bluuebunny/crossref_metadata_2025_split huggingface dataset:
P702Anti-thrombin nanoparticles for reduce vascular damage and promote functional recovery in acute ischemic kidney injury well after reperfusion
Authors: Pan H , Grabau R , Vargas I , Baldwin M , Cara B , Stephenson D , Lindon A , Chalfant C , Wickline S 
Published: October 2019

Abstract

Introduction
We have shown previously that pretreatment of acute ischemic kidney injury (AKI) in mice prior to reperfusion with anti-thrombin perfluorocarbon nanoparticles (PFC NP) limits damage to endothelium and hastens functional recovery. However, whether such treatments are effective after AKI is established is not known. We hypothesized that thrombin would continue to exert deleterious clotting and molecular signaling effects in AKI well after reperfusion that would respond to sustained local inhibition with long acting anti-thrombin nanoparticles.

Methods
23 C57Bl6 mice underwent bilateral kidney ischemia for 17 min, followed by 2 hours reperfusion and i.v. injection of anti-thrombin PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone)-conjugated PFC NP (∼ 13,000 PPACK per PFC NP), or plain PFC NP (control: no drug). At 24 hours BUN was measured, and mice were euthanized for kidney histological assessment (H&E), protein expression (western blot) and eicosanoid mediators of inflammation (LC-MS/MS: AB SCIEX 5500 QTRAP).

Results
BUN at 24 hours after AKI was 63.29±9.09 vs 110.96±6.21 (P<0.002), for treated versus untreated mice, respectively, a 43% improvement. Western blots (Figure) indicated 40% reduction of canonical NF-kB signaling pathway protein p65 (p<0.01) and 2.2 fold increases in Bcl-xL: Bax ratio (P<0.01). Vascular damage, as indicated by glomerular and mesangial hemorrhage (Figure), was reduced, as was tubular cell swelling and edema. Levels of inflammatory procoagulant eicosanoids (e.g., PGE1, TBX2, PGA2, 15-HETE, 5-HETE, etc.) generally were higher in renal medulla than in cortex, and were suppressed by PPACK PFC NP.

Discussion
Continued inhibition of thrombin in AKI with locally-acting PPACK PFC NP preserved vascular integrity, limited renal hemorrhage, mitigated inflammation and tubular cell death, and accelerated functional recovery even when administered 2 hours after reperfusion. Because these PPACK PFC NP do not prolong bleeding times or coagulation parameters beyond ∼30–60 min after injection, yet maintain prolonged local surveillance against activated thrombin, they represent a potentially useful therapeutic strategy for established AKI after an ischemic insult.

Acknowledgement/Funding
DK102691
P705Step by step diagnosis and management of statin intolerance: position paper from an international lipid expert panel
Authors: Penson P , Toth P , Mikhailidis D , Ezhov M , Fras Z , Mitchenko O , Pella D , Sahebkar A , Rysz J , Reiner Z , Jozwiak J , Mazidi M , Banach M 
Published: October 2019

Abstract

Background
Statin intolerance is a clinical syndrome whereby adverse effects associated with statin therapy (most commonly muscle symptoms) result in the discontinuation of therapy. Statin discontinuation is associated with increased risk of adverse cardiac outcomes. Many patients who initially experience adverse effects are able to tolerate statin therapy to some extent. Careful stepwise diagnosis and management of individuals who experience adverse effects is essential to enable optimal reduction of cardiovascular risk.

Purpose
In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step by step approach to the diagnosis and practical management of statin intolerance resulting from muscle symptoms, and other adverse effects with demonstrated statin causality.

Methods
Relevant clinical evidence and international clinical guidelines were discussed and assimilated by ILEP members. Consensus was used to formulate recommendations for the diagnosis and management of statin intolerance.

Results
Consensus resulted in the adoption of three parts to the recommendation. 1) diagnosis of Statin Intolerance; 2) advice for management of all patients with statin intolerance; 3) specific advice for patients who have partial (rather than complete) statin intolerance. Patients with partial statin intolerance are likely to make up the vast majority (even 95%) of statin-intolerant individuals. Each part of the recommendation consists of a four-step process and has an associated acronym to aid memory (see attached recommendations). We adopted the Banach and Mikhailidis four-step approach to diagnosis and we developed novel recommendations for management.
Summary of the ILEP SI recommendations.

Conclusions
We present recommendations, which will enable clinicians to distinguish between rare, severe adverse effects; true statin intolerance, and symptoms incorrectly attributed to statin therapy. In each case we summarize guidelines, clinical evidence and expert opinion pertaining to the optimal management of cardiovascular disease in these patients.

Acknowledgement/Funding
None
P708Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population
Authors: Oguri M , Kato K , Horibe H , Fujimaki T , Sakuma J , Takeuchi I , Murohara T , Yasukochi Y , Yamada Y 
Published: October 2019

Abstract

Background
Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European ancestry populations, genetic variants that contribute to susceptibility to this condition in Japanese individuals remain to be identified definitively.

Purpose
The purpose of the study was to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. We have now performed exome-wide association studies (EWASs) in subjects with early-onset CAD and controls.

Methods
A total of 7256 individuals aged ≤65 years was enrolled in the study. The EWAS was conducted with 1482 subjects with CAD and 5774 controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 31,465 SNPs that passed quality control to CAD was examined with Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association.

Results
The relation of allele frequencies for 31,465 SNPs to CAD with the use of Fisher's exact test showed that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus, and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) related to CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R2), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. After examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, we newly identified 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY, EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34, 20q13.2) that were significantly associated with CAD. Gene ontology analysis showed that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously shown to be associated with CAD or with the 228 genes identified in previous genome-wide association studies of CAD.

Conclusion
We have newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese.
P715Deletion of fibroblast activation protein decreases experimental atherosclerotic plaque formation and vulnerability
Authors: Stein S , Weber J , Nusser-Stein S , Pahla J , Zhang H , Oppi S , Staels B , Gorrell M D , Luscher T F , Matter C M 
Published: October 2019

Abstract

Background
Fibroblast activation protein (FAP) is a serine protease that is upregulated in sites of tissue remodeling, including arthritis, tumors and atherosclerosis. We have reported that FAP degrades type I collagen in human thin-cap fibroatheromata; its expression is enhanced in advanced human plaques and induced by inflammation. However, the role of endogenous FAP in atherosclerosis remains unknown.

Purpose
To investigate the effects of constitutive Fap loss-of-function on atherosclerotic plaque formation and vulnerability.

Methods and results
Male 8-week-old Apoe−/− Fap+/+ and Apoe−/− Fap−/− mice were fed a high-cholesterol diet (1.25% chol) for 12 weeks. En face analyses of thoracoabdominal aortae using Oil Red O (ORO) revealed decreased plaques in Apoe−/− Fap−/− mice (5.7±0.5%; n=21) compared to Apoe−/− Fap+/+ mice (10.7±0.7%; n=24; p<0.0001). In parallel, ORO analyses of serial aortic root cross sections showed diminished plaques in Fap-deficient mice (18.4±3.4% vs 27.6±2.1%). As a surrogate of plaque vulnerability, fibrous cap thickness was increased in Apoe−/− Fap−/− mice (65±6 mm vs 35±3 mm; p<0.01), whereas necrotic core size, plaque macrophages (CD68) and T cells (CD3) accumulation, as well as VCAM1 expression did not differ. These changes were independent of plasma triglycerides, total and LDL-cholesterol levels. Plasma of Fap-deficient mice showed decreased FAP activity compared to Fap wildtype controls. Notably, second harmonics generation in cross sections of aortic root plaques showed that the deposition and density of fibrillar collagens was enhanced in Fap-deficient (25.5±4.4%) compared to control plaques (13.8±2.5%; p<0.05). Consistently, Fap deletion led to an accumulation of uncleaved pre-COL3A1, a proteolytic target of FAP.

Conclusions
Constitutive Fap deletion decreases experimental atherosclerosis and features of plaque vulnerability. Thus, inhibition of FAP expression or activity may be a promising therapeutic target in atherosclerosis.

Acknowledgement/Funding
Swiss National Science Foundation, Swiss Heart Foundation
P740Repeated social defeat exaggerates fibrin-rich clot formation in FeCl3-induced arterial thrombosis mice model by enhancing NETs formation
Authors: Sugimoto T , Yamada H , Kubota H , Miyawaki D , Motoyama S , Wada N , Saburi M , Wakana N , Matoba S 
Published: October 2019

Abstract

Background and objective
Depression is an independent risk factor of cardiovascular disease (CVD). We have recently shown that repeated social defeat (RSD) precipitates depressive-like behaviorsin apoE−/− mice and exaggerates atherosclerosis development by enhancing neutrophil extracellular traps (NETs) formation (BBRC 2018; 500:490). Here, we investigated the impact of RSD on arterial thrombosis.

Methods and results
Eight-week-old male WT mice were exposed to RSDby housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same gage without physical contact. After social interaction testto confirm depressive-like behaviors, defeated mice (19 of 31) and control mice (12 of 14) were underwent arterial injury at 10 wks of age. A filter paper saturated with 10% FeCl3was applied on the adventitial surface of left carotid artery for 3 min and analyzed 3 hrs later. The volume of thrombi calculated by summing8–15 frozen cross-sectional images, each separated by 200 μm, was comparable between the 2 groups. However, fibrinogen/fibrin-positive areas in immunofluorescent images were significantly increased in defeated mice (27.8% vs. 48.8%, Control vs. Defeat, P<0.01).The numberof Ly-6G-positive cells in thrombi was markedly higher in defeated mice (144/mm2 vs. 878/mm2, Control vs. Defeat, P<0.05). Further, Ly-6G-positive cells were almost accumulated at the inner surface of injured artery, which were co-localized with neutrophil elastase, Cit-H3, and CD41-positive staining. Treatment with DNase Icompletely diminished the exaggerated fibrin-rich clot formation in defeated miceto a similar extent of control mice (25.7% vs. 22.3%, Control vs. Defeat, P= NS), while the volume of thrombi and number of Ly-6G-positive cells in thrombi were comparable between the 2 groups even afterDNase I treatment. Platelet aggregations induced by ADP or collagen were comparable between the 2 groups, suggesting that NETs formation primarily contributes to the exaggerated fibrin-rich clot formation in defeated mice.

Conclusions
Our findings demonstrate for the first time that repeated social defeat enhances fibrin-rich clot formation after arterial injury by enhancing NETs formation, suggesting that NETosis could be a new therapeutic target in depression-related CVD development.
P748Afterload-induced TRIF-dependent signaling promotes fibrosis but not cardiomyocyte hypertrophy
Authors: Bettink S I , Kazakov A , Koerbel C , Boehm M , Scheller B , Schirmer S H 
Published: October 2019

Abstract

Background
Pressure overload dependent cardiac remodeling is characterized by a continuous functional loss of cardiomyocytes, cardiomyocyte hypertrophy, cell death and fibrosis. The relevance of the MyD88- and NFκB-independent inflammatory TRIF (TIR-domain-containing adapter protein inducing IFN-β) signaling pathway in myocardial hypertrophy is incompletely understood.

Methods and results
The murine model of afterload induced myocardial hypertrophy (trans-aortic constriction, TAC) was used to investigate the time dependent chemokine expression in C57Bl/6J Wild type (WT) mice after intervention. Myd88- as well as TRIF-dependent chemokines reached their expression maximum at d7 post intervention. This time point was determined for further investigations on TRIF knockout-mice (TRIF−/−) compared to WT mice. While left ventricular (LV) mRNA-expression of TNFalpha and IL6 was upregulated in TRIF−/− mice, CXCL10, CXCL11, RANTES and pathway molecule IRF3 remained unchanged. In the stage of established hypertrophy (35 days after TAC) cytokine levels returned to baseline in WT as well as in TRIF−/− mice.
Cellular hypertrophy (increase in cardiomyocyte size) as well as echocardiographic determined increase of LV mass was similar in TRIF−/− and WT mice at d7 as well as at d35 after TAC. Additionally at d7 and d35 the fractional shortening function didn't show any differences between the groups after TAC.
On the other hand LV interstitial fibrosis (determined by collagen content) was significantly less distinct in TRIF−/− mice (1.4±0.2%) than in WT mice (2.3±0.3%, (p<0.01 TRIF−/− vs. WT) at d7 following TAC. According to that TGFbeta protein expression was more pronounced in WT (318±85% of sham-operated controls) than in TRIF−/− mice (111±15% of sham-operated controls; p<0.05 TRIF−/− vs. WT). These differences in fibrosis and TGFbeta remained at d35. Even the hydroxyproline concentration was higher in LV tissue of the WT mice than in the TRIF−/− mice d35 after TAC (WT: 93.4±7.7μM, TRIF−/− 54.8±9.0μM, p<0.5 TRIF−/− vs. WT). The expression of TGFbeta signaling pathway associated SMAD proteins (SMAD 3, pSMAD3, SMAD4) was up to two fold higher in WT mice than in TRIF−/− mice. Additionally expression of antifibrotic miR29b was more pronounced in TRIF−/− mice (2.34±0.71) than in WT mice (0.98±0.08) after TAC d7.

Conclusion
In afterload induced hypertrophy TRIF-dependent signaling doesn't influence cardiomyocyte hypertrophy. But TRIF plays an important role in the regulation of fibrosis in pressure overload dependent remodeling. Through the modulation of the TGF-beta signaling pathway and antifibrotic microRNAs TRIF signaling is involved in the development of interstitial fibrosis. Especially in the early stage of the cardiac remodeling.

Acknowledgement/Funding
KFO196
P749Dynamic of cardiac magnetic resonance imaging parameters in patients with non-ischemic cardiomyopathies after endomyocardial stem cell transplantation
Authors: Kurlianskaya A , Polonetsky O , Denisevich T , Shatova O , Osmolovskaya T , Isaikina Y , Salauyou D 
Published: October 2019

Abstract

Background
Autologous mesenchymal stem cell (MSC) transplantation can be considered as an alternative method of end-staged chronical heart failure treatment in patients with Non-ischemic Cardiomyopathies (NICMP). About 2/3 NICMP are determined by previous myocarditis, transformed in inflammatory cardiomyopathy (ICM), while only 1/3 of NICMP cases are associated with idiopathic dilated cardiomyopathy (DCM). Application of MSC therapy in different groups of NICMP patients is not sufficiently studied.

Purpose
The purpose of the study was to compare cardiac magnetic resonance imaging (cMRI) parameters in the left ventricle (LV) segments of myocardium in patients with DCM and ICM before and after autologous MSC transplantation.

Methods
The study covered 15 patients with DCM (mean age 45.8±3.1 years; 4 females, 11 males; LV ejection fraction (EF) <40%) and 15 patients with ICM (mean age 46.0±3.6 years; 5 females, 10 males; LV EF <40%). All patients underwent cMRI, endomyocardial injections of 0.2 ml autologous MSC culture (CD105+, CD90+, CD73+ cells) into akinetic and hypokinetic myocardial segments. In total we have analysed 228 segments of NICMP patients.

Results
In patients with ICM we found significant decrease in extracellular volume (ECV) within 6 months after primary examination (from 32 [28; 36]% to 27 [25; 30]%, p=0,007). As a result, ICM patients had lower ECV than DCM patients 6 months after MSC transplantation 27 [26; 29] % and 31 [29; 32]% respectively (p=0,001). Patients with ICM demonstrated an increase in LV systolic myocardial segment thickness (SMST) 6 months after MSC injections (5.91 [5.74; 6.15] mm – baseline vs. 6.67 [6.60; 6.82] mm – 6 months later, p≤0,010) with a bigger increase 12 months after MSC injection (9.58 [9.47; 9.73] mm, p≤0,010). In ICM patients LV SMST was significantly higher than in DCM patients 12 months after MSC transplantation (9.58 [9.47; 9.73] mm vs. 7.38 [7.29; 7.61] mm, p=0.032). ICM patients showed an increase in LV ejection fraction (EF) within 6 months after MSC therapy (from 20 [17; 24]% to 27 [17; 32]%, p=0.043).

Conclusions
Endomyocardial MSC transplantation showed better results in ICM patients compared to DCM patients. It led to a significant decrease in ECV within 12 months in contrast to DCM patients. ICM patients also demonstrated significant increase of LV SMST and LV EF within 6 months after MSC therapy.
P773Initiation of sacubitril/valsartan and optimisation of evidence-based heart failure therapies after hospitalisation for acute decompensated heart failure: An analysis of the TRANSITION study
Authors: Wachter R , Pascual-Figal D , Belohlavek J , Straburzynska-Migaj E , Witte K K , Fonseca C , Cavusoglu Y , Pouleur A C , Goncalvesova E , Lonn E , Noe A , Schwende H , Bao W , Butylin D , Senni M 
Published: October 2019

Abstract

Background
Optimisation of chronic heart failure (HF) therapy remains the key strategy to improve outcomes after hospitalisation for acute decompensated HF (ADHF) with reduced ejection fraction (HFrEF). Initiation and uptitration of disease-modifying therapies is challenging in this vulnerable patient population. We aimed to describe the patterns of treatment optimisation including sacubitril/valsartan (S/V) in the TRANSITION study.

Methods
TRANSITION (NCT02661217) was a randomised, open-label study comparing S/V initiation pre- vs. post-discharge (1–14 days) in patients admitted for ADHF after haemodynamic stabilisation. The primary endpoint was the proportion of patients achieving 97/103 mg S/V twice daily (bid) at 10 weeks post-randomisation. Up-titration of S/V was as per label. Information on dose of S/V and on the use of concomitant HF medication was collected at each study visit up to week 26.

Results
A total of 493 patients received at least one dose of S/V in the pre-discharge arm and 489 patients in the post-discharge arm. One month after randomisation, 45% of patients in the pre-d/c arm vs. 44% in the post-discharge arm used 24/26 mg bid starting dose and 42% vs. 40% were on 49/51 mg S/V bid, respectively. At week 10, 47% of patients had achieved the target dose in the pre-discharge arm vs. 51% in the post-discharge arm. At the end of the follow-up at 26 weeks, the proportion of patients on S/V target dose further increased to 53% in the pre-discharge and 61% in the post-discharge arm (Figure 1). At week 10, the mean dose of S/V was 132 mg in the pre-discharge arm and 136 mg in the post-discharge arm, and at week 26, it was 140 mg and 147 mg, respectively.
Before hospital admission, 52% and 54% of the patients received a beta-blocker (BB) in the pre-discharge and post-discharge group, respectively, and 42% in both arms received a mineralcorticoid receptor antagonist (MRA). At time of discharge, 68% and 71%% of the patients received a BB and 68% and 65% an MRA, in the pre-discharge and post-discharge groups, respectively. These proportions remained stable to week 10 and week 26.
Uptitration of sacubitril/valsartan

Conclusions
In the vulnerable post-ADHF population, initiation of S/V and up-titration to target dose was feasible within 10 weeks in half of the patients alongside with a 20% increase in the use of other disease-modifying medications that remained stable through the end of the 6-month follow-up.

Acknowledgement/Funding
The TRANSITION study was funded by Novartis