bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spontaneous coronary artery dissection: current evidence from cardiac magnetic resonance and angiography screening
Authors: Androulakis E , Azzu A , Papagkikas P , Antonopoulos A , Al-Hussaini A , Pennell D , Mohiaddin R 
Published: October 2022

Abstract

Purpose
To assess the distribution and extent of myocardial infarction, as well as possible clinical significance of peripheral arteriopathy screening in a cohort of patients presented with spontaneous coronary dissection (SCAD) using cardiovascular magnetic resonance (CMR) for cardiac and vascular imaging. The adverse CMR features and predictors of infarction in subgroup analysis were also investigated.

Methods
This is an observational, single centre study of 144 consecutive, angiographically confirmed SCAD survivors &gt;18 years old, based on collected data from Jan 2008-Nov 2020. All scans were performed on a 1.5-Tesla scanner. Cardiac structural and functional indices, myocardial infarct size and distribution were evaluated. In addition, vascular imaging was performed in all patients for thoracic aorta screening as part of the routine protocol, and in 75 patients peripheral arteriopathy screening from Circle of Willis to the iliac arteries was performed using 2D multi-slice and cine imaging, as well as 3D imaging methods.

Results
In the total population, 64% had infarction. Infarct size (%) was predictive of reduced left ventricular ejection fraction (LVEF) (p&lt;0.001) and increased diastolic volumes (p&lt;0.001 for both). Logistic regression showed SCAD in right coronary artery (Odds Ratio (OR): 5.2, p=0.034) predicted the presence of infarction. In the group who also underwent peripheral vascular screening, the overall prevalence of extra-coronary arteriopathy was 27% with fibromuscular dysplasia accounting for one-fourth of the cases (Figure 1). Of note, most positive vascular screening patients (73.3%) exhibited infarction (OR: 7.0, p=0.041), distributed in more than one territory (OR: 4.0, p=0.015) (Figure 2), while infarct size was negatively correlated with LVEF (p&lt;0.001). Right ventricular ejection fraction was significantly reduced in positive screening patients (58.8±7.4 vs. 63.0±8.0, p=0.045). Further subgroup analysis showed pregnancy associated SCAD patients had significantly larger sized infarcts (25.1±6.1 vs. 6.2±0.7%, p&lt;0.001) with reduced LVEF (51.0 vs 63.6±7.6, p&lt;0.001). In logistic regression, this condition also predicted large infarcts &gt;10% (OR: 9.8, p=0.009) in anterior walls (p&lt;0.001).

Conclusions
Patients with SCAD require careful assessment of myocardial structure, function and characterization of infarction which may reflect the underlying pathophysiology. Extra coronary vascular screening, although not established in clinical practice, seems a rational strategy to potentially identify a subgroup with more severe infarction and likely to have vascular pathology.

Funding Acknowledgement
Type of funding sources: None.
Aberrant interaction between TEAD1 and Lamin A/C causes cardiomyopathy
Authors: Yamada S , Ko T , Ito M , Sassa T , Nomura S , Komuro I 
Published: October 2022

Abstract

Background
Mutations in the LMNA gene encoding Lamin A/C, a major component of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM). DCM patients with LMNA mutations have particularly severe clinical courses such as heart transplantation and death due to heart failure. However, underlying mechanisms of LMNA-induced DCM remains elusive.

Methods and results
We identified LMNA Q353R mutation in a DCM family with severe heart failure. We generated Q353R heterozygous knock-in mice, which showed sarcomere dysplasia and perinatal lethality. Integrative single-cell analyses of the fetal murine hearts and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSCMs) revealed that transcriptional regulation of cardiomyocyte maturation/development genes governed by TEAD1 was impaired in LMNA mutant cardiomyocytes. Protein array and immunostaining uncovered increased binding of TEAD1 to mutant Lamin A/C protein and abnormal localization of TEAD1 at the nuclear periphery. Furthermore, TT-10, a Hippo pathway inhibitor, rescued the dysregulation of cardiac developmental genes in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from DCM patients with the LMNA Q353R mutation confirmed the dysregulated expression of TEAD1 and its target genes. These results demonstrated abnormal interaction between TEAD1 and mutant Lamin A/C impairs structural maturation of cardiomyocytes and suggests that LMNA Q353R-related DCM can be treated through intervention in the Hippo pathway.

Conclusion
TEAD1 trapped by mutant Lamin A/C protein at the nuclear membrane perturbs transcriptional maturation in LMNA Q353R-related DCM.

Funding Acknowledgement
Type of funding sources: None.
Characterization of myocardial proteomics in biopsy proven cardiomyopathies
Authors: Lee S H , Chang D K , Kyoung Y J , Kim E S , Kim I C , Youn J C , Kim J S 
Published: October 2022

Abstract

Background
Difference in proteomic expression according to the etiology of cardiomyopathies is not well known.

Purpose
We aimed to identify proteome based pathogenesis in patients with biopsy proven cardiomyopathies.

Methods
Comparative proteomic analysis of biopsy specimens were performed from 9 patients with cardiomyopathy (3 dilated cardiomyopathy (DCM), 2 hypertrophic cardiomyopathy (HCM) and 4 myocarditis) as well as 5 controls (normal endomyocardial biopsy specimen from one-year surveillance of heart transplant recipients) by tandem mass tag combined with liquid chromatography-mass spectrometry. Differential expression protein analysis, gene ontology analysis and Ingenuity pathway analysis were done to discover molecular mechanism for the differentially expressed proteins in each cardiomyopathy compared to the control.

Results
Differential expression protein analysis showed higher proportion of significantly increased proteins (Log2 fold change ≥1) in HCM and myocarditis, whereas higher proportion of significantly decreased proteins (Log2 fold change ≤−1) in DCM compared to controls (Figure). According to the gene ontology analysis, upregulation of neutrophil degranulation, and down-regulation of mitochondrial translation protein was noted in patients with DCM. In patients with HCM, platelet degranulation protein was increased, and mitochondrial ATP synthesis coupled electron transport, was decreased. In patients with myocarditis, neutrophil related proteins and calcium ion binding protein was increased, but muscle cell development, protein was decreased. Ingenuity pathway analysis revealed downregulation of oxidative phosphorylation and upregulation of sirtuin signalling pathway both in DCM and HCM. In myocarditis, various pathways related to inflammation were upregulated with only RHO GDP dissociation inhibitors downregulated.

Conclusions
This study showed that each cardiomyopathy exhibited different proteomic expression compared to normal heart. Further large detailed study is needed to understand the association between proteomic expression and disease pathophysiology.

Funding Acknowledgement
Type of funding sources: None.
Loss of ceramide synthase 5 reduces the development of aortic valve stenosis in mice with high fat diet
Authors: Reese L , Haenschke L , Niepmann S T , Bulic M , Duesing P , Zimmer S , Nickenig G , Bauer R , Jansen F , Zietzer A 
Published: October 2022

Abstract

Background
Ceramide synthase 5 (CerS5) is essential to maintain C:16 ceramide levels in mice. Ceramides contribute to inflammation and calcification, two hallmarks of aortic valve stenosis development. It is known, that loss of CerS5 function reduces diet-induced obesity.

Purpose
The aim of this study was to investigate the effect of ceramide synthase 5 and high-fat diet on the development of aortic valve stenosis with a mouse model.

Methods
Our experiment consists of four groups of mice: Wild type (WT) and CerS5 (−/−) mice, with normal and high fat diet. We induced the aortic valve stenosis development through a wire-injury. For this model, a coronary angiography wire is introduced into the left ventricle over the right carotid artery, followed by rotation on the aortic valve level to generate a defined injury. Development of aortic valve stenosis was determined by measuring the peak velocity 14, 28 and 42 days after the wire-injury. With histological analysis of the aortic valve, we measured macrophage infiltration with CD68 immunostaining and calcification using von Kossa staining. For statistical analysis ANOVA and Turkeys multiple comparisons were performed.

Results
Histological analysis of the aortic valve revealed, that in CerS5 (−/−) mice with high fat diet (HFD) immune cell infiltration is reduced, while there is no difference between CerS5 (−/−) mice and wild type, when fed with normal diet (A). Also calcification showed a trend towards a reduction in CerS5 mice with high fat diet, but was not statistically significant (B). Echocardiography could detect a reduced peak velocity of CerS5 mice with high fat diet, in comparison to the other groups, four and six weeks after wire injury (C).

Conclusion
Our experiments indicate that loss of CerS5 function reduces the development of aortic valve stenosis in mice with high fat diet, by decreasing immune cell infiltration and calcification. Interestingly, in the groups with normal chow, loss of CerS5 function had no effect. In addition, high-fat diet alone had no negative effect in our mouse model. Based on our results it can be assumed that upon high fat diet CerS5 mediates for pro-inflammatory effects in the aortic valve, which are absent on normal diet.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Ernst & Berta Grimmke Foundation (13/19)
SGLT1/2 expression in the heart of transplanted patients is associated with inflammatory induction of oxidative stress: potential protective effect of SGLT2 inhibitors
Authors: Gong D S , Mroueh A , Matsushita K , Fakih W , Auger C , Oak M H , Pieper M P , Morel O , Epailly E , Schini-Kerth V 
Published: October 2022

Abstract

Introduction
Heart transplantation is a life-saving surgical procedure for patients with end-stage cardiac dysfunction, however, such procedures are usually at risk of rejection due to acute inflammatory activation. While such inflammatory induction leaves the newly transplanted heart at risk of functional and structural remodeling subsequent to oxidative damage, current anti-inflammatory treatment options expose the patient to an elevated risk for adverse reactions in addition to absence of cardio-protective effects. Therefore, novel therapies with anti-inflammatory and cardio-protective dual effects are needed. Recently, our group has reported that low-grade inflammation is associated with upregulation of SGLT1/2 in arteries of human with cardiovascular diseases. Yet, the role and function of SGLT2 in human cardiac tissue remains poorly understood.

Aim
This study focuses on the expression pattern of SGLT1/2 in cardiac biopsies of heart transplanted patients and aim to identifying their functional impact.

Methods
Routine endomyocardial Biopsies (23) were performed for the detection of acute rejection heart transplanted patients (less than 2 years) at our University Hospital. Gene expression levels were assessed using RT-qPCR, the in situ tissue localization of proteins by immunofluorescence staining, and the level of oxidative stress by dihydroethidium staining.

Results
Gene expression analysis revealed strong inflammatory reaction in 5 samples indicated by at least 20-fold higher levels of mRNA of IL1B, IL6, TNFA and CD68 compared to the other 18 samples and concomitant with high expression levels of SLC5A1, SLC5A2, AT1R, CYBA, NCF1, ICAM1, VCAM1, MMP2, MMP9 and TGFB1 in contrast to low levels of NOS3. In addition, increased levels of oxidative stress were observed in the same biopsies, which were diminished by the antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibitor (VAS-2870), TNF-α receptor neutralizing antibody (infliximab), ACE inhibitor (perindoprilat), AT1R antagonist (losartan), dual SGLT1/2 inhibitor (sotagliflozin) and selective SGLT2 inhibitor (empagliflozin) with inhibitory effects reaching up to 80%. Immunofluorescence staining indicated signals for nitro-tyrosine, TNF-alpha, SGLT1 and 2 in several samples.

Conclusion
These findings indicate that both isoforms SGLT1 and SGLT2 are expressed in the transplanted human heart and suggest a pattern of expression associated with pro-inflammatory response. They further indicate a potential protective effect of SGLT2 inhibitors in transplanted hearts through mitigating oxidative stress and hence providing a possible novel therapy for heart transplantation recipients to preserve the heart function.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH & Co. KG
A Human atlas of smooth muscle cell gene expression; insights from the FANTOM consortium CAGE dataset
Authors: Vaja R , Atanur S , Mitchell J A , Ahmetaj-Shala B 
Published: October 2022

Abstract

Background
Under normal physiological conditions, smooth muscle cells (SMC's) have a role in both vessel contraction and generation of the extra-cellular matrix. It has now become apparent that SMCs throughout the vasculature play a key role in several cardiovascular conditions including hypertension, atherosclerosis, vasculopathy and myocardial infarction. However, how SMC gene expression compares in different vascular and non-vascular anatomical regions remains unknown.

Purpose
To create a human SMC gene expression map using data from the FANTOM consortium Cap-analysis gene expression (CAGE) dataset, a primary database of almost 600 human primary cell samples.

Methods
The gene level expression data was obtained by aggregating expression levels of all the promoters belonging to same gene as defined by the FANTOM CAGE dataset. The anatomical regions (n: 13) included the following vascular sites: aortic, brachiocephalic, carotid, coronary, internal thoracic & pulmonary arteries. Non-vascular regions included colon, oesophagus, prostate, uterine, trachea and bronchial. Weighted correlation network analysis (WGCNA) was used as an unsupervised approach to identify clustering of gene sets.

Results
Hierarchical clustering (Figure 1) demonstrates a distinct clustering of vascular SMC gene sets (aortic, carotid, coronary, internal thoracic, pulmonary & subclavian arteries). The same pattern of vascular SMC clustering was also seen in WGCNA (Figure 2). Gene ontology enrichment of vascular SMCs that clustered in WGCNA identified common gene sets relating to cytokine and chemokine activity. KEGG pathway analysis highlighted several pathways linked to inflammation (TNF, IL17 & NF-κB signalling) as well as pathways linked to atherosclerosis and lipid metabolism.

Conclusion
Vascular SMCs distinctly cluster away from non-vascular SMC types in humans and the separation is primarily driven by gene sets relating to inflammation, lipid metabolism & atherosclerosis. Mapping SMC gene expression at various anatomical regions in both healthy and diseased states may give us better insight into the role of SMCs in disease progression and could identify novel mechanistic targets for future therapy.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): British Heart Foundation
Dysregulation of cardiac endothelial lncRNA H19 in COVID19 patients induces endothelial dysfunction, which impairs cardiomyocyte function
Authors: Juni R P , Phelp P , Bink D , Espinoza-Gonzales P , Van Bergen A , Kuster D , Van Der Velden J , Krijnen P , Niessen H , Boon R 
Published: October 2022

Abstract

Background
COVID19 is accompanied by cardiac complications. Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. However, their contribution to the cardiac manifestation of COVID19 is unknown.

Methods and results
We discovered that endothelial-enriched lncRNA H19 is downregulated in the heart of patients with COVID19 (∼2 fold, p&lt;0.01). H19 was highly expressed in cardiac microvascular endothelial cells (CMEC) as compared to the other endothelial cell types (∼10 fold, p&lt;0.05), suggesting its cardiac enrichment. H19 silencing in CMEC induced endothelial stress phenotype and a reduction in endothelial markers VE-cadherin and eNOS (∼1.5 fold, p&lt;0.01), indicating its importance in endothelial physiology. Using the endothelial-cardiomyocyte co-culture system we previously developed, we showed that H19 silencing in CMEC reduced cardiomyocyte (CM) relaxation and contraction (∼1.5 fold, p&lt;0.01). Interestingly, exposure to plasma from COVID19 patients decreased endothelial H19 level and impaired endothelial enhancement of CM function. Mechanistically, reduced level of H19 increased endothelial IL6 expression (∼1.5 fold, p&lt;0.01). Further, exposure of CMs to IL6 also impaired CM relaxation and contraction, suggesting that endothelial cells devoid of H19 release IL6 which represses CM function. Interestingly, we found increased IL6 levels in the heart of COVID19 patients (∼2 fold, p&lt;0.05). Indeed, the impairment of endothelial enhancement of CM function upon H19 silencing in CMEC was restored in the presence of tocilizumab, an IL6 receptor antagonist (∼1.5 fold, p&lt;0.01). Furthermore, the impairment of the endothelial control on CM function upon exposure to COVID19 plasma was mitigated when the patients were treated with tocilizumab (∼1.5 fold, p&lt;0.01).

Conclusion
COVID19 reduces cardiac endothelial H19 level and induces impairment of endothelial enhancement of CM function via increased release of endothelial-derived IL6, the effect that can be rescued in the presence of IL6 receptor blocker tocilizumab.

Funding Acknowledgement
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERC
Plasma eicosanoid profiling in the course of proprotein convertase subtilisin-kexin type 9 inhibition: insights from a metabolomic analysis
Authors: Schrutka L , Hagn G , Galli L , Poeschl A , Seidl V , Ondracek A , Bileck A , Lang I , Hengstenberg C , Krychtiuk K , Speidl W , Gerner C , Distelmaier K 
Published: October 2022

Abstract

Background
Treatment with monoclonal antibodies targeting circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) was found to reduce all-cause mortality in addition to cardiovascular events, suggesting pleiotropic effects. Eicosanoids are bioactive metabolites involved in cardiovascular disease and have not yet been studied in the course of PCSK9 inhibition.

Methods
In this prospective translational single-center study, plasma samples were collected from 64 patients before and after initiation of PCSK9 inhibitor treatment. Metabolomic analyses were performed using liquid chromatography coupled to high-resolution mass spectrometry.

Results
A total of 62 bioactive eicosanoids were detected. Among the metabolites, four were significantly decreased by PCSK9 inhibition after one month and remained stable after 6 months (figure): arachidonic acid (p=0.003), 12,13-DiHOME (p&lt;0.001), 9-HpODE_9.91 (p=0.007) and HpODE_7.71 (p=0.011). Phospholipase A2 levels were reduced by 40% after 1 month (p=0.003) and by additional 50% after 6 months of treatment (p=0.015), but did not correlate with eicosanoids (p=0.057). The change in arachidonic acid levels resulted in a significant increase in the ratio of omega-3 to omega-6 polyunsaturated fatty acids (p=0.002).

Conclusion
PCSK9 inhibition leads to significant changes in the eicosanoid profile already after one month, in particular to a downregulation of arachidonic acid. This discovery complements the presumed pleiotropic effects of PCSK9 inhibition and may provide additional benefit in the treatment of atherosclerotic disease.

Funding Acknowledgement
Type of funding sources: None.
Autoantibodies may predict the neurological severity of patients with Wilson disease
Authors: Wolska M , Eyileten C , Nowak A , Palejko A , Cudna A , Litwin T , Antczak-Kowalska M , Kurkowska-Jastrzebska I , Czlonkowska A 
Published: October 2022

Abstract

Background
Wilson's disease (WD) is a rare, autosomal disorder of copper metabolism, in which antibodies mediate and modulate the clinical manifestation of the CNS disease. The aim of this study was to investigate the presence and impact of autoantibodies in the clinical course of WD.

Method
Study involved 88 WD diagnosed and already treated patients with 7-years follow-up. Indirect immunofluorescence assays and Western Blot analysis was used.

Results
Patients who presented neurological manifestations had significantly more frequently ANA, ANCA and ANNA presence than in healthy individuals (p=0.029, p=0.009, p=0.025, respectively). In patients treated with d-penicillamine positive ANA antibodies were observed more frequently (p=0.005), whereas in zinc sulphate treated patients PP, ANCA and ANNA were significantly more frequently positive (p=0.038, p=0.024, p=0.002, respectively). Within the group of patients who died, positive ANA antibodies were significantly more frequent in comparison to patients who survived (p=0.020). Patients presenting positive cANCA had significantly higher UWDRS II, III and total scores compared to patients without ANCA antibody (p=0.033, p=0.022, p=0.022, respectively).

Conclusion
Drug-induced ANCAs may have a predictive value, as it is positively correlated with UWDRS II, III and total score in patients with WD. Only patients with neurological manifestations had significantly higher ANA, ANCA and ANNA presence. Increased positivity of those antibodies may predict the neurological manifestation of the severe cases and may be helpful for the neurological assessment of WD.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): Medical University of Warsaw