Previous studies suggested that hospital volume is inversely related to in-hospital mortality but its impact on likelihood of stent implantation and the number of stents remains unclear.

Purpose
There is a conflict of objectives between nationwide care including short transfer and intervention times and a few large centers with maximum technology and experience. We examine the effect of hospital volume on in-hospital mortality, likelihood of stent implantation, number of stents, length of hospital stay, and reimbursement in a recent nationwide cohort from Germany.

Methods
Using German national electronic health records, all patients who underwent coronary angiography with a documented coronary artery disease were identified by ICD and OPS codes. Risk-adjustment was applied using a predefined set of patient characteristics to account for differences in the risk factor composition of the patient populations between centers.

Results
In 2017, a total of 528,188 patients with a documented coronary artery disease underwent coronary angiography in Germany. Mean age was 69.8 years and 29.3% of patients were female. 55% of all patients received PCI, with a mean number of 1.01 stents implanted per patient. In-hospital mortality was 2.9%, length of hospital stay was 6.5 days and mean reimbursement was €5,531. Multivariable regression analyses showed a positive linear association between hospital volumes and the likelihood of stent implantation (p=0.003) as well as the number of implanted stents (p=0.020). No association was found between hospital volumes and in-hospital mortality (p=0.105), length of hospital stay (p=0.201) or reimbursement (p=0.108). Inspection of the non-linear impact of procedure volumes on stent implantation practices indicates a ceiling effect in the volume-outcome relationship: implantation likelihood and number of stents per patient are lowest in centers with less than 100 procedures per year (34.4% and 0.62, respectively). Then, implantation likelihood and number of stents constantly increase until the volume category of 500 procedures per year and center. For centers with &gt;500 procedures per year, the likelihood of stent implantation and the number of implanted stents remained relatively constant (about 60% and 1.07, respectively).

Conclusion
Patients undergoing coronary angiography in low-volume centers are less frequently subject to PCI but at comparable risk for in-hospital mortality. Furthermore, the data suggest that more complex cases are treated in high volume centers with consistent mortality rates and thus constant safety is ensured in high volume hospitals. Thresholds are discussed.
Impact of hospital volumes on PCI

Funding Acknowledgement
Type of funding source: None
What drives success in models predicting heart failure outcome?
Authors: Gutman R , Shalit U , Caspi O , Aronson D 
Published: November 2020

Abstract

Introduction
The development of acute heart failure (AHF) is a critical decision-point in the natural history of heart failure and carries a dismal prognosis. The lack of appropriate risk-stratification tools for AHF patients limits physician ability to precisely tailor patient-specific therapy regimen at this important juncture. Machine learning (ML) based strategies may enhance risk stratification by incorporating analysis of high-dimensional patient data with multiple covariates and novel prediction methodologies.
In this study, we aimed at evaluating the drivers for success in prediction models and establishing an institute-tailored ML-based prediction model for real-time decision support.

Methods
We used a cohort of all AHF patients admitted during a 12 years period including 10,868 patients. A total of 372 covariates were collected from admission to the end of the hospitalization (demographics, lab-tests, medical therapies, echocardiographic and administrative data). Data preprocessing included features cleaning, train-test split, imputation and normalization. We assessed model performance across two axes (1) type of prediction method and (2) type and number of covariates. The primary outcome was one-year survival from hospital discharge. For the model-type axis we experimented with seven different methods: Logistic Regression (LR), Random Forest (RF), Cox model (Cox), XGBoost, a deep neural-network (NeuralNet) and an ensembled model.

Results
Data pre-processing methodology combined with multiple-covariates achieved an out-ofsample AUROC prediction accuracy of more than 80% with almost all prediction models: L1/L2-LR (80.4%/80.3%); Cox (80.1%); XGBoost (80.7%); NeuralNet (80.5%). The number of covariates was a significant modifier of prediction success (p&lt;0.001), the use of multiple-covariates (372) performed better (AUROC 80.4% for L1-LR) compared with using only a set of known clinical covariates (AUROC 77.8%).

Conclusions
The choice of the predictive modeling method is secondary to the multiplicity and type of covariates for predicting AHF prognosis. The application of a structured data pre-processing combined with the use of multiple-covariates results in an accurate, institute-tailored, risk prediction in AHF.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Yad Hanadiv
Sudden cardiac death in cancer patients: results from the Paris-Sudden Death Expertise Centre
Authors: Mirabel M , Hulot J.S , Lillo-Lelouet A , Jouven X , Marijon E 
Published: November 2020

Abstract

Background
Sudden cardiac death (SCD) in cancer patients regardless of their therapies has not been addressed.

Methods
Population-based registry (2011) via multiple sources to collect every case of SCD in Paris and its suburbs, covering a population of 6.6 million. Data of SCD patients (2011–2017) were analysed by identifying patients with known cancer or past medical history of cancer. Categorical variables were compared using chi-square test or Fisher's exact test; continuous variables using Student t-test or Wilcoxon rank sum test, as appropriate.

Results
Of 22,570 out of hospital cardiac arrests, 3,311 SCD patients (124 cancer patients and 3,187 non cancer patients) were admitted alive to the hospital and were included in the analysis. Characteristics of patients and cardiac arrest circumstances differed on univariate analysis (Table). The final aetiology of SCD varied: more respiratory causes to SCD (pulmonary embolism and hypoxia) among cancer patients and less acute coronary artery syndromes.

Conclusions
SCD in cancer patients differs significantly when compared to non-cancer patients. Coronary events are less prominent whereas respiratory causes are common aetiologies in cancer.

Funding Acknowledgement
Type of funding source: None
The neuro-cardiac junction defines an extracellular microdomain required for neurotrophic signaling
Authors: Mongillo M , Franzoso M , Prando V , Dokshokova L , Di Bona A , Basso C , Gorelik J , Vitiello L , Zaglia T 
Published: November 2020

Abstract

Background
Sympathetic neurons (SNs) innervate the myocardium with a defined topology that allows physiological modulation of cardiac activity. Neurotrophins released by cardiac cells control SN viability and myocardial distribution, which are impaired in heart diseases with reduced (e.g. heart failure) or heterogenous sympathetic stimulation (e.g. arrhythmias). We previously demonstrated that SNs interact directly with cardiomyocytes (CMs) at neuro-cardiac junctions (NCJ), and such structured contact sites allow neurons to efficiently activate β-adrenoceptors on the myocyte membrane.

Aims
We here asked whether NCJs are functional for retrograde (myocyte to neuron) neurotrophic signaling.

Methods and results
Electron microscopy and immunofluorescence on mouse heart slices and SN/CM co-cultures showed that the NGF receptor, TrkA, is preferentially found in correspondence of the NCJ. Consistently, neurons taking structured contact with CMs showed fast TrkA activation and its retrograde transport to the soma, which was monitored using live confocal imaging in cells expressing TrkA-RFP. In accord with NGF dependent effects, CM-contacted SN showed larger synaptic varicosities and did not require NGF supplementation in the culture medium. In support that NGF locally released at NCJs sustains SN viability, the neurotrophin concentration in the culture medium was 1.61 pg/mL, and did not suffice to maintain neuronal viability, which was also perturbed (66% decrease of neuronal density) by silencing NGF expression in CMs. These results support that the NCJ is essential for intercellular neurotrophin signaling. Consistently, by applying competitive inhibition of TrkA with increasing doses of K252a, we estimated NGF concentration at the contact site to be about 1000-fold higher than that released by CM in the culture medium.
To seek for the structural determinants of the NCJ, we focused on dystrophin, based on the finding that the protein accumulates on the CM membrane portion contacted by SNs, as observed in mouse heart slices, and co-cultured CMs. In support of a role of CM-expressed dystrophin in neurotrophic signaling, hearts from dystrophin-KO (mdx) mice showed 74.36% decrease of innervation, with no significant changes of NGF expression. In line with the purported role of NCJs, in co-cultures between wild type SNs and mdx CMs, TrkA activation (TrkA movements toward SN soma (%): WTCM-WTSN=18±4; MDXCM-WTSN= 12±3; p&lt;0,05) and neuronal survival were reduced.

Conclusions
Taken together, our results suggest that NGF-dependent signaling to SNs requires a direct and specialized interaction with myocytes, and that loss of dystrophin at the CM membrane impairs retrograde signaling to the neurons leading to cardiac sympathetic dys-innervation.

Funding Acknowledgement
Type of funding source: Public Institution(s). Main funding source(s): University of Padova
Sirtuin 4 contributes to heart failure development by increasing mitochondrial oxidative stress
Authors: Koentges C , Khan E , Birkle S , Hoelscher M , Pfeil K , Gollmer J , Hoffmann M.M , Bode C , Zirlik A , Bugger H 
Published: November 2020

Abstract

Sirtuin 4 (SIRT4) is a mitochondrial NAD+-dependent deacylase which inhibits the oxidation of glucose and fatty acids, and has been implicated in the regulation of oxidative stress. Given the importance of cardiac energy depletion and ROS during heart failure development, we aimed to define the role of SIRT4 in the development of heart failure. Mice with deletion (SIRT4−/−) or overexpression (SIRT4 TG) of SIRT4 were subjected to transverse aortic constriction (TAC) for 12 weeks or underwent sham procedures. Using echocardiography, ejection fraction (EF) was not different between SIRT4 TG and WT mice subjected to sham operations. In contrast, TAC induced a more pronounced decrease in EF (35% vs. 51%; p&lt;0.05), and a more pronounced increase in LV endsystolic diameter (4.5mm vs. 3.6mm; p&lt;0.05) and myocardial fibrosis (2.2-fold; p&lt;0.05) in SIRT4 TG mice compared to WT mice. Myocardial levels of the lipid peroxidation product 4-hydroxynonenal were increased in WT mice following TAC and were synergistically increased in SIRT4 TG mice following TAC (+66% vs. WT TAC; p&lt;0.05). Administration of the mitochondria-targeted antioxidant MitoQ normalized 4-hydroxynonenal levels, markedly attenuated the decline in EF and almost normalized endsystolic LV diameter in SIRT4 TG mice following TAC. Cardiac function and morphology were unaffected in SIRT4−/− mice during normal or increased workload conditions. Thus, while SIRT4 is not required to maintain cardiac function even in response to increased energy demands, increased expression of SIRT4 accelerates the development of heart failure following TAC, at least in part due to increased mitochondrial oxidative stress.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Research Foundation
Novel mechanism in cardiac injury: immune checkpoints
Authors: Screever E.M , Axelrod M.L , Blair M.A , Trykall D.Z , Barnett J.V , Roden D.M , Johnson D.B , Balko J.M , Meijers W.C , Moslehi J.J 
Published: November 2020

Abstract

Background
Immune checkpoint inhibitors (ICI), specifically directed against CTLA-4 and PD-1, have revolutionized cancer therapy but are associated with immune-related adverse events, including fulminant myocarditis. The mechanisms are unknown, but one possibility is that CTLA-4 and PD-1 play a critical role in cardiovascular homeostasis.

Purpose
The purpose of this study is to investigate the role of these immune checkpoints in cardiac injury. We hypothesize that cardiomyocytes can express immune checkpoint ligands in response to stress and that CTLA-4 and/or PD-1 play a key role in cardiac response to injury.

Methods
We measured expression levels of CTLA-4 ligands (Cd80, Cd86) and PD-1 ligands (Pdcdl1, Pdcdl2) in in vitro and in vivo models of cardiac injury, including iPSC-derived cardiomyocytes (iPSC-CM) and diseased human cardiac samples. Immunofluorescent staining and multiplex immunohistochemistry were used to derive more granular data on cell type expressing specific immune checkpoint associated proteins. To determine the functional role of CTLA-4 and PD-1 in cardiac injury, myocardial infarction (MI) was induced in C57Bl/6 mice treated with anti-CTLA-4 or in mice with a genetic knock-out of CTLA-4 and PD-1 (Pdcd1−/−Ctla4+/+ and Pdcd1−/−Ctla4+/−). Flow cytometry was performed 2-days post-MI to determine immune cell infiltration, echocardiography was performed 7-days and 28-days post-MI and plasma samples were analyzed for ANP and Troponin I.

Results
Doxorubicin or hypoxia increased expression of Cd80, Cd86, Pdcdl1 and Pdcdl2 in iPSC-CM. After MI, isolated cardiomyocytes from the ischemic/border zone area yielded significant increased expression of both Cd80 and Cd86, which was confirmed at the protein level. However, pharmacologic inhibition of CTLA-4 during MI resulted in better survival compared to no treatment (p&lt;0.007). No differences were seen in immune cell infiltration, troponin I and ANP levels and echocardiography. Pdcd1−/-Ctla4+/+ and Pdcd1−/−Ctla4+/− mice showed a decrease in immune cell infiltration.

Conclusions
Whole hearts, isolated cardiomyocytes and iPSC-CM from both mice and humans express immune checkpoint ligands in response to cardiac injury. Pharmacologic or genetic inhibition of CTLA-4 and PD-1 in MI did not result in adverse effects regarding survival, cardiac function, immune cell infiltration and heart enzyme levels in mice. These data support the hypothesis that immune checkpoint pathways play a role in cardiac injury and in these preliminary studies immune checkpoint inhibition during cardiac ischemic injury did not result in adverse effects.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466
Loss of smooth muscle SDF-1/CXCL12 leads to cardiac hypertrophy and aortic valve stenosis
Authors: Ghadge S.K , Messner M , Seiringer H , Zeller T , Boernigen D , Weninger W.J , Geyer S.H , Sopper S , Poelzl G , Tepekoeylue C , Zaruba M.M 
Published: November 2020

Abstract

Background
Stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptors CXCR4/CXCR7 have prominent role in cardiovascular development and myocardial repair following ischemic injury. Nevertheless, detailed mechanisms of the cell specific role of SDF-1 are poorly understood. Since SDF-1-EGFP lineage tracking revealed high expression of SDF-1 in smooth muscle cells, we aimed to investigate the cell specific role by generating a smooth muscle cell specific SDF-1 (SM-SDF-1−/−) knockout mouse model.

Methods
SDF-1 expression was analyzed utilizing SDF-1-EGFP reporter mice. Conditional SM-SDF-1 KO mice were generated using Tagln-Cre; SDF-1fl/fl mice. Hearts were analysed with histology and high-resolution episcopic microscopy. Cardiac function was assessed utilizing echocardiography. RNAseq, qRT-PCR, flow cytometry and western blotting were performed. Cardiac fibrosis, apoptotic index, cell proliferation, aortic valve calcification were analyzed. SM-SDF-1−/− mice were treated with the CXCR7 agonist TC14012 (10mg/kg/I.P).

Results
SDF-1-EGFP lineage tracking and immunofluorescence revealed high expression of SDF-1 particularly in smooth muscle cells and less frequently in perivascular and endothelial cells. Conditional SM-SDF-1−/− mice showed a high pre- and perinatal mortality (50%). Immunohistochemistry of SM-SDF-1−/− mice revealed severe cardiac hypertrophy, associated with increased cardiac fibrosis, apoptotic cell death, thinned and dilated arteries and significantly decreased M2 like CD11b+/CD206+ cells. Echocardiography confirmed concentric hypertrophy, with decreased stroke volume. As a possible reason for cardiac hypertrophy, SDF-1 mutants exhibited aortic stenosis due to aortic valve thickening associated with downregulation of the SDF-1 co-receptor CXCR7. We further noticed increased plasma levels of SDF-1 in aortic stenosis patients suggesting a cardioprotective role. Transcriptome analyses from KO hearts showed an abnormal extracellular matrix (ECM) remodelling with a specific upregulation of the important valve related proteoglycans Versican, Glycan. Western blot analysis revealed activation of AKT and ERK, whereas CXCR7 expression was significantly downregulated in KO mice. To rescue the phenotype we treated KO mice with the CXCR7 agonist (TC14012) which partially attenuated aortic valve remodelling through activation of the ERK signalling pathway.

Conclusion
Our data suggest that SDF-1 is critically involved in maintaining the homeostasis of the aortic valve by regulating CXCR7 signalling. Pharmacological activation of CXCR7 might be a promising therapeutic target to limit the progression of aortic valve stenosis.
Ghadge_SM-SDF-1−/−

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund, Austrian research promotion agency
Human genetic determinants of the gut microbiome and their associations with health and disease: a phenome-wide association study
Authors: Groot H , Van De Vegte Y.J , Verweij N , Lipsic E , Karper J.C , Van Der Harst P 
Published: November 2020

Abstract

Background
Recent small-scale studies have suggested a link between the human gut microbiome and highly prevalent diseases. However, the extent to which the human gut microbiome can be considered a determinant of disease and healthy aging has not been well established. In this study, we aimed to determine the spectrum of diseases that are linked to the human gut microbiome through the utilization of its genetic determinants as a proxy for its composition.

Methods
Data from 422,417 unrelated individuals of Caucasian British ancestry with available genotype and matching genetic data from the UK biobank was analysed in this study. 35 single nucleotide polymorphisms (SNPs) known to influence the human gut microbiome were used to perform the phenome-wide association study. Our main outcome was the probability (risk) of health and disease outcomes associated with human genetic determinants of the microbiome.

Results
From the total sample analysed (mean age was 57±8 years), 194,567 (46%) subjects were male. Median exposure was 66-person years (interquartile range 59 to 72). Seven SNPs known to influence the human gut microbiome were significantly associated with 29 health and disease outcomes (false discovery rate &lt;5%, P value &lt;9.14×10–4) including food intake, health status parameters (inflammation, blood pressure and lipid levels), hypertension, type 2 diabetes mellitus, hypercholesterolemia, heart failure, renal failure, and osteoarthritis.

Conclusions
Human genetic determinants of the gut microbiome are associated with 29 specific health and disease outcomes including hypertension, type 2 diabetes mellitus, hypercholesterolemia, heart failure, renal failure, and osteoarthritis. Microbiota and their metabolites play an important role in the interplay between overlapping pathophysiological processes and could be considered as potential targets for the maintenance of health and reduction of disease risk.
Heat map

Funding Acknowledgement
Type of funding source: None
Circular RNAs as prognostic biomarkers after cardiac arrest
Authors: Stefanizzi F , Zhang L , Nielsen N , Devaux Y , Salgado-Somoza A 
Published: November 2020

Abstract

Background/Introduction
More than 400,000 cases of cardiac arrest (CA) occur every year in Europe and only 10% of these patients survive without major neurological sequelae. Predicting outcome after CA would allow adapting healthcare. However, current prognostication modalities and biomarkers lack accuracy, requiring the discovery of new ones. Previous studies suggest that circulating noncoding RNAs (ncRNAs) constitute a reservoir of novel biomarkers. In particular, circular RNAs (circRNAs), a class of long ncRNAs, appear to have a promising biomarker potential.

Purpose
We aimed to identify circulating circRNAs able to predict neurological outcome and survival after CA.

Methods
Whole blood samples were collected from patients of the Target Temperature Management trial (TTM-trial; NCT01020916) 48h after CA in PAXgene RNA tubes. A discovery phase was conducted by RNA sequencing in a subgroup of 46 patients, among which 23 survived with no major neurological sequelae (cerebral performance category score 1 – CPC1) and 23 died within 6 months (CPC5). A validation phase was conducted by quantitative RT-PCR in 542 patients. Logistic regression was used to assess the association between circRNAs and 6-month neurological outcome. Kaplan Meier curves and Cox regression were used to test the ability of circRNAs to predict patients' survival at 6 months.

Results
The discovery phase identified 282 circRNAs in blood samples. Among these, twenty-one circRNAs were differentially expressed between patients with CPC1 and patients with CPC5 (p&lt;0.05). Experiments using RNAse R digestion confirmed the circularity of selected circRNAs. In the validation phase with 542 patients, one circRNA (circ016) was differentially expressed between patients with good neurological outcome at 6 months (CPC1–2) compared to patients with poor neurological outcome (CPC3–5) (p&lt;0.001). Univariate analysis confirmed the association between circ016 and neurological outcome (odds ratio (OR) [95% confidence interval (CI)] 6.1 [2.2–16.7]). After adjustment with clinical and demographic parameters, circ016 remained a significant predictor of neurological outcome (OR [95% CI] 6.0 [1.4–26.1]) (Figure 1). In Kaplan-Meier analysis, circ016 was associated with 6-month survival (log rank test p&lt;0.001). In Cox regression, circ016 predicted 6-month survival with a hazards ratio of 4.4 [2.1–9]. Patients with high levels of circ016 were at high risk of poor neurological outcome and death.

Conclusions
Circulating levels of circRNAs measured 48h after CA are associated with neurological outcome and survival at 6 months. We have identified several circRNAs with potential to aid in outcome prediction after CA. These circRNAs remain to be independently validated in large patient cohorts.
Figure 1

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Research Fund of Luxembourg, Ministry of Higher Education and Research of Luxembourg