Cardiovascular Research最新文献

{"title":"PITX2 deficiency leads to atrial mitochondrial dysfunction.","authors":"Jasmeet S Reyat, Laura C Sommerfeld, Molly O'Reilly, Victor Roth Cardoso, Ellen Thiemann, Abdullah O Khan, Christopher O'Shea, Sönke Harder, Christian Müller, Jonathan Barlow, Rachel J Stapley, Winnie Chua, S Nashitha Kabir, Olivia Grech, Oliver Hummel, Norbert Hübner, Stefan Kääb, Lluis Mont, Stéphane N Hatem, Joris Winters, Stef Zeemering, Neil V Morgan, Julie Rayes, Katja Gehmlich, Monika Stoll, Theresa Brand, Michaela Schweizer, Angelika Piasecki, Ulrich Schotten, Georgios V Gkoutos, Kristina Lorenz, Friederike Cuello, Paulus Kirchhof, Larissa Fabritz","doi":"10.1093/cvr/cvae169","DOIUrl":"10.1093/cvr/cvae169","url":null,"abstract":"<p><strong>Aims: </strong>Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation (AF). PITX2 is restricted to left atrial cardiomyocytes (aCMs) in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy, and AF are not fully understood.</p><p><strong>Methods and results: </strong>To identify mechanisms linking PITX2 deficiency to AF, we generated and characterized PITX2-deficient human aCMs derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganized sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared with isogenic controls. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with AF compared with 43 patients with sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria.</p><p><strong>Conclusion: </strong>PITX2 deficiency causes atrial mitochondrial dysfunction and a metabolic shift to glycolysis in human aCMs. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1907-1923"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous infusions of mesenchymal stromal cells have cumulative beneficial effects in a porcine model of chronic ischaemic cardiomyopathy.","authors":"Xian-Liang Tang, Marcin Wysoczynski, Anna M Gumpert, Mitesh Solanki, Yan Li, Wen-Jian Wu, Shirong Zheng, Halina Ruble, Hong Li, Heather Stowers, Shengnan Zheng, Qinghui Ou, Nida Tanveer, Jan Slezak, Dinesh K Kalra, Roberto Bolli","doi":"10.1093/cvr/cvae173","DOIUrl":"10.1093/cvr/cvae173","url":null,"abstract":"<p><strong>Aims: </strong>The development of cell therapy as a widely available clinical option for ischaemic cardiomyopathy is hindered by the invasive nature of current cell delivery methods. Furthermore, the rapid disappearance of cells after transplantation provides a cogent rationale for using repeated cell doses, which, however, has not been done thus far in clinical trials because it is not feasible with invasive approaches. The goal of this translational study was to test the therapeutic utility of the intravenous route for cell delivery.</p><p><strong>Methods and results: </strong>Pigs with chronic ischaemic cardiomyopathy induced by myocardial infarction received one or three intravenous doses of allogeneic bone marrow mesenchymal stromal cells (MSCs) or placebo 35 days apart. Rigour guidelines, including blinding and randomization, were strictly followed. A comprehensive assessment of left ventricular (LV) function was conducted with three independent methods (echocardiography, magnetic resonance imaging, and haemodynamic studies). The results demonstrate that three doses of MSCs improved both load-dependent and independent indices of LV function and reduced myocardial hypertrophy and fibrosis; in contrast, one dose failed to produce most of these benefits.</p><p><strong>Conclusions: </strong>To our knowledge, this is the first study to show that intravenous infusion of a cell product improves LV function and structure in a large animal model of chronic ischaemic cardiomyopathy and that repeated infusions are necessary to produce robust effects. This study, conducted in a clinically relevant model, supports a new therapeutic strategy based on repeated intravenous infusions of allogeneic MSCs and provides a foundation for a first-in-human trial testing this strategy in patients with chronic ischaemic cardiomyopathy.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1939-1952"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A non-genetic model of vascular shunts informs on the cellular mechanisms of formation and resolution of arteriovenous malformations.","authors":"Marie Ouarné, Andreia Pena, Daniela Ramalho, Nadine V Conchinha, Tiago Costa, Romain Enjalbert, Ana M Figueiredo, Marta Pimentel Saraiva, Yulia Carvalho, Miguel O Bernabeu, Lenka Henao Misikova, S Paul Oh, Cláudio A Franco","doi":"10.1093/cvr/cvae160","DOIUrl":"10.1093/cvr/cvae160","url":null,"abstract":"<p><strong>Aims: </strong>Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to AV shunt formation and how shunts can be reverted are poorly understood.</p><p><strong>Methods and results: </strong>Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in the volume of venous endothelial cells (EC)-hypertrophic venous cells-are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of the mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signalling cell-autonomously regulates EC volume in pro-angiogenic conditions, establishing a link with hereditary haemorrhagic telangiectasia-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts.</p><p><strong>Conclusion: </strong>Our findings highlight that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocate for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1967-1984"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin- and empagliflozin-induced arterial relaxation.","authors":"Elizabeth A Forrester, Miguel Benítez-Angeles, Kaitlyn E Redford, Tamara Rosenbaum, Geoffrey W Abbott, Vincenzo Barrese, Kim Dora, Anthony P Albert, Johs Dannesboe, Isabelle Salles-Crawley, Thomas A Jepps, Iain A Greenwood","doi":"10.1093/cvr/cvae156","DOIUrl":"10.1093/cvr/cvae156","url":null,"abstract":"<p><strong>Aims: </strong>Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport.</p><p><strong>Methods and results: </strong>The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression was determined by western blot and immunohistochemistry. Kv7.4/5/KCNE4 and TRPV1 currents were measured in the presence and absence of dapagliflozin and empagliflozin. All SGLT inhibitors (1-100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors.</p><p><strong>Conclusion: </strong>SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1811-1824"},"PeriodicalIF":10.2,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to: Clinical Case 29-The role of transthoracic echocardiography on patients presenting with shock of unknown etiology.","authors":"","doi":"10.1093/cvr/cvae112","DOIUrl":"10.1093/cvr/cvae112","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1825"},"PeriodicalIF":10.2,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-species single-cell RNA sequencing reveals divergent phenotypes and activation states of adaptive immunity in human carotid and experimental murine atherosclerosis.","authors":"Hauke Horstmann, Nathaly Anto Michel, Xia Sheng, Sophie Hansen, Alexandra Lindau, Katharina Pfeil, Marbely C Fernández, Timoteo Marchini, Holger Winkels, Lucia Sol Mitre, Tijani Abogunloko, Xiaowei Li, Timothy Bon-Nawul Mwinyella, Mark Colin Gissler, Heiko Bugger, Timo Heidt, Konrad Buscher, Ingo Hilgendorf, Peter Stachon, Sven Piepenburg, Nicolas Verheyen, Thomas Rathner, Teresa Gerhardt, Patrick Malcolm Siegel, Wolfgang Kurt Oswald, Tina Cohnert, Alma Zernecke, Josef Madl, Peter Kohl, Amanda C Foks, Constantin von Zur Muehlen, Dirk Westermann, Andreas Zirlik, Dennis Wolf","doi":"10.1093/cvr/cvae154","DOIUrl":"10.1093/cvr/cvae154","url":null,"abstract":"<p><strong>Aims: </strong>The distinct functions of immune cells in atherosclerosis have been mostly defined by pre-clinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression are only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches.</p><p><strong>Methods and results: </strong>Single-cell RNA-sequencing (scRNA-seq) was performed to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire demonstrated an unexpectedly high heterogeneity and was dominated by cells of the T-cell lineage, a finding confirmed by immunohistochemistry. Bioinformatical integration with 7 mouse scRNA-seq data sets from adventitial and atherosclerotic vascular tissue revealed a total of 51 identities of cell types and differentiation states, of which some were only poorly conserved between species and exclusively found in humans. Locations, frequencies, and transcriptional programmes of immune cells in mouse models did not resemble the immune cell landscape in human carotid atherosclerosis. In contrast to standard mouse models of atherosclerosis, human plaque leucocytes were dominated by several T-cell phenotypes with transcriptional hallmarks of T-cell activation and memory formation, T-cell receptor, and pro-inflammatory signalling. Only mice at the age of 22 months partially resembled the activated T-cell phenotype. In a validation cohort of 43 patients undergoing carotid endarterectomy, the abundance of activated immune cell subsets in the plaque defined by multi-colour flow cytometry associated with the extent of clinical atherosclerosis.</p><p><strong>Conclusion: </strong>Integrative scRNA-seq reveals a substantial difference in the immune cell composition of murine and human carotid atherosclerosis-a finding that questions the translational value of standard mouse models for adaptive immune cell studies. Clinical associations suggest a specific role for T-cell driven (auto-)immunity in human plaque formation and instability.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1713-1726"},"PeriodicalIF":10.2,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of endothelial-to-mesenchymal transition in a large animal preclinical arteriovenous fistula model leads to improved remodelling and reduced stenosis.","authors":"Yang Xu, Adam Korayem, Ana S Cruz-Solbes, Nirupama Chandel, Tomoki Sakata, Renata Mazurek, Spyros A Mavropoulos, Taro Kariya, Tadao Aikawa, Kelly P Yamada, Valentina D'Escamard, Bhargavi V'Gangula, Andrew H Baker, Lijiang Ma, Johan L M Björkegren, Valentin Fuster, Manfred Boehm, Kenneth M Fish, Rami Tadros, Kiyotake Ishikawa, Jason C Kovacic","doi":"10.1093/cvr/cvae157","DOIUrl":"10.1093/cvr/cvae157","url":null,"abstract":"<p><strong>Aims: </strong>Vein grafts are used for many indications, including bypass graft surgery and arteriovenous fistula (AVF) formation. However, patency following vein grafting or AVF formation is suboptimal for various reasons, including thrombosis, neointimal hyperplasia, and adverse remodelling. Recently, endothelial-to-mesenchymal transition (EndMT) was found to contribute to neointimal hyperplasia in mouse vein grafts. We aimed to evaluate the clinical potential of inhibiting EndMT and developed the first dedicated preclinical model to study the efficacy of local EndMT inhibition immediately prior to AVF creation.</p><p><strong>Methods and results: </strong>We first undertook pilot studies to optimize the creation of a femoral AVF in pigs and verify that EndMT contributes to neointimal formation. We then developed a method to achieve local in vivo SMAD3 knockdown by dwelling a lentiviral construct containing SMAD3 shRNA in the femoral vein prior to AVF creation. Next, in Phase 1, six pigs were randomized to SMAD3 knockdown or control lentivirus to evaluate the effectiveness of SMAD3 knockdown and EndMT inhibition 8 days after AVF creation. In Phase 2, 16 pigs were randomized to SMAD3 knockdown or control lentivirus and were evaluated to assess longer-term effects on AVF diameter, patency, and related measures at 30 days after AVF creation. In Phase 1, compared with controls, SMAD3 knockdown achieved a 75% reduction in the proportion of CD31+ endothelial cells co-expressing SMAD3 (P < 0.001) and also a significant reduction in the extent of EndMT (P < 0.05). In Phase 2, compared with controls, SMAD3 knockdown was associated with an increase in the minimum diameter of the venous limb of the AVF (1.56 ± 1.66 vs. 4.26 ± 1.71 mm, P < 0.01) and a reduced degree of stenosis (P < 0.01). Consistent with this, neointimal thickness was reduced in the SMAD3 knockdown group (0.88 ± 0.51 vs. 0.45 ± 0.19 mm, P < 0.05). Furthermore, endothelial integrity (the proportion of luminal cells expressing endothelial markers) was improved in the SMAD3 knockdown group (P < 0.05).</p><p><strong>Conclusion: </strong>EndMT inhibition in a preclinical AVF model by local SMAD3 knockdown using gene therapy led to reduced neointimal hyperplasia, increased endothelialization, and a reduction in the degree of AVF stenosis. This provides important proof of concept to pursue this approach as a clinical strategy to improve the patency of AVFs and other vein grafts.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1768-1779"},"PeriodicalIF":10.2,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Burden of risk factors in women and men with unrecognized myocardial infarction: a systematic review and meta-analysis †.","authors":"Julie A E van Oortmerssen, Noluthando Ntlapo, Martijn J Tilly, Wichor M Bramer, Hester M den Ruijter, Eric Boersma, Maryam Kavousi, Jeanine E Roeters van Lennep","doi":"10.1093/cvr/cvae188","DOIUrl":"10.1093/cvr/cvae188","url":null,"abstract":"<p><p>Unrecognized myocardial infarction (MI) is an MI that remains undetected in the acute phase and is associated with an unfavourable prognosis. With this systematic review and meta-analysis, we evaluated the burden of cardiovascular risk factors in individuals with unrecognized MI. We searched general population-based cohort studies diagnosing unrecognized MI by electrocardiogram or myocardial imaging up to 24 November 2023. Pooled mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs) were determined, and random-effects meta-analyses were performed. Fourteen cohort studies were included involving 200 450 individuals (mean age 62.8 ± 9.9 years, 56.0% women), among which 4322 (2.2%) experienced unrecognized MI (mean age 66.3 ± 8.2 years, 47.8% women) and 4653 (2.1%) recognized MI (mean age 68.5 ± 7.3 years, 33.8% women). Compared to individuals without MI, those with unrecognized MI had higher body mass index (MD 0.27, 95% CI 0.16-0.39) and systolic blood pressure (MD 4.48, 95% CI 2.81-6.15) levels, and higher prevalence of hypertension (RR 1.27, 95% CI 1.06-1.51) and diabetes mellitus (RR 1.67, 95% CI 1.36-2.06). Furthermore, individuals with unrecognized MI had lower prevalence of hypertension (RR 0.92, 95% CI 0.88-0.97) and diabetes mellitus (RR 0.80, 95% CI 0.70-0.92). Individuals with unrecognized MI are characterized by a substantial burden of metabolic risk factors. Our findings suggest insufficient recognition and management of cardiovascular risk factors among individuals with unrecognized MI.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1683-1692"},"PeriodicalIF":10.2,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coronavirus disease 2019-related myocardial injury is associated with immune dysregulation in symptomatic patients with cardiac magnetic resonance imaging abnormalities.","authors":"Andrej Ćorović, Xiaohui Zhao, Yuan Huang, Stephen R Newland, Deepa Gopalan, James Harrison, Despina Giakomidi, Shanna Chen, Natalia S Yarkoni, Christopher Wall, Marta Peverelli, Rouchelle Sriranjan, Arianna Gallo, Martin J Graves, Andrew Sage, Paul A Lyons, Nyarie Sithole, Martin R Bennett, James H F Rudd, Ziad Mallat, Tian X Zhao, Meritxell Nus, Jason M Tarkin","doi":"10.1093/cvr/cvae159","DOIUrl":"10.1093/cvr/cvae159","url":null,"abstract":"<p><strong>Aims: </strong>While acute cardiovascular complications of coronavirus disease 2019 (COVID-19) are well described, less is known about longer-term cardiac sequelae. For many individuals with cardiac signs or symptoms arising after COVID-19 infection, the aetiology remains unclear. We examined immune profiles associated with magnetic resonance imaging (MRI) abnormalities in patients with unexplained cardiac injury after COVID-19.</p><p><strong>Methods and results: </strong>Twenty-one participants {mean age 47 [standard deviation (SD) 13] years, 71% female} with long COVID-19 (n = 17), raised troponin (n = 2), or unexplained new-onset heart failure (n = 2), who did not have pre-existing heart conditions or recent steroid/immunosuppression treatment, were enrolled a mean 346 (SD 191) days after COVID-19 infection in a prospective observational study. Cardiac MRI and blood sampling for deep immunophenotyping using mass cytometry by time of flight and measurement of proteomic inflammatory markers were performed. Nine of the 21 (43%) participants had MRI abnormalities (MRI(+)), including non-ischaemic patterns of late gadolinium enhancement and/or visually overt myocardial oedema in 8 people. One patient had mildly impaired biventricular function without fibrosis or oedema, and two had severe left ventricular (LV) impairment. MRI(+) individuals had higher blood CCL3, CCL7, FGF-23, and CD4 Th2 cells, and lower CD8 T effector memory (TEM) cells, than MRI(-). Cluster analysis revealed lower expression of inhibitory receptors PD1 and TIM3 in CD8 TEM cells from MRI(+) patients than MRI(-) patients, and functional studies of CD8 T αβ cells showed higher proportions of cytotoxic granzyme B+(GZB+)-secreting cells upon stimulation. CD8 TEM cells and CCL7 were the strongest predictors of MRI abnormalities in a least absolute shrinkage and selection operator regression model (composite area under the curve 0.96, 95% confidence interval 0.88-1.0). CCL7 was correlated with diffuse myocardial fibrosis/oedema detected by quantitative T1 mapping (r = 0.47, P = 0.04).</p><p><strong>Conclusion: </strong>COVID-19-related cardiac injury in symptomatic patients with non-ischaemic myocarditis-like MRI abnormalities is associated with immune dysregulation, including decreased peripheral CD8 TEM cells and increased CCL7, persisting long after the initial infection.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1752-1767"},"PeriodicalIF":10.2,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zonation and ligand and dose dependence of sphingosine 1-phosphate receptor-1 signalling in blood and lymphatic vasculature.","authors":"Ilaria Del Gaudio, Anja Nitzsche, Kevin Boyé, Philippe Bonnin, Mathilde Poulet, Toan Q Nguyen, Ludovic Couty, Hoa T T Ha, Dat T Nguyen, Amaury Cazenave-Gassiot, Khaoula Ben Alaya, Patrice Thérond, Jerold Chun, Markus R Wenk, Richard L Proia, Daniel Henrion, Long N Nguyen, Anne Eichmann, Eric Camerer","doi":"10.1093/cvr/cvae168","DOIUrl":"10.1093/cvr/cvae168","url":null,"abstract":"<p><strong>Aims: </strong>Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for the endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet, as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC autonomous S1P production, it is unclear if relative reductions in circulating S1P can cause endothelial dysfunction. It is also unclear how EC S1PR1 insufficiency, whether induced by deficiency in circulating ligand or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets.</p><p><strong>Methods and results: </strong>We here fine map the zonation of S1PR1 signalling in the murine blood and lymphatic vasculature, superimpose cell-type-specific and relative deficiencies in S1P production to define ligand source and dose dependence, and correlate receptor engagement to essential functions. In naïve blood vessels, despite broad expression, EC S1PR1 engagement was restricted to resistance-size arteries, lung capillaries, and a subset of high-endothelial venules (HEVs). Similar zonation was observed for albumin extravasation in EC S1PR1-deficient mice, and brain extravasation was reproduced with arterial EC-selective S1pr1 deletion. In lymphatic ECs, S1PR1 engagement was high in collecting vessels and lymph nodes and low in blind-ended capillaries that drain tissue fluids. While EC S1P production sustained S1PR1 signalling in lymphatics and HEV, haematopoietic cells provided ∼90% of plasma S1P and sustained signalling in resistance arteries and lung capillaries. S1PR1 signalling and endothelial function were both surprisingly sensitive to reductions in plasma S1P with apparent saturation around 50% of normal levels. S1PR1 engagement did not depend on sex or age but modestly increased in arteries in hypertension and diabetes. Sphingosine kinase (Sphk)-2 deficiency also increased S1PR1 engagement selectively in arteries, which could be attributed to Sphk1-dependent S1P release from perivascular macrophages.</p><p><strong>Conclusion: </strong>This study highlights vessel subtype-specific S1PR1 functions and mechanisms of engagement and supports the relevance of S1P as circulating biomarker for endothelial function.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1794-1810"},"PeriodicalIF":10.2,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}