tbuckley/cabot-search huggingface dataset:
The smooth-walled human RVOT contains trabeculations that cause conduction delay
Authors: B Jensen, F M Bosada, M Blok, K T Scholman, I R Efimov, B J Boukens
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements None. Background The right ventricular outflow tract (RVOT) is the outlet from the right ventricle and is the initiating substrate of life-threatening arrhythmias. While the luminal wall of the RVOT is often assumed to be without the complex trabecular meshwork that characterizes the right ventricular free wall, the anatomy of the RVOT is an understudied subject. Aim to investigate whether trabeculations occur in the RVOT and to assess whether this impacts electrical propagation. Methods Human hearts were investigated using high-resolution MRI, histology, RNA-sequencing, and optical and electrical mapping. Results We used high-resolution MRI and serial sectioning to reconstruct the macroscopic details of the human RVOT and identified cases exhibiting much trabeculation. The smooth lumen of the RVOT varied between 9% and 23% of the total RV anterior surface (N=11). Histological analysis on additional six hearts indicated that the RVOT compact layer is thinner when trabeculations are present. RNA sequencing of four human donor hearts revealed enrichment in the subendocardial region of 88 genes associated with cardiac conduction and trabeculations (P adjusted&amp;lt;0.05). Finally, we selected two human donor hearts showing trabeculations in the RVOT from which we generated wedge preparation and performed optical and electrical mapping. The trabecular regions demonstrated high degree of fractionation when compared to non-trabeculated regions, which coincided with delayed activation. Conclusion Trabeculations are found in the RVOT, and their extent varies among individuals. This impacts on the thickness of the compact wall in the RVOT, restricting the depth of tissue at which clinical interventions can be performed, as well as influencing electrical propagation and possible arrhythmogenicity.
Ectopic Pitx2 expression and sinoatrial node dysfunction in mice recapitulating a novel cardiac syndrome identified in unrelated families with deletions in a gene desert on chromosome 4q25
Authors: L Van Der Maarel, F Bosada, M R Mungroo, F H T Tiel-Groenesteege, B Jensen, H Devalla, V M Christoffels
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Research Councin/NWO Introduction Several unrelated families presenting with a complex, heterogeneous cardiac syndrome including sinoatrial node dysfunction and atrial fibrillation were found to share overlapping deletions in a 1.5 Megabase pair gene desert on chromosome 4q25. These overlapping regions contain evolutionarily conserved CTCF binding sites that modulate the separation of topologically associating domains containing the transcription factor-encoding gene PITX2 and noncoding RNA genes. Aim To understand mechanistically how the deletion in the gene desert causes sinoatrial node dysfunction and atrial arrhythmias. Methods Mice lacking the orthologue of the minimally overlapping genomic region deleted in affected patients were generated. Electrophysiology, morphology, tissue composition, and transcriptomes were analysed in this mouse model. Results These mice recapitulated major morpho-functional features of the syndrome, including sinoatrial node dysfunction and atrial arrhythmogenesis . Out of the 15 genes flanking the gene desert, only Pitx2 expression was deregulated in the sinoatrial node. During development, cardiac Pitx2c expression is normally restricted to the left side where it drives left sinus venosus and left atrial morphogenesis and prevents the formation of a left-sided sinoatrial node. The PITX2 locus has also been associated with atrial fibrillation in GWAS. Immunohistochemistry together with 3D volume analysis showed that Pitx2c was ectopically expressed in half of the pacemaker cardiomyocytes of the developing and postnatal sinoatrial node while its expression in the left atrium was maintained. Key transcription factors that drive pacemaker cell differentiation, Tbx3, Isl1 and Shox2, were lost where Pitx2c was ectopically expressed. Moreover, a conserved long non-coding RNA (Playrr) previously linked to Pitx2 regulation in the developing dorsal mesentery, was downregulated in the sinoatrial node of homozygous mutants. The downregulation of the pacemaker gene program additionally coincided with the activation of the atrial myocardial gene program in half of the pacemaker cardiomyocytes. Conclusion We generated a mouse model of a novel human cardiac syndrome including sinoatrial node dysfunction associated with the deletion of critical CTCF binding sites in a gene desert on chromosome 4q25. This deletion induced ectopic Pitx2c expression in the sinoatrial node alongside a substantial loss of pacemaker cardiomyocyte identity and a gain in a working atrial myocardium-like phenotype in the sinoatrial node of affected mice.Loss of pacemaker cardiomyocyte identitySinoatrial node dysfunction in mutants
Annual vascular and bleeding outcomes in East Asian poststenting patients with acute coronary syndrome: The BRIC-ACS II trial
Authors: D Li, Y Yu, Y Chen
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: None. Main funding source(s): no Objective We aim to determine the incidence of events in the ‘real-world’ ACS Chinese patients over 1-year after PCI. Methods and Results From November 2017 till April 2020, we enrolled post-stenting ACS patients (n=5515) from 30 hospitals with the strict 1-year follow-up (n=5150). Only 153(3.0%) patients developed MACE (a composite of all-cause death, myocardial infarction, ischemic stroke, or urgent coronary revascularization). The cumulative incidence of annual bleeding (BARC≥2) was 5.8% (298/5150). The BARC≥2 bleeding was higher 298 (5.8%) and was not associated with worsened MACE (P =0.52). Patients treated with ticagrelor (n=1620, 6.0%) had a significantly increased risk of bleeding than those treated with clopidogrel (n=2331; 4.1%) (HR=1.486; 95% CI:1.12-1.97; P=0.006), but similar risk of vascular MACE (2.7% vs 2.8%; HR= 0.94; 95% CI:0.64-1.38; P=0.747).The factors independently associated with the comprehensive risk of BARC≥2 bleeding and MACE, including female gender, renal insufficiency, peptic ulcer, atrial fibrillation, continuous use of ticagrelor and non-continuous DAPT. The discrimination of the nomogram model was further tested by the ROC curve (AUC value:0.610 (95% CI, 0.577-0.642)). Conclusions The annual incidence of BARC≥2 bleeding in ACS patients treated with PCI in China was higher (5.8%) than MACE (3.0%). DAPT with ticagrelor increased the bleeding rates with no trend towards MACE reduction.
The interpretation of field and LEAP potentials recorded from cardiomyocyte monolayers
Authors: B Boukens, A C Ernault, R F M Al-Shama, J R Li, H D Devalla, J R De Groot, R F M Coronel, E Vigmond
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements None. Multi-electrode arrays (MEA) are the method of choice for electrophysiological characterization of cardiomyocyte monolayers. The field potentials recorded using a MEA are like extracellular electrograms recorded from ventricular myocardium using conventional electrodes. Nevertheless, different criteria are often used to interpret field potential and extracellular electrogram, which hampers correct interpretation and translation to the patient. To validate criteria for extracellular electrograms analysis applicable to field potentials, we used neonatal rat cardiomyocytes to generate monolayers. We recorded field potentials using a MEA and simultaneously recorded action potentials using sharp micro-electrodes. In parallel we recreated our experimental setting in silico and performed simulations. We demonstrate that the amplitude of the local RS-complex of a field potential correlated with conduction velocity, but only in the lower ranges of conduction velocities. The time of the peak of the T-wave of the field potentials correlated well with APD90 and the time of the steepest upslope with APD50. By injecting current into the monolayer, we could record a local extracellular action potential (LEAP). The LEAP was of low amplitude and highly depolarized, and the shape differed markedly from the shape of the local action potential. Criteria for interpreting extra cellular electrograms should also be applied to field potentials. This will provide a strong basis for analysis of heterogeneity in conduction velocity and repolarization in cultured monolayers of cardiomyocytes especially at low conduction velocities. A LEAP is not a recording of the local action potential but is generated by intracellular current provided by neighboring cardiomyocytes.
Gut microbiota alterations after acute coronary syndrome: a single center, case-control pilot study
Authors: N Suntornlekha, K Leemasawat, P Suwannasom, N Apaijai, S Sriwichaiin, K Suparan, N Chattipakorn, S Chattipakorn
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Research Council of Thailand Background Decreasing of gut microbiota diversity has been reported in coronary artery disease. However, the data of gut microbiota alterations after acute coronary syndrome (ACS) are still limited. Objective To determine the stool microbiota differences between ACS and controls. Also determine stool microbiota changes between ACS onset and 3 months apart. Methods We conducted a single-center, case-control pilot study. Ten ACS patients, aged between 18 to 80 years old, were consented. Echocardiogram, blood and fecal samples were obtained within 24 hours of hospitalization, then additionally 3 months apart. Ten of controls were also enrolled and collected the data. 16S ribosomal RNA gene was used to identify fecal bacteria. Results The mean age and gender were similar between both groups. The abundance of stool Clostridial was significantly decreased in ACS compared with controls (mean 8.476 ±0.570 vs. 9.254 ±0.829 Log10 copies/uL, p=0.025) and remained unchanged after 3 months (mean 8.256 ±0.787 Log10 copies/uL, p=0.483). The gut dysbiosis was not correlated with left ventricular function and medications. Conclusion Gut dysbiosis was observed in ACS patients and persisted afterward, regardless of LVEF and treatment. Gut dysbiosis might be an ACS risk marker in high cardiovascular risk patients. Further studies are warranted.Bacterial composition of fecal samples
Cardioprotective effects of Empagliflozin in cardiac volume overload-induced by aortocaval fistula in rats
Authors: M Sykora, K Andelova, V Farkasova, Z Honetschlagerova, E Goncalvesova, N Tribulova, B Szeiffova Bacova
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Slovak Research and Development Agency under the contract no. 21-0410 VEGA grants no. 2/0006/23 Heart failure is characterized by reduction in cardiac output and the occurrence of malignant arrhythmias, thereby contributing significantly to high morbidity and mortality worldwide. Myocardial structural remodelling is a key factor contributing to the development of these life-threatening events and belongs to unsolved clinical issues challenging to investigate in animal models. The aim of our study was to explore the impact of cardiac volume overload (VO) on structural remodelling and electrical coupling protein, connexin43 (Cx43) in the left and right heart ventricles as well as the efficacy of treatment with SGLT2i, Empagliflozin. Aortocaval fistula (ACF) was surgically induced in 6-month-old Wistar rats, to develop VO during 4 weeks, followed by oral administration of Empagliflozin 10 mg/kg/b.w. daily for 5 weeks. At the end of the experiment, biometric parameters were registered and left and right heart tissue samples were snap-frozen and kept at -80°C for western blot analysis and microscopic examination. Findings revealed an increase of heart, left and right ventricular mass due to ACF-VO versus sham controls, which was associated, with eccentric myocardial hypertrophy. Noteworthy, Empagliflozin reduced heart, left and right ventricular mass. Levels of myocardial protein Cx43, that determine electrical coupling among cardiomyocytes, were reduced by ACF-VO, while normalized by treatment with Empagliflozin. Moreover, treatment attenuated ACF-VO-induced increase of interstitial collagen visualized by van Gieson staining. It was in line with the protein expression of MMP-2, which is involved in structural remodeling. The protein levels of PKCε, concerned/associated with modulation of Cx43 and extracellular matrix, were decreased due to ACV-VO but normalized after treatment with Empagliflozin. On the other hand, protein levels of PKCδ, involved in proapoptotic and prohypertrophic pathways, were increased and normalized by Empagliflozin. The changes were more pronounced in the right ventricle compared to the left heart ventricle. In summary, our pilot results point out the benefit of Empagliflozin due to the suppression of myocardial structural remodelling and preservation of Cx43 in the rat ACF-VO model. Furthermore, this Empagliflozin-induced cardioprotection was associated with the normalization of Cx43, MMP-2, and PKC levels independent of glucose control. However, further analyses are needed to reveal the molecular mechanisms of the cardioprotective effects of Empagliflozin.
miRNA signature related to atherosclerotic lesion induced shear stress modifications in familial hypercholesterolemia patients with subclinical atherosclerosis: a bioinformatics systems biology study
Authors: T Padro, R Escate, L Perez De Isla, O Muniz-Grijalbo, P Mata, L Badimon
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Institute of Health Carlos III (ISCIII) Background Patients with familial hypercholesterolemia (FH), even when appropriately treated, are at risk of premature clinical atherosclerotic cardiovascular disease (ASCVD) presentation. Although atherosclerosis (AT) is directly related to hemodynamic disturbances affecting the vascular geometry, there is scarce information on whether there is miRNA-mediated/flow-mediated modulation of atherosclerosis in FH. Purpose To identify a differential plasma miRNA signature related to fluid shear stress (FSS) in well controlled FH-patients with asymptomatic atherosclerosis. Methods FH-patients (N=49) with subclinical atherosclerosis, identified by computed tomographic angiography, and a reference cohort of non-FH subjects (N=32), both from a national FH-Registry, were included in the study. Coronary plaque volume and phenotype was analyzed by means of the QAngio CT imaging system. miRNAs associated to FSS were defined in silico by bioinformatics (KEGG, Cytoscape, GTEX portal, miRWalk, miRBase tools) and validated in plasma samples by RT-qPCR using TaqMan technology. Results By in silico analysis, 7 miRNAs targeting genes involved in features of functions (ROS production, oxidative stress, leukocyte transendothelial/migration-inflammation and vasodilation) of shear stress-induced cellular dysfunction and atherosclerosis (KEGG, hsa05418) were identified by miRWalk and miRBase databases. Of the 7 miRNAs, a 6-miRNA signature showed significantly lower plasma levels in FH-patients than in the non-FH group (P&amp;lt;0.01 for: miR-30e-5p, miR-378a-3p, let-7d-3p, and miR-550-5p; P=0.03 for miR-324-3p). In the FH-group, miR-324-3p, miR-30e-5p, miR-378a-3p and let-7d-3p significantly discriminated patients stratified by the plaque volume of non-calcified lesions (fibro-lipidic phenotype), using the median plaque volume as cut-off value. And even further, a high percentage (65-70%) of FH-subjects with low levels of the 4 miRNA had plaque volumes above the median. Interestingly, this miRNA-signature did not differentiate FH-patients stratified by the volume of calcified plaques. Conclusion FH-patients show a significantly lower content of an atherosclerosis/shear stress signature of 4 miRNAs targeting genes involved in subclinical atherosclerosis progression in FH.
Selective inhibition of Histone deacetylases reverses vascular remodeling and improves right ventricle function in pulmonary hypertension
Authors: K B Kurakula, X Sun, R M F Berger, S Bonnet, H J Bogaard, M J Goumans
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Longfonds and CVON Background Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodeling of pulmonary vessels, leading to increased vascular resistance and ultimately right ventricle (RV) failure. Disturbed BMPR2/TGFβ signaling is a driver of disease progression. Inhibition of Histone deacetylases (HDACs) using small molecule inhibitors attenuated vascular remodeling, however, they worsened RV function in animal models of PAH. Objectives The aim of this study is to validate if the selective HDAC inhibitor Quisinostat reverses pulmonary vascular remodeling and improves RV function. Methods and results We found that protein levels of HDAC1 are increased in the lungs of PAH patients. Treating microvascular endothelial cells (MVECs) and smooth muscle cells of PAH patients with Quisinostat significantly decreased TGF-β signaling and strongly decreased cell proliferation and the levels of inflammatory cytokines. In the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, Quisinostat reversed abnormal vascular remodeling and improved RV function. Furthermore, Quisinostat could be combined safely with the contemporary PAH standard of care. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding, and no systemic or cardiotoxic effects were observed. Conclusions Our data demonstrate that selective inhibition of HDACs reverses pulmonary vascular remodeling and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH.
Targeting glutaminolysis pathway in trained immunity induced by oxidized low-density lipoprotein
Authors: A Scarpa, L Groh, K Placek, V Matzaraki, S Bekkering, K Hiller, M G Netea, N P Riksen
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft DFG Atherosclerosis is a chronic inflammatory disease of the arterial wall that causes cardiovascular disease. Monocyte-derived macrophages importantly contribute to atherogenesis. Monocytes can be primed to exhibit increased responsiveness upon a secondary non-related stimulus, a phenomenon called trained immunity. Intracellular metabolic and epigenetic reprogramming lays the basis of trained immunity. One of the stimuli that can induce trained immunity is oxidized low-density lipoprotein (oxLDL). oxLDL-trained monocytes exhibit an increase in metabolic pathways such as glycolysis, OXPHOS, and cholesterol biosynthesis. The glutaminolysis pathway that fuels the tricarboxylic acid (TCA) cycle is essential for trained immunity induction by b-glucan, the cell wall component of Candida albicans. The goal of this project is to investigate the involvement of the glutaminolysis pathway in oxLDL-induced trained immunity in isolated human primary monocytes. We exposed monocytes for 24 hours to oxLDL, allowed subsequent differentiation into macrophages for six days in culture medium, and assessed cytokine production capacity upon restimulation. Co-incubation of oxLDL with the inhibitor that blocks glutaminase, the enzyme that generates glutamate from glutamine, significantly reduced cytokine production capacity in oxLDL-trained cells. We further showed that glutaminolysis is necessary for oxLDL-induced increase in oxygen consumption (OCR) and glycolysis rate (ECAR). Single nucleotide polymorphisms in glutaminolysis genes were shown to correlate with ex vivo oxLDL-induced trained immunity in 243 healthy volunteers. These data suggest an important role of glutaminolysis in the establishment of oxLDL-induced trained immunity. To unravel the molecular mechanisms behind this observation we plan to perform epigenetic as well as metabolic analyses of the monocytes trained in the presence of the inhibitor.
Modulating sialylation as therapeutic approach for preventing age-associated cardiac dysfunction
Authors: A Tarantino, D Melgari, A Ghiroldi, I Lavota, P Rota, S Calamaio, M Piccoli, C Pappone, L Anastasia
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Ministry of Health Voltage-gated sodium channel Nav1.5 plays a pivotal role in the proper functioning of cardiac muscle cells. Sialylation, a post-translational modification involving the addition of negatively charged sialic acid moieties, is essential for Nav1.5 functionality. Altered sialylation has been observed in various cardiovascular diseases, including Chagas disease and congenital disorders of glycosylation affecting the heart. Furthermore, sialylation status has been shown to change during human adult life, impacting brain and muscle structural properties. Cardiac arrhythmias increase in prevalence with age, contributing to higher morbidity and mortality in older people. Using an aging mouse model, we observed a decline in cardiac sialic acid levels and NaV1.5 associated with the aging process. In compelling in vitro experiments on HEK293 cells and induced pluripotent stem cell-derived cardiomyocytes, diminished external sialic acid induces Nav1.5 channel internalization, activating endocytic pathways and leading to proteasome-mediated degradation. Intriguingly, proteomic analysis revealed that introducing a specific sialic acid precursor increased membrane protein trafficking, restoring Nav1.5 protein levels and the sodium current. Electrophysiological experiments demonstrated functional recovery and highlighted the rapid response, observable within just 2 hours of sialic acid stimulation. In summary, this study provides novel insights into the complex relationship between sialic acid and NaV1.5 channel trafficking, offering new perspectives and promising therapeutic strategies to prevent cardiac dysfunction in elderly.Modulating sialylation on NaV1.5 channelOur project goal