bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic nutrition index predicts outcomes in critically ill stroke patients: a database-based cohort study
Authors: Zhang B , Zhu Q , Lu Z 
Published: October 2021

Abstract

Background
Although there are many indicators to assess nutritional status, a more comprehensive and objective indicator is still needed in clinical practice. In this study, we evaluated the relationship between the prognostic nutritional index (PNI) and clinical outcomes in patients with critically ill stroke.

Methods
Subjects who were diagnosed as stroke in the Beth Israel Deaconess Medical Center between 2001 and 2012 were identified from the Medical Information Mart for Intensive Care (MIMIC) III database. PNI was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). The multivariate logistic regression and the Cox regression analysis were performed to assess the impact of PNI on 3-month and 4-year mortality in stroke patients.

Results
A total of 624 subjects were included in this study. Compared with the high-PNI group, those in the Low PNI group had lower body mass index (BMI), hemoglobin, neutrophil count, lymphocyte count and albumin. On the contrary, Age, Blood urea nitrogen (BUN), Creatinine (Cre), simplified acute physiologic scoreII (SAPSII) score and sequential organ failure assessment (SOFA) score of the low PNI group were higher than the high PNI group. After adjusting for other confounders, PNI was independently associated with 3-month mortality (adjusted odds ratio = 1.910; 95% confidence interval, 1.244–2.933; P=0.003). By the Kaplan-Meier analysis, patients in the low PNI group presented significantly shorter survival time and higher death rate. The Cox regression model indicated low PNI as an independent risk factor of 4-year all-cause mortality of stroke patients (hazard ratio = 1.824; 95% CI, 1.340–2.483; P&lt;0.001).

Conclusions
Low PNI is independently associated with short-term and long-term prognosis in patients with critically ill stroke.

Funding Acknowledgement
Type of funding sources: None.
Exploring biomarkers of age in routine diagnostics for the risk stratification of older patients in the emergency department
Authors: Bahrmann P , Kunz A L , Schoenstein A , Giannitsis E , Wahl H.-W , Katus H , Frey N , Bahrmann A 
Published: October 2021

Abstract

Objectives
To estimate the association of the routinely applied biological age-related biomarkers hs-TnT, CRP and Hemoglobin (Hb) with mortality for the purpose of older patient's risk stratification in the emergency department (ED).

Design
Exploratory, prospective cohort study with a follow-up at 2.5 years after recruitment start.

Setting and participants
A cardiological emergency department (ED), chest pain unit, of our University Hospital. N=256 cardiological ED patients with a minimum age of 70 years and with an expected life-expectancy above 24h.

Methods
Data from the hospital files were supplemented by a questionnaire. Patients were followed-up for mortality by requesting registry office information.

Results
Among N=256 patients 63 died over the follow-up period. Positive results in each of the three biomarkers alone as well as the combination were associated with increased all-cause mortality at follow-up. The number of positive age-related biomarkers appeared to be strongly indicative of the risk of mortality, even when controlled for major confounders (age, sex, BMI, creatinine clearance, and comorbidity).

Conclusion and implications
In older ED patients, biomarkers explicitly related to biological aging processes such as hs-TnT, CRP and Hb were independently of each other as well as combined associated with an increased risk of all-cause mortality. Thus, they may have the potential to be used to supplement the general risk stratification of older patients in the ED. Validation of the results in a large dataset is needed.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Robert Bosch Foundation, Stuttgart, Germany Kaplan-Meier curves with 95% CIKaplan-Meier curves for patients grouped
Bleeding risk in patients with atrial fibrillation treated with combined anti-platelet and NOAC therapy
Authors: Kim Y R , Shin D G , Kim S 
Published: October 2021

Abstract

Background
The combined use of antiplatelet agents (APT) and non-vitamin K antagonist oral anticoagulants (NOACs) in patient with atrial fibrillation (AF) is commonly encountered in clinical practice. The purpose of this study was to compare the clinical outcomes between combination therapy (NOAC and APT) and monotherapy (NOAC only).

Methods and results
We analyzed patients who were prescribed NOACs between January 2012 and December 2016. The primary outcome was major or any bleeding events and the secondary outcomes were stroke/systemic embolism (SE) and major adverse cardiac events (MACE). Of 1,068 participants, there were 264 (24.7%) patients in the combination group.
The prevalence of diabetes (p=0.017) and history of stroke and transient ischemic attacks (p&lt;0.001) was higher in the combination group than in the monotherapy group. During the mean 14.6±9.8 months of follow-up, the incidence of any bleeding was significantly higher in the combination group than in the monotherapy group (p&lt;0.001). Major bleeding, stroke/SE, and MACE between the two groups were similar. The rate of under-dosage NOACs prescriptions was higher in the combination group than in the monotherapy group (p=0.024).

Conclusions
The combination therapy had higher incidences of any bleeding events compared to the monotherapy. However, there was no difference in stroke/SE and MACE.
The bleeding risk in patients taking the combination of NOACs and APT should be carefully evaluated.

Funding Acknowledgement
Type of funding sources: None. Figure 1. Primary and secondary outcomes
Expressing a truncated SARS-COV-2 spike protein in mouse heart induces cardiac hypertrophy
Authors: Negron S , Kessinger C , Lin Z 
Published: October 2021

Abstract

Cardiac injury is common in hospitalized and non-hospitalized COVID-19 patients, for which systemic inflammation stress is one of the causes (Topol, 2020). Although rare, COVID-19 cases that SARS-CoV-2 infecting cardiomyocytes (CMs) have been reported. In vitro, SARS-CoV-2 infection of human induced-pluripotent-cells derived CMs triggered innate immune responses and induced apoptosis (Bojkova et al., 2020; Chen et al., 2020). Therefore, the current literature indicates that the heart is attacked by SARS-CoV-2 directly or indirectly; however, the underlying mechanism remains largely unknown. Involved in the pathogenesis of heart diseases, Toll-like receptors (TLR) are a family of pattern recognition receptors that sense the pathogenic stimuli and signal the cardiac residential cells to cope with harsh conditions (Yu and Feng, 2018). Among the best characterized TLR signaling pathways is TLR4/NF-kB axis (Lu et al., 2008), in which TLR4 convey the danger signals through its down stream kinases, such as TAK1 and TBK1, to activate NF-kB. SARS-CoV-2 Spike protein is well known for its role of mediating virus entry into host cells, but its immunogenic role has not been clearly defined. Recently, we have found that SARS-CoV-2 Spike protein directly interacts with TLR4 and activates NF-kB transcriptional activity. Pharmaceutically blocking either TBK1 or TAK1 attenuates Spike protein's immunogenic activity. To pinpoint Spike protein's role in the heart, we generated an AAV to specifically express a truncated Spike protein (S1-TM) in the CMs. Our data show that expressing S1-TM in CMs induces cardiac hypertrophy and decreases heart systolic function in mice. On the molecular level, Spike protein increases RelA (p65 subunit of the NF-kB complex) and activates the expression of pro-inflammatory cytokine genes. In summary, our study suggests that Spike protein directly interacts with TLR4 to trigger innate immune signaling, and that Spike protein induced CM innate immune responses might be one of the underlying mechanisms of cardiac injury in COVID-19.

Funding Acknowledgement
Type of funding sources: Other. Main funding source(s): Masonic Medical Research Institute
Altered atrial restitution dynamics and refractoriness in metabolic syndrome due to up-regulation of potassium repolarizing currents increases susceptibility to atrial fibrillation
Authors: Calvo C J , Rodriguez A , Almar E , Arias O , Lozano W , Alberola A , Zarzoso M 
Published: October 2021

Abstract

Background
Metabolic alterations, such as Metabolic Syndrome (MS), describe an association of factors including diabetes, hypertension, obesity and dyslipidemia, linked to higher risk and prevalence of overall cardiovascular disease, arrhythmogenesis and sudden cardiac death. Obese and diabetic patients have shown an increased risk for developing atrial fibrillation (AF). However, underlying mechanisms are not understood.

Purpose
To study the effects of MS and obesity remodeling in atrial restitution dynamics, frequency-dependent adaptation, refractoriness and its potential susceptibility to AF.

Methods
Electrophysiological experimental data from High-fat (HF-O, standard rabbit chow with an additional 15% fat) and Hig-fat High-Sucrose Metabolic Syndrome (HFHS-MS, 10% hydrogenated coconut oil and 5% lard, 15% high-sucrose dissolved in water) rabbit models were used to adjust computational models atrial electrophysiology remodeling under each condition. Additionally, isoproterenol and AF conditions were considered to challenge both in-silico models. Validation and sensitivity analysis were performed for each model parameters. Computational simulations in conditions of pacing at different pacing cycle lengths was assessed at 100, 125, 150, 200, 250, 350, 450, 500, 650, 750, 850, 1000 ms. Restitution dynamics were automatically determined and analyzed, as well as restitution slopes and presence of automaticity, early after-depolarizations, alternans and cardiac arrhythmia induction.

Results
Shortening of action potential duration and refractoriness in the left atrium was observed under HFHS-MS. Upstroke velocity, maximum excitability and sodium availability were altered both in HF-O and HFHS-MS. HF-O remodeling showed presence of alternans at high pacing frequencies. Repolarization restitution was shortened in conditions of ISO and MS-AF. Restitution slopes were &gt;1 in HF-O and HFHS-MS, which was correlated to higher susceptibility to AF, and further increased in MS-AF. Under MS-AF, abbreviation in APD in both atria, resulted in increased reentrant frequencies in AF, which was exacerbated under IK1 up-regulation, increasing atrial vulnerability.

Conclusions
HFHS-MS underlies modifications in atrial electrophysiology including shorter refractoriness in HFHS-MS, as well as modifications in atrial excitability, which may be pro-arrhythmic mainly at high frequency rates. This could be explained in part by an up-regulation of outward potassium channels. These results could partially explain increased susceptibility for AF in MS.

Funding Acknowledgement
Type of funding sources: None.
Monounsaturated fatty acid antagonizes saturated fatty acid-induced cardiomyopathy via improving membrane fatty acid composition and endoplasmic reticulum stress
Authors: Yamamoto T Y , Endo J E , Shinmura K S , Sano M S , Fukuda K F 
Published: October 2021

Abstract

Background
Obesity-induced lipotoxicity causes cardiac dysfunction in our modern lifestyle. Previously, we have shown that an increase in cardiomyocyte membrane saturated fatty acid (SFA)/ monounsaturated FA (MUFA) ratio mediates endoplasmic reticulum (ER) stress, which was implicated in the pathogenesis of SFA-induced cardiomyopathy. Furthermore, SFA supressed Sirt1/ stearoyl-CoA desaturase-1 (SCD1, converting enzyme from SFA to MUFA) signaling, which further worsened the membrane SFA/MUFA ratio.

Purpose
To evaluate the effectiveness of targeting membrane fatty acid composition by MUFA.

Methods and results
In wild-type mice, 16-weeks SFA-rich high lard diet feeding (HLD) caused activation of PPARα signaling and the accumulation of toxic lipid intermediates (diacylglycerol and ceramide) in the heart to the same extent as a MUFA-rich high olive oil diet feeding (HOD). However, only the HLD impaired Sirt1 activity, SCD1 expression, diastolic function (increased left ventricular end-diastolic pressure (LVEDP) and end-diastolic pressure-volume relationship (EDPVR)), and cardiac remodeling (hypertrophy and fibrosis). Lipidome analysis showed that HLD-induced diastolic dysfunction coincided with an increase in membrane SFA/MUFA ratio and ER stress induction. 8-weeks HOD after 8-weeks HLD (HOD switch) showed the same degree of obesity and PPARα activation with 16-weeks HLD. By contrast, HOD switched heart were less severe Sirt1/SCD1 signaling dysregulation, increased in membrane SFA/MUFA ratio, ER stress, and cardiomyopathy (hypertrophy, fibrosis, and diastolic dysfunction) compared to 16-weeks HLD. Moreover, in cardiomyocyte-specific Sirt1 knockout mice, HOD switched heart also showed less severe increase in membrane SFA/MUFA ratio, ER stress, and cardiomyopathy compared to 16-weeks HLD although decreased SCD1 expression was not changed.

Conclusions
We demonstrated that MUFA-rich diet counteracted SFA-induced Sirt1/SCD1 signaling dysregulation and prevented SFA-induced increase in membrane SFA/MUFA ratio. Hence, MUFA-rich diet antagonized SFA-induced ER stress and cardiomyopathy even if Sirt1 deactivated heart (e.g., aged heart). Targeting the cardiomyocyte membrane SFA/MUFA ratio by MUFA might have a new therapeutic potential for SFA-induced cardiomyopathy.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): JSPS KAKENHI
Autonomic and cardiac evaluation upon sub-therapeutic doxorubicin administration
Authors: Amaro-Leal Â , Machado F , Afonso A I , Rocha I , Geraldes V 
Published: October 2021

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent that improves the survival and quality of life of patients with solid tumours. However, these improvements are counterbalanced by various dose-dependent side effects including cardiac dysfunction, which may occur in a subset of patients leading to treatment discontinuation. In addition, despite overall insufficiently studied, available data clearly show that women are more susceptible to drugs toxicity due to sex differences in drug metabolism or sensitivity. Regarding doxorubicin, apart its acute toxicity, women are also more vulnerable to late cardiotoxicity. Currently, there are no robust clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline and, despite treatment personalization, subclinical signs of toxicity are not yet well identified.
Thus, in the present work, we sought to characterize the toxic effects of a sub-therapeutic dose of doxorubicin upon cardiovascular and autonomic function. For that, adult healthy female wistar rats (n=14), aged &gt;3 months, were intraperitoneally treated with doxorubicin (2 mg/kg) at weekly intervals for up to 4 weeks. A control (Ctrl, n=7) group received saline solution 0,9% NaCl as a vehicle. Rats underwent an echocardiographic evaluation at 4 weeks. Blood pressure, heart rate and respiratory frequency were assessed in an acute experiment. Cardiovascular variability studies in the time-frequency domain (LF, HF and LF/HF calculation) and cardiorespiratory reflexes assessment were performed. T-Student test for paired observations was applied (level significance p&lt;0.05)
DOX-treated animals showed a severe bradypnea and hypotension, significant decrease in ejection fraction and fractional shortening, sympatho-inhibition and reduced baroreceptor reflex gain and chemoreflex sensitivity. Our functional results might be due to cellular respiratory dysfunction and vascular adaptations induced by doxorubicin via TNF alpha actions at central nervous system (CNS) and peripheral level.
In fact, peripheral TNF alpha release elicits NO production, which through vasodilation will induce hypotension and baroreceptor reflex adjustments. Reinforcing these actions, and despite doxorubicin low ability to pass BBB, TNF alpha acting at CNS induces neuronal apoptosis and impairment of mitochondrial function which might also contribute to affect autonomic and respiratory function, expressed by a decreased chemoreflex sensitivity and sympathetic tone.
In conclusion, sub-therapeutic doses of doxorubicin are able to produce per se the impairment of autonomic and cardiac functions. Thus, a tight monitoring of these functions in patients treated with therapeutic doses of doxorubicin is highly recommended.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação para a Ciência e a Tecnologia
Circulating metabolome does not predict development of aortic stenosis
Authors: Koljonen E , Karkkainen O , Klavus A , Voutilainen A , Turpeinen A , Virtanen J , Lehtonen M , Auriola S , Kauhanen J , Hartikainen J , Rysa J 
Published: October 2021

Abstract

Background
Calcific aortic valve disease (CAVD) is the most common valvular heart disease in Western world. CAVD is ranging from mild aortic valve sclerosis to severe obstructive aortic stenosis (AS). The development of AS has been associated with several risk factors including age, sex and hypertension. However, there is limited knowledge about factors that predict the development of aortic stenosis.

Purpose
We investigated if the circulating metabolite profile can predict the development of aortic stenosis in Finnish males.

Methods
We did a non-targeted LC-MS metabolomics analysis to baseline (1984–1989) serum samples from a prospective population-based Kuopio Ischemic Heart Disease risk factor study (KIHD) cohort of 2682 random Finnish males aged from 42 to 60 years. During the follow-up (until year 2020), 53 subjects developed either moderate (peak flow gradient 36–64mmHg or mean flow gradient 20–40mmHg) or severe aortic valvular stenosis (peak flow gradient over 64mmHg or mean gradient over 40mmHg). The AS patients were collected from the KIHD database using appropriate ICD-10 -codes for aortic valvular disease (from baseline to the end of the year 2017) and the diagnosis was checked manually using hospital medical records of the individuals.

Results
The AS patients seemed to have altered lipid metabolism and possibly altered composition of gut microbiota, since several acylcarnitines (e.g. octanoylcarnitine [Cohen's d=−0.40], decanoylcarnitine [d=−0.43], layroylcarnitine [d=−0.41], and oleoylcarnitine [d=−0.40]), and branched chain amino acids (BCAA, e.g. leucine [d=0.39], and isoleucine [d=0.49]) had p-values below 0.05. However, after correction for multiple testing, there were no significant differences between the cases and controls.

Conclusions
The present preliminary results, in need of verification with a larger set of samples, suggest that subjects, who will later develop AS might have reduced levels of acylcarnitines and increased levels of BCAA when compared to matched controls. However, these changes do not have large effects sizes and are likely not good candidates for biomarkers to predict future diagnosis of AS.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): The Finnish Cultural Foundation, The Finnish Foundation for Cardiovascular Research.
Novel perfusion ex-vivo culture system enables physiological and pathological studies on porcine arteries
Authors: Matos R , Maselli D , McVey J , Campagnolo P 
Published: October 2021

Abstract

Introduction
Routine cardiovascular interventions such as cardiac bypass, balloon angioplasty and stenting provoke vascular activation and remodelling often leading to rehospitalization and further interventions. Conventional in vitro models fail to account for the complex vascular environment essential for vascular tissue fitness.

Purpose
Our research aims to culture whole porcine arteries in using a novel cost efficient and versatile perfusion system (EasyFlow) and identify the contribution of adventitial progenitors to post-injury remodelling.

Methods
EasyFlow insert was 3D printed to convert a conventional 50 ml centrifuge tube into a mini bioreactor. Porcine arteries were excised and cultured under constant pulsatile flow for up to 7 days. Injury was performed by balloon catheter at day 0. Tissues were evaluated by doppler ultrasound, immunofluorescence and confocal imaging and PCR, at different timepoints.

Results
The EasyFlow adaptor takes advantage of 50 ml centrifuge tubes isolating reaction space from the environment and reducing the culture volume. The adaptability of the design facilitates the incubation of vessels of different size and origin while the self-contained perfusion allows parallel cultures and minimal media consumption. EasyFlow perfusion culture of porcine arteries preserves the endothelial coverage and the smooth muscle cell organisation, as compared to static culture.
Gene expression analysis and immunofluorescence indicated an increased expression of platelet-derived growth factor receptor beta (PDGFRb) and a decrease in smooth muscle actin (SMA) in the static culture, compared to the perfusion. Furthermore, static culture showed an increased cellular activation in adventitia (proliferating cell nuclear antigen expression), as compared to perfused tissues. Balloon injury followed by flow culture recapitulated the early hallmarks of vascular remodelling, including intimal denudation indicated by loss of platelet endothelial cell adhesion molecule signal, smooth muscle cell disarray shown by loss of actin stress fibre organisation and activation in the media, as supported by confocal microscope and gene expression analysis, accompanied by significant morphological changes based on ultrasound imaging.

Conclusion
This work lay the basis for future investigations into the pathological remodelling of blood vessels, by providing a robust and controlled culture system for the maintenance of porcine blood vessels in culture.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): University of Surrey En-Face Staining of Arterial Lumen