bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visualization of fibroblast activation after myocardial infarction using 68Ga-FAPI-PET
Authors: Kupusovic J , Kessler L , Ferdinandus J , Hirmas N , Fendler W , Totzeck M , Herrmann K , Wakili R , Rischpler C , Rassaf T , Siebermair J 
Published: October 2021

Abstract

Introduction
Fibroblast activation protein (FAP) alpha specifically expressed by activated fibroblasts has been shown to be significantly involved in processes of tissue healing after injury, including fibrotic remodeling after myocardial infarction (MI). Positron-emission tomography (PET) with the tracer FAP-inhibitor (FAPI) is a novel diagnostic tool primarily described in oncologic patients for tumor stroma detection. We present data from a pilot study investigating patients after MI who underwent subsequent 68Ga-FAPI-PET for assessment of potential FAP-related myocardial remodeling.

Methods
In this retrospective study we analyzed a cohort of 10 post-MI patients who underwent 68Ga-FAPI-PET imaging with respect to cardiac tracer pattern. Standardized maximum and mean uptake values and total volume of tracer enrichment (fibroblast activation volume, FAV) of the infarcted area were calculated. A visual grading scale was established to assess the level of agreement between maximum localized tracer uptake and segments belonging to the supply area of the culprit vessel. Tracer uptake was correlated to clinical variables, with readers blinded to the clinical characteristics.

Results
Focal 68Ga-FAPI uptake was detected in all 10/10 patients after MI. According to our grading system for visual agreement of polar map segments and culprit lesion, we observed a very good (in 37.5% of patients) and a moderate (62.5% of patients) match between tracer uptake and the culprit lesion, respectively. We demonstrated a negative correlation of FAV uptake and left ventricular systolic function (R2=−0.69, p&lt;0.05) and a very strong positive correlation of FAV and peak creatinine kinase level (R2=0.90, p&lt;0.01).

Conclusion
Increased myocardial 68Ga-FAPI uptake, serving as a surrogate for FAP expression after MI, corresponds well to the supply area of the culprit coronary vessel as well as to biomarker levels of myocardial injury. This imaging technique represents a highly promising, novel bio-signal in the assessment of myocardial injury and consecutive remodeling. Large controlled studies are warranted to further evaluate the prognostic impact of this novel imaging technique.

Funding Acknowledgement
Type of funding sources: None.
Cardiac function is normal in most patients recovered from COVID-19
Authors: Tangen J , Aukrust P , Barrat-Due A , Troseid M , Christoffer Olsen I , Nezvalova-Henriksen K , Kaasine T , Dyrhol-Riise A M , Rygh Holten A , Finbraten A K , Josefsen T A , Lee K C , Haugaa K H , Skulstad H , Edvardsen T 
Published: October 2021

Abstract

Background
There are conflicting results regarding impaired cardiac function in patients that have recovered from COVID-19. Cardiovascular magnetic resonance (CMR) studies have revealed a very high frequency of cardiac involvement (78%) and ongoing myocardial inflammation (60%) in patients recently recovered from COVID-19. Findings are advocating further investigation of the long-term myocardial consequences of COVID-19 disease.

Purpose
We aimed to investigate left ventricular (LV) and right ventricular (RV) function by a comprehensive echocardiographic study in patients recovered from COVID-19 infection 3 months after admission to hospital.

Methods
All patients (n=92) had been hospitalized for COVID-19 and were examined with echocardiography three months after hospitalization. They were 59±13 years, and 43% were women. LV function was assessed by ejection fraction (EF) and global longitudinal strain (GLS) and RV function was measured by fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE) and RV GLS free wall. Tricuspid regurgitation pressure gradient was measured to estimate pulmonary artery pressure.

Results
LV EF was 63±6% and LV GLS was −18.6±2.2%. All patients had normal EF &gt;53%, but 10 showed signs of subtle impaired LV function by LV GLS (≥ −16%). Only two of these did not have hypertension, LV hypertrophy, diabetes or other preexisting diagnosis of heart disease explaining subtle LV dysfunction. All had normal RV FAC (48±7%) and TAPSE (2.3±0.3 cm). We found modestly impaired RV longitudinal function (RV GLS free wall &gt;−25%) in 30% patients, but none had RV GLS worse than −20%. One-third of all patients with reduced RV GLS had signs of elevated pulmonary arterial pressures, which might impact the assessment of RV function.

Conclusions
Traditional echocardiographic parameters showed normal function in all hospitalized COVID-19 patients three months after hospital admittance. Approximately one-third had subtle ventricular dysfunction detected by sensitive echocardiographic methods, but these findings could mostly be explained by systemic or pulmonary hypertension. We cannot, however, exclude that a slight reduction in cardiac function in a minority of our patients was caused by the COVID-19 infection.

Funding Acknowledgement
Type of funding sources: Public hospital(s). Main funding source(s): National Clinical Therapy Research in the Specialist Health Services, Norway
MicroRNA-126 mimic administration accelerates vascular perfusion recovery and angiogenesis in a hind limb ischemia model
Authors: Theofilis P , Vogiatzi G , Oikonomou E , Gazouli M , Siasos G , Katifelis H , Perrea D , Vavouranakis M , Iliopoulos D C , Tsioufis C , Tousoulis D 
Published: October 2021

Abstract

Background
Peripheral arterial disease caused mainly by atherosclerosis portent significant morbidity, adverse prognosis and mortality, with localized treatment approaches aiming at symptom alleviation and improvement of circulation. Recently, scientific interest has been shifted towards epigenomics, with microRNAs appearing as a future therapeutic target in ischemic cardiovascular diseases due to their potential in regulating angiogenesis.

Purpose
We investigated the pro-angiogenic effect of miRNA-126 mimic in an in vivo model of hind limb ischemia.

Methods
Ten-week-old male C57Bl/6 mice (n=20) were subjected to left femoral artery ligation and were treated with microRNA-126 mimic at a dose of 5mg/kg (Group A, n=10) or 0.2ml normal saline (Group B, n=10) on days 1, 3 and 7. Laser Doppler imaging was performed to verify successful ligation on day 0 and to evaluate differences in the ischemic-to-normal (I/N) hind limb perfusion ratio on day 7 and 28. Muscle tissue expression of microRNA-126 and vascular endothelial growth factor (VEGF) was determined via PCR.

Results
Following microRNA-126 mimic administration in Group A subjects, we noted a qualitative and quantitative stepwise increase in I/N hind limb perfusion ratio [Day 0: 0.354 (0.276, 0.455) vs. Day 8: 0.775 (0.700, 0.844) vs. Day 28: 0.681 (0.660, 0.896), p=0.001] (Figure 1, Panels A and B). In Group B a stepwise increase of lesser magnitude was observed in I/N hind limb perfusion ratio [Day 0: 0.267 (0.164, 0.383) vs. Day 8: 0.400 (0.338, 0.418) vs. Day 28: 0.539 (0.483, 0.603), p=0.074]. Importantly, over time changes of I/N hind limb perfusion ratio were significantly higher in group A compared to group B (p for interaction=0.005) (Figure 1, Panel B). Muscle tissue expression of microRNA-126 in the ischemic hind limb of Group A was 350-fold lower compared to the ischemic hind limb of Group B (p&lt;0.001) (Figure 1, Panel C). A higher expression (14.2-fold) of VEGF in the ischemic hind limb of microRNA-126-treated mice compared to that of control group was detected (p&lt;0.001) (Figure 1, Panel C). A statistically significant negative correlation was noted between microRNA-126 and VEGF tissue expression levels in the ischemic limbs of both Group A and B subjects whereas no correlation between microRNA-126 and VEGF was observed in the non-ischemic hind limbs of the entire study population (Figure 1, Panel D).

Conclusion
MicroRNA-126 mimic delivery in the ischemic hind limb of mice can accelerate vascular perfusion recovery via angiogenesis, which is mediated by VEGF expression.

Funding Acknowledgement
Type of funding sources: None. Figure 1
The uptake of trimethylamine N-oxide (TMAO) and its influence on endothelial cell identity and inflammation
Authors: Rittig S , Gaal L , Kokot K , Gaul S , Okun J , Laufs U , Boeckel J.-N 
Published: October 2021

Abstract

Background and purpose
Trimethylamine N-oxide (TMAO) is associated with a higher risk of atherosclerotic diseases. However, the underlying molecular mechanisms are not completely understood. Inflammation and following endothelial-to-mesenchymal transition (EndMT) – a process where endothelial cells (ECs) lose their function and phenotype and gain a mesenchymal character – contribute to the development of atherosclerosis. We therefore aimed to investigate the potential uptake of TMAO into ECs and its potential impact on inflammation and subsequent EndMT.

Methods and results
Tandem mass spectrometry revealed a time-dependent uptake of TMAO into primary human endothelial cells of 0.5 nmol/mg protein within the first 30 minutes and of 5.8 nmol/mg within 24 hours. The uptake of TMAO resulted in a significant increase of inflammation as measured by E-selectin expression (+63.8-fold). A prolonged treatment with TMAO for 3 days resulted in an increase of EndMT indicated by a significant increase of the mesenchymal marker genes Versican (+6.8-fold) and Calponin (+11.9-fold), as well as a concomitant decrease of the endothelial marker LYVE1 (−92%). For identification of a potential TMAO transporter in human endothelial cells, we screened for the expression of Solute Carrier Family member transporters in ECs. Through our research, overexpression of the carrier A5 in ECs resulted in a 36% higher intracellular TMAO concentration as early as 30 minutes. In turn, causing a knockdown of A5 prevented TMAO induced inflammation (−77.8% induction of E-Selectin) and EndMT (−98,3% induction of Versican and −461% induction of Calponin).

Conclusion
Using a large screening approach, we identified A5 as the first TMAO transporter described in ECs. TMAO uptake results in increased inflammation of ECs and induction of EndMT. The data identify a novel mechanism of TMAO uptake into human ECs that may help to better understand lifestyle-mediated effects on atherosclerosis.

Funding Acknowledgement
Type of funding sources: None.
The role of cellular senescence in aortic dissection
Authors: Nakao E , Aoki H , Majima R , Hashimoto Y , Shibata R , Hayashi M , Ohno-Urabe S , Furusho A , Nishida N , Hirakata S , Fukumoto Y 
Published: October 2021

Abstract

Background
Aortic dissection (AD) is a catastrophic disease that occurs suddenly. The acute mortality is high and those who survived frequently suffer from serious complications such as aneurysm formation and distal ischemia due to progressive destruction of the aortic walls. Currently, no reliable predictor is available for AD development and surgical intervention is the only therapeutic option to prevent the fatal events after AD development, because the pathogenesis of AD is largely unknown.
Clinical and experimental studies highlighted the importance of inflammation in AD pathogenesis, although the trigger of inflammation remains unclear. Recently, we found that cell proliferation precedes the inflammatory response in AD. Because cell proliferation triggers cellular senescence and senescent cells secrete of proinflammatory cytokines and matrix metalloproteinases, we hypothesized that cellular senescence may participate in AD pathogenesis.

Objective
We investigated if cellular senescence contributes to AD development and progression in a mouse model of AD.

Methods and results
A mouse AD model was created by continuous infusion of beta-aminopropionitrile and angiotensin II (BAPN+AngII), where AD starts to develop in 3 days and occurs to most of the mice in 14 days accompanied by frequent AD rupture and death. Infusion of BAPN+AngII resulted in the appearance of senescent cells that are positive for senescence-associated beta-galactosidase, and expression of senescence markers Arf and Ink4a in the aortic walls. Appearance of cellular senescence occurred in one day of BAPN+AngII infusion and continued throughout the observational period of 14 days. We examined the role of cellular senescence in AD pathogenesis by oral administration of ABT263 which is known as “senolytics” that eliminates senescent cells. ABT263 treatment reduced the expression of the senescence markers. In the vehicle-treated group, the mortality was 66.7% (12/18), whereas that of ABT263-treated group was 35% (14/20, P&lt;0.05 by log-rank test). The severity of AD, as assessed by the lesion length in vehicle group was33.2±3.1 mm, whereas that in ABT263 group was 24.6±1.8 mm (P&lt;0.05).

Conclusions
These findings demonstrated that cellular senescence precedes AD development, and ABT263 effectively prevented AD progression and death, indicating the involvement of cellular senescence in AD pathogenesis. Therefore, cellular senescence represents a potential predictor and a therapeutic target for AD.

Funding Acknowledgement
Type of funding sources: None.
Pulmonary artery radiofrequency ablation in an acute porcine model of pulmonary arterial hypertension
Authors: Goncharova N , Vakhrushev A , Condori Leandro H I , Skorik Y U , Murashova L , Korobchenko L , Andreeva E , Mitrofanova L , Koshevaya E , Lebedev D , Moiseeva O , Mikhaylov E 
Published: October 2021

Abstract

Introduction
Pulmonary hemodynamics improvement after pulmonary artery denervation (PADN) was demonstrated in PAH. Questions arise regarding PADN perioperative effectiveness and the accuracy of the target nerves damage. The aim of the study was to evaluate whether PADN decreases pulmonary artery pressure (PAP) in acute thromboxane A2 (U46619)–induced PAH, and damages PA perivascular nerve fibers.

Materials and methods
10 male Landrace swine (34.7±5.1 kg). In 6 swine acute reversible target mean PAP of 40 mm Hg was induced with synthetic thromboxane A2 infusion (U46619). Control group: 4 swine with PADN. Hemodynamics was assessed throughout the study, PAH modeling was done before and 20 min after PADN (radiofrequency energy, 40 Watts), followed by pathology and immunohistochemical studies.

Results
The mean number of RF applications was 17.5±3.6. Pulmonary embolism (PE) was observed after PADN in 3 swine with U46619 infusion, which were excluded. There was no differences in mPAP, PVR and U46619 dosage after PADN in PAH model (12.3±3.5 vs 12.1±1 mm Hg, p=0.2; 150.4±48.7 vs 129.2±64.1 dynes s cm–5; p=0.2; 24.9±3.3 vs 22.4±4.1 mcg; p=0.18; respectively). Similar hemodynamic results were observed in the control group after PADN (mPAP; p=0.3; PVR; p=0.58). S100 expression was evident in the majority of RFA PA species and in some species loss in tyrosine hydroxylase and M1 acetylcholine receptors expression was detected with no hemodynamic correlation.

Conclusions
PADN using an electrophysiological catheter with unipolar energy does not lead to an acute PA perivascular nerve fibers destruction and detectable mPAP changes in U46619-induced PAH. Delayed nerve damage might be attributable to PADN effects observed in previous studies.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant from the Ministry of Science and Higher Education of the Russian Federation (agreement #075-15-2020-800).
Tofogliflozin improved pulmonary hypertension due to heart failure with preserved ejection fraction in mice
Authors: Joki Y J , Konishi H K , Takasu K T , Minamino T M 
Published: October 2021

Abstract

Introduction
Pulmonary hypertension (PH) caused by left heart diseases is categorized as the group 2 (PH-LHD). PH-LHD due to heart failure with preserved LV ejection fraction (HFpEF) is more prevalent in patients with metabolic syndrome and shows poorer prognosis than LHD without PH. Tofogliflozin (TOFO) is an SGLT2 inhibitor utilized for diabetic treatment. Recent studies revealed that the SGLT2 inhibitor has a beneficial effect on heart failure; however, it remains unclear whether the SGLT2 inhibitor is effective for the treatment of PH-LHD.

Hypothesis
We hypothesized that TOFO has a protective effect on PH with HFpEF.

Methods
We generated two murine models for PH-LHD due to HFpEF, a transverse aortic constriction (TAC) model and a high fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3 mg/kg) for 4weeks. In another model, AKR/J mice were fed HFD or normal chow diet and treated with TOFO (3mg/kg in water) for 20 weeks. We then measured physical data including body weight (BW), left ventricular weight (LV), right ventricular weight (RV), and right ventricular systolic pressure (RVSP) and performed echocardiography.

Results
Mice treated with TOFO demonstrated increased urine glucose level. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RV/LV ratio and RVSP in TAC mice (Figure 1). HFD fed AKR/J mice demonstrated increased BW and PH as demonstrated by increased RV/LV ratio and RVSP compared with the normal chow group. TOFO treatment ameliorated the increases of BW, RV/LV ratio, and RVSP in HFD fed AKR/J mice (Figure 2).

Conclusions
TOFO treatment improved pulmonary hypertension in two models for PH-LHD due to HFpEF, suggesting that the SGLT2 inhibitor is effective for the treatment of this condition.

Funding Acknowledgement
Type of funding sources: None. Figure 2. TOFO reduced RVSP caused by HFD
Detection of direct oral anticoagulants with the dilute Russels viper venom time – observations in a real life setting
Authors: Kloeter T , Siegemund T , Siegemund A , Laufs U , Petros S , Metze M 
Published: October 2021

Abstract

Background
The detection of direct oral anticoagulants (DOACs) in emergency settings still remains challenging, especially when dedicated anti-Xa or anti-IIa tests are not readily available or the specific DOAC is unknown. The dilute Russel's viper venom time (dRVVT) is widely known in lupus anticoagulant (LA) testing and may also provide helpful information regarding the residual antithrombotic activity of DOACs. Yet real world data describing the effect of DOACs on the dRVVT is scarce.

Objective
The study aimed to evaluate the sensitivity and specificity of dRVVT for different DOAC plasma levels.

Methods
A total of 80 patients were recruited – 20 patients for each approved DOAC (apixaban, edoxaban, rivaroxaban and dabigatran). Blood plasma was sampled before (baseline), 6 and 12 hours after DOAC-intake and at plasma peak time. DRVVT was measured using the LA1 screening assay for lupus anticoagulant. Plasma levels were measured by calibrated anti-Xa or anti-IIa tests. Additionally, activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured.

Results
All DOACs significantly prolonged the dRVVT. The effects were more pronounced at higher DOAC plasma levels. The area under the receiver operating characteristic (ROC) curve regarding a plasma level cut-off of 30 ng/ml was 0.92 (95% confidence interval (CI) 0.823 to 1.00) for apixaban, 0.97 (95% CI 0.902 to 1.00) for edoxaban, 0.87 (95% CI 0.649 to 1.00) for rivaroxaban and 0.96 (95% CI 0.871 to 1.00) for dabigatran.

Conclusion
A dose dependent effect of all approved direct oral anticoagulants (DOACs) on the dilute Russel's viper venom time (dRVVT) was documented in our real world setting, while relevant DOAC plasma levels did not affect standard coagulation tests. The negative predictive value for the dRVVT was high even at low DOAC plasma levels. The dRVVT could therefore be helpful to rule out relevant antithrombotic plasma activity caused of DOACs in emergency situations.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): Universität Leipzig Figure 1. ROC curves
Interconnection of the level of uric acid at risk of development of type 2 diabetes mellitus on FINDRISC scale in women moderate and high cardiovascular risk
Authors: Komir I , Isayeva G , Emelyanova N 
Published: October 2021

Abstract

Aim
To establish a relationship between the level of uric acid and the risk of development of type 2 diabetes mellitus (DM2) on the FINDRISC scale in women of moderate and high cardiovascular risk.

Material and methods
103 women (average age (58,39±11,09) years) with moderate and high cardiovascular risk were examined. Women were divided into groups depending on age: 1 group of age to 50 years old, 2 groups with the age of 50–60 years old, 3 groups more than 60 years. The risk of developing the DM2 in the next 10 years was evaluated using the FINDRISC questionnaire. The level of uric acid was determined by a photometric substantial method. For statistical analysis, SPSSIBM, version 19.0.

Results
It has been established that women, in general, had an increased risk of developing DM2 (11,0 [7,0–14,0] points). The level of uric acid in them was (295,0 [230,0–380,5] μmol/l). In the distribution of women by age, there was no probable difference in uric acid levels (257,0 [249,0–257,5]; 256,0 [210,7–353,3]; 295,0 [231,0–362,5] μmol/l; p&gt;0,05). However, the risk of developing DM2 has probably grown in women depending on age (4,00 [0,25–9,25]; 9,50 [7,00–14,00]; 14,50 [12,50–16,00] points). Uric acid correlated with the FINDRISC scale at the significance level (0,489, p=0,05). However, with the distribution of women, depending on age, we observed the interconnection of uric acid with the risk of developing DM2 at the level of significance only in women 2 groups (0,604, p=0,01).

Conclusions
The level of uric acid is interacting with the risk of developing DM2 on the FINDRISC scale in women of moderate and high cardiovascular risk at the age of 50–60 years.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): Government Institution “L.T. Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine”, Department of Chronic Non-communicable Disease Prevention
Suppression of telomere capping defects of Saccharomyces cerevisiae yku70 and yku80 mutants by telomerase
Authors: Holland Cory L , Sanderson Brian A , Titus James K , Weis Monica F , Riojas Angelica M , Malczewskyj Eric , Wasko Brian M , Lewis L Kevin 
Published: October 2021

Abstract
The Ku complex performs multiple functions inside eukaryotic cells, including protection of chromosomal DNA ends from degradation and fusion events, recruitment of telomerase, and repair of double-strand breaks (DSBs). Inactivation of Ku complex genes YKU70 or YKU80 in cells of the yeast Saccharomyces cerevisiae gives rise to mutants that exhibit shortened telomeres and temperature-sensitive growth. In this study, we have investigated the mechanism by which overexpression of telomerase suppresses the temperature sensitivity of yku mutants. Viability of yku cells was restored by overexpression of the Est2 reverse transcriptase and TLC1 RNA template subunits of telomerase, but not the Est1 or Est3 proteins. Overexpression of other telomerase- and telomere-associated proteins (Cdc13, Stn1, Ten1, Rif1, Rif2, Sir3, and Sir4) did not suppress the growth defects of yku70 cells. Mechanistic features of suppression were assessed using several TLC1 RNA deletion derivatives and Est2 enzyme mutants. Supraphysiological levels of three catalytically inactive reverse transcriptase mutants (Est2-D530A, Est2-D670A, and Est2-D671A) suppressed the loss of viability as efficiently as the wild-type Est2 protein, without inducing cell senescence. Roles of proteins regulating telomere length were also determined. The results support a model in which chromosomes in yku mutants are stabilized via a replication-independent mechanism involving structural reinforcement of protective telomere cap structures.