Publications by authors named "Gemma Vilahur"

138 Publications

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Nat Rev Cardiol 2022 Jan 13. Epub 2022 Jan 13.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.
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http://dx.doi.org/10.1038/s41569-021-00665-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757397PMC
January 2022

Glycosylated apolipoprotein J in cardiac ischaemia: molecular processing and circulating levels in patients with acute ischaemic events.

Eur Heart J 2022 Jan;43(2):153-163

Cardiovascular Program-ICCC-IR, Hospital Santa Creu i Sant Pau, c/Sant Antoni MaClaret 167, 08025 Barcelona, Spain.

Aim: Using proteomics, we previously found that serum levels of glycosylated (Glyc) forms of apolipoprotein J (ApoJ), a cytoprotective and anti-oxidant protein, decrease in the early phase of acute myocardial infarction (AMI). We aimed to investigate: (i) ApoJ-Glyc intracellular distribution and secretion during ischaemia; (ii) the early changes in circulating ApoJ-Glyc during AMI; and (iii) associations between ApoJ-Glyc and residual ischaemic risk post-AMI.

Methods And Results: Glycosylated apolipoprotein J was investigated in: (i) cells from different organ/tissue origin; (ii) a pig model of AMI; (iii) de novo AMI patients (n = 38) at admission within the first 6 h of chest pain onset and without troponin T elevation at presentation (early AMI); (iv) ST-elevation myocardial infarction patients (n = 212) who were followed up for 6 months; and (v) a control group without any overt cardiovascular disease (n = 144). Inducing simulated ischaemia in isolated cardiac cells resulted in an increased intracellular accumulation of non-glycosylated ApoJ forms. A significant decrease in ApoJ-Glyc circulating levels was seen 15 min after ischaemia onset in pigs. Glycosylated apolipoprotein J levels showed a 45% decrease in early AMI patients compared with non-ischaemic patients (P < 0.0001), discriminating the presence of the ischaemic event (area under the curve: 0.934; P < 0.0001). ST-elevation myocardial infarction patients with lower ApoJ-Glyc levels at admission showed a higher rate of recurrent ischaemic events and mortality after 6-month follow-up (P = 0.008).

Conclusions: These results indicate that ischaemia induces an intracellular accumulation of non-glycosylated ApoJ and a reduction in ApoJ-Glyc secretion. Glycosylated apolipoprotein J circulating levels are reduced very early after ischaemia onset. Its continuous decrease indicates a worsening in the evolution of the cardiac event, likely identifying patients with sustained ischaemia after AMI.
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http://dx.doi.org/10.1093/eurheartj/ehab691DOI Listing
January 2022

Cardiovascular disease and COVID-19: a consensus paper from the ESC Working Group on Coronary Pathophysiology & Microcirculation, ESC Working Group on Thrombosis and the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Heart Rhythm Association (EHRA).

Cardiovasc Res 2021 12;117(14):2705-2729

Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

The cardiovascular system is significantly affected in coronavirus disease-19 (COVID-19). Microvascular injury, endothelial dysfunction, and thrombosis resulting from viral infection or indirectly related to the intense systemic inflammatory and immune responses are characteristic features of severe COVID-19. Pre-existing cardiovascular disease and viral load are linked to myocardial injury and worse outcomes. The vascular response to cytokine production and the interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and angiotensin-converting enzyme 2 receptor may lead to a significant reduction in cardiac contractility and subsequent myocardial dysfunction. In addition, a considerable proportion of patients who have been infected with SARS-CoV-2 do not fully recover and continue to experience a large number of symptoms and post-acute complications in the absence of a detectable viral infection. This conditions often referred to as 'post-acute COVID-19' may have multiple causes. Viral reservoirs or lingering fragments of viral RNA or proteins contribute to the condition. Systemic inflammatory response to COVID-19 has the potential to increase myocardial fibrosis which in turn may impair cardiac remodelling. Here, we summarize the current knowledge of cardiovascular injury and post-acute sequelae of COVID-19. As the pandemic continues and new variants emerge, we can advance our knowledge of the underlying mechanisms only by integrating our understanding of the pathophysiology with the corresponding clinical findings. Identification of new biomarkers of cardiovascular complications, and development of effective treatments for COVID-19 infection are of crucial importance.
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http://dx.doi.org/10.1093/cvr/cvab298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500019PMC
December 2021

Unraveling the Complexity of HDL Remodeling: On the Hunt to Restore HDL Quality.

Biomedicines 2021 Jul 12;9(7). Epub 2021 Jul 12.

Cardiovascular Program, Institut de Recerca, Hospital Santa Creu i Sant Pau, 08025 Barcelona, Spain.

Increasing evidence has cast doubt over the HDL-cholesterol hypothesis. The complexity of the HDL particle and its proven susceptibility to remodel has paved the way for intense molecular investigation. This state-of-the-art review discusses the molecular changes in HDL particles that help to explain the failure of large clinical trials intending to interfere with HDL metabolism, and details the chemical modifications and compositional changes in HDL-forming components, as well as miRNA cargo, that render HDL particles ineffective. Finally, the paper discusses the challenges that need to be overcome to shed a light of hope on HDL-targeted approaches.
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http://dx.doi.org/10.3390/biomedicines9070805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301317PMC
July 2021

Microvesicles carrying LRP5 induce macrophage polarization to an anti-inflammatory phenotype.

J Cell Mol Med 2021 08 19;25(16):7935-7947. Epub 2021 Jul 19.

Cardiovascular Program ICCC, IR-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.

Microvesicles (MV) contribute to cell-to-cell communication through their transported proteins and nucleic acids. MV, released into the extracellular space, exert paracrine regulation by modulating cellular responses after interaction with near and far target cells. MV are released at high concentrations by activated inflammatory cells. Different subtypes of human macrophages have been characterized based on surface epitopes being CD16 macrophages associated with anti-inflammatory phenotypes. We have previously shown that low-density lipoprotein receptor-related protein 5 (LRP5), a member of the LDLR family that participates in lipid homeostasis, is expressed in macrophage CD16 with repair and survival functions. The goal of our study was to characterize the cargo and tentative function of macrophage-derived MV, whether LRP5 is delivered into MV and whether these MV are able to induce inflammatory cell differentiation to a specific CD16 or CD16 phenotype. We show, for the first time, that lipid-loaded macrophages release MV containing LRP5. LDL loading induces increased expression of macrophage pro-inflammatory markers and increased release of MV containing pro-inflammatory markers. Conditioning of fresh macrophages with MV released by Lrp5-silenced macrophages induced the transcription of inflammatory genes and reduced the transcription of anti-inflammatory genes. Thus, MV containing LRP5 induce anti-inflammatory phenotypes in macrophages.
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http://dx.doi.org/10.1111/jcmm.16723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358886PMC
August 2021

Impact of Diabetes Mellitus on the Potential of Autologous Stem Cells and Stem Cell-Derived Microvesicles to Repair the Ischemic Heart.

Cardiovasc Drugs Ther 2021 Jul 12. Epub 2021 Jul 12.

Cardiovascular-Program ICCC, IR-Hospital Santa Creu I Sant Pau, IIB Sant Pau, C/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.

Ischemic heart disease remains the leading cause of morbidity and mortality worldwide. Despite the advances in medical management and catheter-based therapy, mortality remains high, as does the risk of developing heart failure. Regenerative therapies have been widely used as an alternative option to repair the damaged heart mainly because of their paracrine-related beneficial effects. Although cell-based therapy has been demonstrated as feasible and safe, randomized controlled trials and meta-analyses show little consistent benefit from treatments with adult-derived stem cells. Mounting evidence from our group and others supports that cardiovascular risk factors and comorbidities impair stem cell potential thus hampering their autologous use. This review aims to better understand the influence of diabetes on stem cell potential. For this purpose, we will first discuss the most recent advances in the mechanistic understanding of the effects of diabetes on stem cell phenotype, function, and molecular fingerprint to further elaborate on diabetes-induced alterations in stem cell extracellular vesicle profile. Although we acknowledge that multiple sources of stem or progenitor cells are used for regenerative purposes, we will focus on bone marrow hematopoietic stem/progenitor cells, mesenchymal stem cells residing in the bone marrow, and adipose tissue and briefly discuss endothelial colony-forming cells.
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http://dx.doi.org/10.1007/s10557-021-07208-9DOI Listing
July 2021

Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart.

Cardiovasc Res 2021 08;117(10):2161-2174

Institute for Cardiovascular Prevention (IPEK), LMU Munich, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.
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http://dx.doi.org/10.1093/cvr/cvab200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344830PMC
August 2021

Antiplatelet Activity of Isorhamnetin via Mitochondrial Regulation.

Antioxidants (Basel) 2021 Apr 25;10(5). Epub 2021 Apr 25.

Thrombosis Research Center, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Medical Technology School, Universidad de Talca, Talca 3460000, Chile.

With the diet, we ingest nutrients capable of modulating platelet function, which plays a crucial role in developing cardiovascular events, one of the leading causes of mortality worldwide. Studies that demonstrate the antiplatelet and antithrombotic potential of bioactive compounds are vital to maintaining good cardiovascular health. In this work, we evaluate the flavonol isorhamnetin's antiplatelet effect on human platelets, using collagen, thrombin receptor activator peptide 6 (TRAP-6), and phorbol myristate acetate (PMA) as agonists. Isorhamnetin induced a significant inhibition on collagen- and TRAP-6-induced platelet aggregation, with half-maximum inhibitory concentration (IC) values of 8.1 ± 2.6 and 16.1 ± 11.1 µM, respectively; while it did not show cytotoxic effect. Isorhamnetin reduced adenosine triphosphate levels (ATP) in platelets stimulated by collagen and TRAP-6. We also evidenced that isorhamnetin's antiplatelet activity was related to the inhibition of mitochondrial function without effect on reactive oxygen species (ROS) levels. Additionally, we investigated isorhamnetin's effect on thrombus formation in vitro under flow conditions on the damaged vessel wall. In this context, we demonstrate that isorhamnetin at 20 µM induced a significant inhibition on platelet deposition, confirming its antithrombotic effect. Our findings corroborate the antiplatelet and antithrombotic potential of isorhamnetin present in many foods of daily consumption.
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http://dx.doi.org/10.3390/antiox10050666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146847PMC
April 2021

Triglyceride-induced cardiac lipotoxicity is mitigated by Silybum marianum.

Atherosclerosis 2021 05 27;324:91-101. Epub 2021 Mar 27.

Cardiovascular Program-ICCC, Research Institute Hospital de La Santa Creu I Sant Pau, IIB-Sant Pau, Barcelona, Spain; CiberCV, Institute Carlos III, Madrid, Spain; Chair UAB, Barcelona, Spain. Electronic address:

Background And Aims: Silybum marianum (SM) is an herbal product with cytoprotective and antioxidant properties. We have previously demonstrated that SM ameliorates ventricular remodeling and improves cardiac performance. Here, we evaluated whether SM could exert beneficial effects against cardiac lipotoxicity in a pig model of closed-chest myocardial infarction (MI).

Methods: Study 1 investigated the effect of SM administration on lipid profile and any potential SM-related adverse effects. Animals received SM or placebo during 10 days and were afterward sacrificed. Study 2 evaluated the effectiveness of SM daily administration in reducing cardiac lipotoxicity in animals subjected to a 1.5h myocardial infarction (MI), who were subsequently reperfused for 2.5h and euthanized or kept under study for three weeks and then sacrificed.

Results: Animals administered a 10-day SM regime presented a sharp decline in plasma triglyceride levels vs. controls, with no other modifications in lipid profile. The decrease in triglyceride concentration was accompanied by a marked reduction in triglyceride intestinal absorption and glycoprotein-P expression. Three weeks post-MI the triglyceride content in the ischemic myocardium of the SM-treated animals was significantly lower than in the ischemic myocardium of placebo-controls. This effect was associated with an enhanced cardiac expression of PPARγ and triglyceride clearance receptors. This long-term SM-administration induced a lower expression of lipid receptors in subcutaneous adipose tissue. No SM-related side-effects were registered.

Conclusion: SM administration reduces plasma triglyceride levels through attenuation of triglyceride intestinal absorption and modulates cardiac lipotoxicity in the ischemic myocardium, likely contributing to improve ventricular remodeling.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.014DOI Listing
May 2021

Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease.

Eur Heart J 2021 06;42(23):2265-2269

Department of Cardiology, Ludwig-Maximilians-Universität München (LMU Munich), Munich, Germany.

Transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to younger patients at lower risk. Although thromboembolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion. Based on recent studies and randomized controlled trials, this viewpoint document provides updated therapeutic insights in antithrombotic treatment during and after TAVI.
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http://dx.doi.org/10.1093/eurheartj/ehab196DOI Listing
June 2021

Antithrombotic therapy in diabetes: which, when, and for how long?

Eur Heart J 2021 06;42(23):2235-2259

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.

Cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbidity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM. This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis secondary to quantitative and qualitative changes in coagulation factors. However, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in different clinical scenarios including coronary, cerebrovascular, and peripheral artery diseases. Antiplatelet therapy combinations as well as combination of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individuals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications and predisposition to bleeding events. This review provides the reader with an up-to-date guide for antithrombotic management of individuals with DM and highlights gaps in knowledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population.
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http://dx.doi.org/10.1093/eurheartj/ehab128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203081PMC
June 2021

Prevention of stroke in patients with chronic coronary syndromes or peripheral arterial disease.

Eur Heart J Suppl 2020 Nov 6;22(Suppl M):M26-M34. Epub 2020 Dec 6.

Cardiovascular Research Unit, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.

Stroke is a common and devastating condition caused by atherothrombosis, thromboembolism, or haemorrhage. Patients with chronic coronary syndromes (CCS) or peripheral artery disease (PAD) are at increased risk of stroke because of shared pathophysiological mechanisms and risk-factor profiles. A range of pharmacological and non-pharmacological strategies can help to reduce stroke risk in these groups. Antithrombotic therapy reduces the risk of major adverse cardiovascular events, including ischaemic stroke, but increases the incidence of haemorrhagic stroke. Nevertheless, the net clinical benefits mean antithrombotic therapy is recommended in those with CCS or symptomatic PAD. Whilst single antiplatelet therapy is recommended as chronic treatment, dual antiplatelet therapy should be considered for those with CCS with prior myocardial infarction at high ischaemic but low bleeding risk. Similarly, dual antithrombotic therapy with aspirin and very-low-dose rivaroxaban is an alternative in CCS, as well as in symptomatic PAD. Full-dose anticoagulation should always be considered in those with CCS/PAD and atrial fibrillation. Unless ischaemic risk is particularly high, antiplatelet therapy should not generally be added to full-dose anticoagulation. Optimization of blood pressure, low-density lipoprotein levels, glycaemic control, and lifestyle characteristics may also reduce stroke risk. Overall, a multifaceted approach is essential to best prevent stroke in patients with CCS/PAD.
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http://dx.doi.org/10.1093/eurheartj/suaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916419PMC
November 2020

Biomarkers of coagulation and fibrinolysis in acute myocardial infarction: a joint position paper of the Association for Acute CardioVascular Care and the European Society of Cardiology Working Group on Thrombosis.

Eur Heart J Acute Cardiovasc Care 2021 May;10(3):343-355

Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Blvd. 161, 8200 Aarhus N, Denmark.

The formation of a thrombus in an epicardial artery may result in an acute myocardial infarction (AMI). Despite major advances in acute treatment using network approaches to allocate patients to timely reperfusion and optimal antithrombotic treatment, patients remain at high risk for thrombotic complications. Ongoing activation of the coagulation system as well as thrombin-mediated platelet activation may both play a crucial role in this context. Whether measurement of circulating biomarkers of coagulation and fibrinolysis could be useful for risk stratification in secondary prevention is currently not fully understood. In addition, measurement of such biomarkers could be helpful to identify thrombus formation as the leading mechanism for AMI. The introduction of biomarkers of myocardial injury such as high-sensitivity cardiac troponins made rule-out of AMI even more precise. However, elevated markers of myocardial injury cannot provide proof of a type 1 AMI, let alone thrombus formation. The combined measurement of markers of myocardial injury with biomarkers reflecting ongoing thrombus formation might be helpful for the fast and correct diagnosis of an atherothrombotic type 1 AMI. This position paper gives an overview of the current knowledge and possible role of biomarkers of coagulation and fibrinolysis for the diagnosis of AMI, risk stratification, and individualized treatment strategies in patients with AMI.
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http://dx.doi.org/10.1093/ehjacc/zuaa025DOI Listing
May 2021

The key contribution of platelet and vascular arachidonic acid metabolism to the pathophysiology of atherothrombosis.

Cardiovasc Res 2021 07;117(9):2001-2015

Department of Bioethics and Safety, Section of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Arachidonic acid is one of the most abundant and ubiquitous ω-6 polyunsaturated fatty acid, present in esterified form in the membrane phospholipids of all mammalian cells and released from phospholipids by several phospholipases in response to various activating or inhibitory stimuli. Arachidonic acid is the precursor of a large number of enzymatically and non-enzymatically derived, biologically active autacoids, including prostaglandins (PGs), thromboxane (TX) A2, leukotrienes, and epoxyeicosatetraenoic acids (collectively called eicosanoids), endocannabinoids and isoprostanes, respectively. Eicosanoids are local modulators of the physiological functions and pathophysiological roles of blood vessels and platelets. For example, the importance of cyclooxygenase (COX)-1-derived TXA2 from activated platelets in contributing to primary haemostasis and atherothrombosis is demonstrated in animal and human models by the bleeding complications and cardioprotective effects associated with low-dose aspirin, a selective inhibitor of platelet COX-1. The relevance of vascular COX-2-derived prostacyclin (PGI2) in endothelial thromboresistance and atheroprotection is clearly shown by animal and human models and by the adverse cardiovascular effects exerted by COX-2 inhibitors in humans. A vast array of arachidonic acid-transforming enzymes, downstream synthases and isomerases, transmembrane receptors, and specificity in their tissue expression make arachidonic acid metabolism a fine-tuning system of vascular health and disease. Its pharmacological regulation is central in human cardiovascular diseases, as demonstrated by biochemical measurements and intervention trials.
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http://dx.doi.org/10.1093/cvr/cvab003DOI Listing
July 2021

PCSK9 in Myocardial Infarction and Cardioprotection: Importance of Lipid Metabolism and Inflammation.

Front Physiol 2020 12;11:602497. Epub 2020 Nov 12.

Institute for Physiology, Justus-Liebig University Giessen, Giessen, Germany.

Extensive evidence from epidemiologic, genetic, and clinical intervention studies has indisputably shown that elevated low-density lipoprotein cholesterol (LDL-C) concentrations play a central role in the pathophysiology of atherosclerotic cardiovascular disease. Apart from LDL-C, also triglycerides independently modulate cardiovascular risk. Reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma LDL-C, but it is also associated with a reduction in triglyceride levels potentially through modulation of the expression of free fatty acid transporters. Preclinical data indicate that PCSK9 is up-regulated in the ischaemic heart and decreasing PCSK9 expression impacts on infarct size, post infarct inflammation and remodeling as well as cardiac dysfunction following ischaemia/reperfusion. Clinical data support that notion in that PCSK9 inhibition is associated with reductions in the incidence of myocardial infarction, stroke, and coronary revascularization and an improvement of endothelial function in subjects with increased cardiovascular risk. The aim of the current review is to summarize the current knowledge on the importance of free fatty acid metabolism on myocardial ischaemia/reperfusion injury and to provide an update on recent evidence on the role of hyperlipidemia and PCSK9 in myocardial infarction and cardioprotection.
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http://dx.doi.org/10.3389/fphys.2020.602497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688516PMC
November 2020

Scientists on the Spot: from the Scientists of Tomorrow to the scientist of today.

Cardiovasc Res 2020 11;116(13):e184-e185

Cardiovascular Program-ICCC, Research Institute-Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain.

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http://dx.doi.org/10.1093/cvr/cvaa277DOI Listing
November 2020

Ticagrelor in Post-STEMI Adverse Ventricular Remodeling: There Is More Than Meets the Platelet.

JACC Cardiovasc Interv 2020 10;13(19):2235-2237

Cardiovascular Program-ICCC, Research Institute Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.jcin.2020.09.006DOI Listing
October 2020

Cardiovascular Risk Factors and Differential Transcriptomic Profile of the Subcutaneous and Visceral Adipose Tissue and Their Resident Stem Cells.

Cells 2020 10 3;9(10). Epub 2020 Oct 3.

Cardiovascular-Program ICCC, IR-Hospital Santa Creu I Sant Pau, IIB Sant Pau, 08025 Barcelona, Spain.

Background: The increase in the incidence of obesity and obesity-related cardiovascular risk factors (CVRFs) over the last decades has brought attention on adipose tissue (AT) pathobiology. The expansion of AT is associated with the development of new vasculature needed to perfuse the tissue; however, not all fat depots have the same ability to induce angiogenesis that requires recruitment of their own endothelial cells. In this study we have investigated the effect of different CVRFs, on the angiogenic capacity of the subcutaneous (SAT) and visceral (VAT) adipose tissue and on the function of their mesenchymal cell reservoir.

Methods: A transcriptomic approach was used to compare the different angiogenic and inflammatory profiles of the subcutaneous and visceral fat depots from individuals with obesity, as well as their resident stem cells (ASCs). Influence of other risk factors on fat composition was also measured. Finally, the microvesicles (MVs) released by ASCs were isolated and their regenerative potential analyzed by molecular and cellular methodologies.

Results: Obesity decreases the angiogenic capacity of AT. There are differences between SAT and VAT; from the 21 angiogenic-related genes analyzed, only three were decreased in SAT compared with those decreased in VAT. ASCs isolated from both fat depots showed significant differences; there was a significant up-regulation of the VEGF-pathway on visceral derived ASCs. ASCs release MVs that stimulate endothelial cell migration and angiogenic capacity.

Conclusions: In patients with obesity, SAT expresses a greater number of angiogenic molecules than VAT, independent of the presence of other CVRFs.
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http://dx.doi.org/10.3390/cells9102235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600037PMC
October 2020

The ESC Working Group on Thrombosis.

Eur Heart J 2020 09;41(33):3130-3131

Privatklinik Lauterbacher Mühle am Ostersee, Iffeldorf, Germany and Ludwig-Maximilians Universität München, Munich, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehaa482DOI Listing
September 2020

High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study.

Metabolism 2020 11 4;112:154351. Epub 2020 Sep 4.

Cardiovascular Epidemiology and Genetics Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Consorcio CIBER, M.P. Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain; Medicine Department, Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain. Electronic address:

Background: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD).

Methods: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis.

Results: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data.

Conclusions: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not.
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http://dx.doi.org/10.1016/j.metabol.2020.154351DOI Listing
November 2020

HDL (High-Density Lipoprotein) Remodeling and Magnetic Resonance Imaging-Assessed Atherosclerotic Plaque Burden: Study in a Preclinical Experimental Model.

Arterioscler Thromb Vasc Biol 2020 10 27;40(10):2481-2493. Epub 2020 Aug 27.

Cardiovascular Program-ICCC, Research Institute-Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain (S.B., L.C., N.M.-G., O.J.-B., E.P., M.A., M.G., T.P., L.B., G.V.).

Objective: HDL (high-density lipoprotein) role in atherosclerosis is controversial. Clinical trials with CETP (cholesterylester transfer protein)-inhibitors have not provided benefit. We have shown that HDL remodeling in hypercholesterolemia reduces HDL cardioprotective potential. We aimed to assess whether hypercholesterolemia affects HDL-induced atherosclerotic plaque regression. Approach and Results: Atherosclerosis was induced in New Zealand White rabbits for 3-months by combining a high-fat-diet and double-balloon aortic denudation. Then, animals underwent magnetic resonance imaging (basal plaque) and randomized to receive 4 IV infusions (1 infusion/wk) of HDL isolated from normocholesterolemic (NC-HDL; 75 mg/kg; n=10), hypercholesterolemic (HC-HDL; 75 mg/Kg; n=10), or vehicle (n=10) rabbits. Then, animals underwent a second magnetic resonance imaging (end plaque). Blood, aorta, and liver samples were obtained for analyses. Follow-up magnetic resonance imaging revealed that NC-HDL administration regressed atherosclerotic lesions by 4.3%, whereas, conversely, the administration of HC-HDLs induced a further 6.5% progression (<0.05 versus basal). Plaque characterization showed that HC-HDL administered animals had a 2-fold higher lipid and cholesterol content versus those infused NC-HDL and vehicle (<0.05). No differences were observed among groups in CD31 levels, nor in infiltrated macrophages or smooth muscle cells. Plaques from HC-HDL administered animals exhibited higher Casp3 (caspase 3) content (<0.05 versus vehicle and NC-HDL) whereas plaques from NC-HDL infused animals showed lower expression of Casp3, Cox1 (cyclooxygenase 1), inducible nitric oxide synthase, and MMP (metalloproteinase) activity (<0.05 versus HC-HDL and vehicle). HDLs isolated from animals administered HC-HDL displayed lower antioxidant potential and cholesterol efflux capacity as compared with HDLs isolated from NC-HDL-infused animal and vehicle or donor HDL (<0.05). There were no differences in HDL-ApoA1 content, ABCA1 (ATP-binding cassette transporter A1) vascular expression, and SRB1 (scavenger receptor B1) and ABCA1 liver expression.

Conclusions: HDL particles isolated from a hypercholesterolemic milieu lose their ability to regress and stabilize atherosclerotic lesions. Our data suggest that HDL remodeling in patients with co-morbidities may lead to the loss of HDL atheroprotective functions.
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http://dx.doi.org/10.1161/ATVBAHA.120.314956DOI Listing
October 2020

Activation of C-reactive protein proinflammatory phenotype in the blood retinal barrier : implications for age-related macular degeneration.

Aging (Albany NY) 2020 07 16;12(14):13905-13923. Epub 2020 Jul 16.

Group of Ocular Inflammation, Clinical and Experimental Studies, Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.

The retinal pigment epithelium (RPE) is considered one of the main targets of age-related macular degeneration (AMD), the leading cause of irreversible vision loss among the ageing population worldwide. Persistent low grade inflammation and oxidative stress eventually lead to RPE dysfunction and disruption of the outer blood-retinal barrier (oBRB). Increased levels of circulating pentameric C-reactive protein (pCRP) are associated with higher risk of AMD. The monomeric form (mCRP) has been detected in drusen, the hallmark deposits associated with AMD, and we have found that mCRP induces oBRB disruption. However, it is unknown how mCRP is generated in the subretinal space. Using a Transwell model we found that both pCRP and mCRP can cross choroidal endothelial cells and reach the RPE and that mCRP, but not pCRP, is able to cross the RPE monolayer in ARPE-19 cells. Alternatively, mCRP can originate from the dissociation of pCRP in the surface of lipopolysaccharide-damaged RPE in both ARPE-19 and primary porcine RPE lines. In addition, we found that the proinflammatory phenotype of mCRP in the RPE depends on its topological localization. Together, our findings further support mCRP contribution to AMD progression enhancing oBRB disruption.
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http://dx.doi.org/10.18632/aging.103655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425453PMC
July 2020

Peripartum cardiomyopathy: can the link between prolactin and PAI-1 provide a clue?

Cardiovasc Res 2020 09;116(11):1791-1793

Cardiovascular Program ICCC- Research Institute Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Avda. Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.

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http://dx.doi.org/10.1093/cvr/cvaa109DOI Listing
September 2020

Molecular networks in Network Medicine: Development and applications.

Wiley Interdiscip Rev Syst Biol Med 2020 11 19;12(6):e1489. Epub 2020 Apr 19.

Department of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Maximus-von-Imhof-Forum 3, Freising, Germany.

Network Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein-protein interaction networks, correlation-based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approaches to Omics Big Data (including genetics, epigenetics, transcriptomics, metabolomics, and proteomics) using computational biology tools and, thereby, has the potential to provide improvements in the diagnosis, prognosis, and treatment of complex diseases. We discuss briefly the types of molecular data that are used in molecular network analyses, survey the analytical methods for inferring molecular networks, and review efforts to validate and visualize molecular networks. Successful applications of molecular network analysis have been reported in pulmonary arterial hypertension, coronary heart disease, diabetes mellitus, chronic lung diseases, and drug development. Important knowledge gaps in Network Medicine include incompleteness of the molecular interactome, challenges in identifying key genes within genetic association regions, and limited applications to human diseases. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Translational, Genomic, and Systems Medicine > Translational Medicine Analytical and Computational Methods > Analytical Methods Analytical and Computational Methods > Computational Methods.
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http://dx.doi.org/10.1002/wsbm.1489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955589PMC
November 2020

Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis.

Cardiovasc Res 2021 01;117(1):29-42

Department of Infection, Immunity and Cardiovascular Disease, Bateson Centre & INSIGNEO Institute, University of Sheffield, Sheffield S10 2RX, UK.

Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.
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http://dx.doi.org/10.1093/cvr/cvaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797212PMC
January 2021

Intravenous Statin Administration During Myocardial Infarction Compared With Oral Post-Infarct Administration.

J Am Coll Cardiol 2020 03;75(12):1386-1402

Cardiovascular Research Center-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; CiberCV, Institute Carlos III, Barcelona, Spain. Electronic address:

Background: Beyond lipid-lowering, statins exert cardioprotective effects. High-dose statin treatment seems to reduce cardiovascular complications in high-risk patients. The ideal timing and administration regime remain unknown.

Objectives: This study compared the cardioprotective effects of intravenous statin administration during myocardial infarction (MI) with oral administration immediately post-MI.

Methods: Hypercholesterolemic pigs underwent MI induction (90 min of ischemia) and were kept for 42 days. Animals were distributed in 3 arms (A): A1 received an intravenous bolus of atorvastatin during MI; A2 received an intravenous bolus of vehicle during MI; and A3 received oral atorvastatin within 2 h post-MI. A1 and A3 remained on daily oral atorvastatin for the following 42 days. Cardiac magnetic resonance analysis (days 3 and 42 post-MI) and molecular/histological studies were performed.

Results: At day 3, A1 showed a 10% reduction in infarct size compared with A3 and A2 and a 50% increase in myocardial salvage. At day 42, both A1 and A3 showed a significant decrease in scar size versus A2; however, A1 showed a further 24% reduction versus A3. Functional analyses revealed improved systolic performance in A1 compared with A2 and less wall motion abnormalities in the jeopardized myocardium versus both groups at day 42. A1 showed enhanced collagen content and AMP-activated protein kinase activation in the scar, increased vessel density in the penumbra, higher tumor necrosis factor α plasma levels and lower peripheral blood mononuclear cell activation versus both groups.

Conclusions: Intravenous administration of atorvastatin during MI limits cardiac damage, improves cardiac function, and mitigates remodeling to a larger extent than when administered orally shortly after reperfusion. This therapeutic approach deserves to be investigated in ST-segment elevation MI patients.
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http://dx.doi.org/10.1016/j.jacc.2020.01.042DOI Listing
March 2020

Highlights from the 2019 International Aspirin Foundation Scientific Conference, Rome, 28 June 2019: benefits and risks of antithrombotic therapy for cardiovascular disease prevention.

Ecancermedicalscience 2020 13;14:998. Epub 2020 Jan 13.

Unit of Cardiology, Department of Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden.

At the 2019 International Aspirin Foundation Scientific Conference 'Benefits and Risks of Antithrombotic Therapy for Cardiovascular Disease Prevention', held in Rome, Italy, international experts sought to discuss and debate the optimal antithrombotic strategy for the secondary prevention of cardiovascular disease (CVD) and to seek agreement around dosing and target populations for aspirin use in primary disease prevention. Getting the best evidence to support real-life decisions in the clinic can be complex, and individualising management in order to balance both the risks and benefits of different disease prevention strategies appears to be the best approach. It is hoped that future decision-making tools and biomarkers will help direct treatments at those most likely to benefit.
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http://dx.doi.org/10.3332/ecancer.2020.998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032943PMC
January 2020

Interatrial block can occur in the absence of left atrial enlargement: New experimental model.

Pacing Clin Electrophysiol 2020 04 3;43(4):427-429. Epub 2020 Apr 3.

Department of Anatomy and Cell Biology, Faculty of Medicine, University of Extremadura, Badajoz, Spain.

We present the surface electrocardiogram of an open-chest anesthetized healthy adult swine after direct application of ice at the transversus sinus of the pericardium where the Bachmann's region is located. Gradual and transient interatrial block (IAB) in the absence of structural atrial disease is described. This new experimental model demonstrated that IAB is an independent entity from left atrial enlargement.
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http://dx.doi.org/10.1111/pace.13895DOI Listing
April 2020

Advances in HDL: Much More than Lipid Transporters.

Int J Mol Sci 2020 Jan 22;21(3). Epub 2020 Jan 22.

Cardiovascular ICCC Program, Research Institute-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08001 Barcelona, Spain.

High Density Lipoprotein (HDL) particles, beyond serving as lipid transporters and playing a key role in reverse cholesterol transport, carry a highly variable number of proteins, micro-RNAs, vitamins, and hormones, which endow them with the ability to mediate a plethora of cellular and molecular mechanisms that promote cardiovascular health. It is becoming increasingly evident, however, that the presence of cardiovascular risk factors and co-morbidities alters HDLs cargo and protective functions. This concept has led to the notion that metrics other than HDL-cholesterol levels, such as HDL functionality and composition, may better capture HDL cardiovascular protection. On the other hand, the potential of HDL as natural delivery carriers has also fostered the design of engineered HDL-mimetics aiming to improve HDL efficacy or as drug-delivery agents with therapeutic potential. In this paper, we first provide an overview of the molecules known to be transported by HDL particles and mainly discuss their functions in the cardiovascular system. Second, we describe the impact of cardiovascular risk factors and co-morbidities on HDL remodeling. Finally, we review the currently developed HDL-based approaches.
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http://dx.doi.org/10.3390/ijms21030732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037660PMC
January 2020
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