Publications by authors named "Lina Badimon"

357 Publications

Triglyceride-induced cardiac lipotoxicity is mitigated by Silybum marianum.

Atherosclerosis 2021 Mar 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
March 2021

Cardiovascular rna markers and artificial intelligence may improve covid-19 outcome: position paper from the eu-cardiorna cost action ca17129.

Cardiovasc Res 2021 Apr 11. Epub 2021 Apr 11.

Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg.

The coronavirus disease 2019 (COVID-19) pandemic has been as unprecedented as unexpected, affecting more than 105 million people worldwide as of February 8th, 2020 and causing more than 2.3 million deaths according the World Health Organization. Not only affecting the lungs and provoking acute respiratory distress, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to infect multiple cell types including cardiac and vascular cells. Hence a significant proportion of infected patients develop cardiac events such as arrhythmias and heart failure. Patients with cardiovascular comorbidities are at highest risk of cardiac death. To face the pandemic and limit its burden, health authorities have launched several fast track calls for research projects aiming to develop rapid strategies to combat the disease, as well as longer-term projects to prepare for the future. Biomarkers have the possibility to aid in clinical decision making and tailoring healthcare in order to improve patient quality of life. The biomarker potential of circulating RNAs has been recognized in several disease conditions, including cardiovascular disease. RNA biomarkers may be useful in the current COVID-19 situation. The discovery, validation and marketing of novel biomarkers, including RNA biomarkers, require multi-centre studies by large and interdisciplinary collaborative networks, involving both the academia and the industry. Here, members of the EU-CardioRNA COST Action CA17129 summarize the current knowledge about the strain that COVID-19 places on the cardiovascular system and discuss how RNA biomarkers can aid to limit this burden. They present the benefits and challenges of the discovery of novel RNA biomarkers, the need for networking efforts and the added value of artificial intelligence to achieve reliable advances.
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http://dx.doi.org/10.1093/cvr/cvab094DOI Listing
April 2021

PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation.

Front Cardiovasc Med 2021 23;8:639727. Epub 2021 Mar 23.

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

The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.
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http://dx.doi.org/10.3389/fcvm.2021.639727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021767PMC
March 2021

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

Eur Heart J 2021 Mar 25. Epub 2021 Mar 25.

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
March 2021

THE YEAR IN BASIC VASCULAR BIOLOGY RESEARCH: FROM MECHANORECEPTORS AND NETS TO SMARTPHONE DATA AND OMICS.

Cardiovasc Res 2021 Mar 21. Epub 2021 Mar 21.

Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillian-Universität (LMU) München, German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

2020 has been an extraordinary year. The emergence of COVID-19 has driven urgent research in pulmonary and cardiovascular science and other fields. It has also shaped the way that we work with many experimental laboratories shutting down for several months, while bioinformatics approaches and other large data projects have gained prominence. Despite these setbacks, vascular biology research is stronger than ever. On behalf of the European Society of Cardiology Council for Basic Cardiovascular Science (ESC CBCS), here we review some of the vascular biology research highlights for 2020. This review is not exhaustive and there are many outstanding vascular biology publications that we were unable to cite due to page limits. Notwithstanding this, we have provided a snapshot of vascular biology research excellence in 2020 and identify topics that are in the ascendency and likely to gain prominence in coming years.
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http://dx.doi.org/10.1093/cvr/cvab105DOI Listing
March 2021

Reparative cell therapy for the heart: critical internal appraisal of the field in response to recent controversies.

ESC Heart Fail 2021 Mar 2. Epub 2021 Mar 2.

Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CIBERCV, Madrid, Spain.

The concept that cell-based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.
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http://dx.doi.org/10.1002/ehf2.13256DOI Listing
March 2021

New trials in the scene of cardiovascular disease: innovation, controversy, and reassurance.

Authors:
Lina Badimon

Cardiovasc Res 2021 Mar;117(4):e52-e54

Cardiovascular Program, IR-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Ciber CV, 08025 Barcelona, Spain.

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http://dx.doi.org/10.1093/cvr/cvab048DOI Listing
March 2021

The Key Contribution Of Platelet And Vascular Arachidonic Acid Metabolism To The Pathophysiology Of Atherothrombosis.

Cardiovasc Res 2021 Jan 23. Epub 2021 Jan 23.

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 hemostasis 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
January 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

Sex differences and emerging new risk factors for atherosclerosis and its thrombotic complications.

Curr Pharm Des 2020 Nov 17. Epub 2020 Nov 17.

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

Cardiovascular disease (CVD) stays as the world's leading cause of death and disability in both men and women, but with different prognostic and outcome between sexes. Although the burden of CVD is generally related to the conventional risk factors, the relevance of non-traditional risk factors is increasingly recognized to explain the so-called "residual risk". Men and women share many similarities regarding classical cardiovascular risk factors, but have different disease pathophysiology, clinical presentations, prevalence and outcome of CVD. How sex-specificities regarding effects of nontraditional risk factors may contribute to the evolution of atherosclerosis and its clinical manifestations in male and female remain largely under-analyzed. The present review summarizes the current knowledge for sex differences in atherosclerotic plaque composition and clinical evolution in association to risk factors such as inflammation, lipoprotein(a), haemostasis, intraplaque calcification and depression. We further discuss the potential sex-differential impact of chronic infectious diseases, gut microbiome and, epigenetic gene expression regulation for atherosclerosis and the effect of female-specific disorders in CVD.
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http://dx.doi.org/10.2174/1381612826666201118094209DOI Listing
November 2020

Aspirin for primary prevention of ST segment elevation myocardial infarction in persons with diabetes and multiple risk factors.

EClinicalMedicine 2020 Oct 20;27:100548. Epub 2020 Sep 20.

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

Background: Controversy exists as to whether low-dose aspirin use may give benefit in primary prevention of cardiovascular (CV) events. We hypothesized that the benefits of aspirin are underevaluated.

Methods: We investigated 12,123 Caucasian patients presenting to hospital with acute coronary syndromes as first manifestation of CV disease from 2010 to 2019 in the ISACS-TC multicenter registry (ClinicalTrials.gov, NCT01218776). Individual risk of ST segment elevation myocardial infarction (STEMI) and its association with 30-day mortality was quantified using inverse probability of treatment weighting models matching for concomitant medications. Estimates were compared by test of interaction on the log scale.

Findings: The risk of STEMI was lower in the aspirin users (absolute reduction: 6·8%; OR: 0·73; 95%CI: 0·65-0·82) regardless of sex (p for interaction=0·1962) or age (p for interaction=0·1209). Benefits of aspirin were seen in patients with hypertension, hypercholesterolemia, and in smokers. In contrast, aspirin failed to demonstrate a significant risk reduction in STEMI among diabetic patients (OR:1·10;95%CI:0·89-1·35) with a significant interaction (p: <0·0001) when compared with controls (OR:0·64,95%CI:0·56-0·73). Stratification of diabetes in risk categories revealed benefits (p interaction=0·0864) only in patients with concomitant hypertension and hypercholesterolemia (OR:0·87, 95% CI:0·65-1·15), but not in smokers. STEMI was strongly related to 30-day mortality (OR:1·93; 95%CI:1·59-2·35).

Interpretation: Low-dose aspirin reduces the risk of STEMI as initial manifestation of CV disease with potential benefit in mortality. Patients with diabetes derive substantial benefit from aspirin only in the presence of multiple risk factors. In the era of precision medicine, a more tailored strategy is required.

Funding: None.
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http://dx.doi.org/10.1016/j.eclinm.2020.100548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599315PMC
October 2020

CDR132L: another brick in the wall towards the use of miRNAs to treat cardiovascular disease.

Eur Heart J 2021 Jan;42(2):202-204

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

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http://dx.doi.org/10.1093/eurheartj/ehaa870DOI Listing
January 2021

Peripheral artery disease and clinical outcomes in patients with atrial fibrillation: A report from the FANTASIIA registry.

Eur J Clin Invest 2021 Apr 2;51(4):e13431. Epub 2020 Nov 2.

Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares: CIBERCV, Madrid, Spain.

Background: Atrial fibrillation (AF) and peripheral artery disease (PAD) are common conditions that increase cardiovascular risk. We determined the association between PAD and prognosis in a cohort of real-world patients receiving oral anticoagulant therapy for nonvalvular AF.

Methods: We prospectively included 1956 patients (mean age 73.8 ± 9.5 years, 44.0% women) receiving oral anticoagulant therapy for AF. Clinical characteristics were collected at baseline. Patients were followed for a period of 3 years. Survival analysis and multivariable regression analyses were performed to assess variables related to death, stroke, bleeding, myocardial infarction and major adverse cardiovascular events (MACE).

Results: Patients with PAD (n = 118; 6%) exhibited higher rates of cardiovascular risk factors and cardiovascular diseases. After 3 years of follow-up, there were a total of 255 deaths (no PAD 233, vs PAD 22), 45 strokes (43 vs 2), 146 major bleedings (136 vs 10) and 168 MACE (148 vs 20). On univariate analysis, there was a higher risk of cardiovascular mortality (2.02%/year no PAD vs 4.08%/year PAD, P = .02), myocardial infarction (0.99%/year no PAD vs 2.43%/year PAD, P = .02) and MACE (3.18%/year no PAD vs 6.99%/year PAD, P < .01). There was no statistically significant association with these events after multivariable adjustment.

Conclusions: In a large cohort of anticoagulated patients with AF, the presence of PAD represents a higher risk subgroup and is associated with worse crude outcomes. The exact contribution of the PAD independently of other cardiovascular diseases or risk factors requires further investigation.
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http://dx.doi.org/10.1111/eci.13431DOI Listing
April 2021

Transcriptomics Research to Improve Cardiovascular Healthcare.

Eur Heart J 2020 09;41(35):3296-3298

Cardiovascular Research Unit, Luxembourg Institute of Health, 1A-B rue Edison.

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http://dx.doi.org/10.1093/eurheartj/ehaa237DOI Listing
September 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

PCSK9 and LRP5 in macrophage lipid internalization and inflammation.

Cardiovasc Res 2020 Sep 29. Epub 2020 Sep 29.

CIBER-CV, Instituto de Salud Carlos III, Spain.

Aims: Atherosclerosis, the leading cause of cardiovascular diseases, is driven by high blood cholesterol levels and chronic inflammation. Low-Density Lipoprotein Receptor (LDLR) play a critical role in regulating blood cholesterol levels by binding to and clearing LDLs from the circulation. The disruption of the interaction between Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) and LDLR reduces blood cholesterol levels. It is not well known whether other members of the LDLR superfamily may be targets of PCSK9. The aim of this work was to determine if LDLR-related protein 5 (LRP5) is a PCSK9 target, and to study the role of PCSK9 and LRP5 in foam cell formation and lipid accumulation.

Methods And Results: Primary cultures of human inflammatory cells (monocytes and macrophages) were silenced for LRP5 or PCSK9 and challenged with LDLs. We first show that LRP5 is needed for macrophage lipid uptake since LRP5-silenced macrophages show less intracellular CE accumulation. In macrophages, internalization of LRP5-bound LDL is already highly evident after 5 hours of LDL incubation and lasts up to 24hours; however in the absence of both LRP5 and PCSK9 there is a strong reduction of CE accumulation indicating a role for both proteins in lipid uptake. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in lipid-loaded macrophages. Finally PCSK9 participates in TLR4/NFkB signaling; a decreased TLR4 protein expression levels and a decreased nuclear translocation of NFκB was detected in PCSK9 silenced cells after lipid loading, indicating a down-regulation of the TLR4/NFκB pathway.

Conclusion: Our results show that both LRP5 and PCSK9 participate in lipid uptake in macrophages. In the absence of LRP5 there is a reduced release of PCSK9 indicating that LRP5 also participates in the mechanism of release of soluble PCSK9. Furthermore, PCSK9 up-regulates TLR4/NFκB favoring inflammation.

Translational Perspective: We demonstrate that PCSK9 and LRP5 contribute to lipid uptake. We also show that LRP5 participates in PCSK9 transport to the plasma membrane and that PCSK9 inhibition protects against agLDL-induced inflammation associated to the TLR4/NFκB pathway. These results offer new targets to prevent the progression of inflammation and hypercholesterolemia and their increased risk of cardiovascular events.
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http://dx.doi.org/10.1093/cvr/cvaa254DOI Listing
September 2020

Sex Differences in Modifiable Risk Factors and Severity of Coronary Artery Disease.

J Am Heart Assoc 2020 10 28;9(19):e017235. Epub 2020 Sep 28.

Department of Experimental, Diagnostic and Specialty Medicine University of Bologna Bologna Italy.

Background It is still unknown whether traditional risk factors may have a sex-specific impact on coronary artery disease (CAD) burden. Methods and Results We identified 14 793 patients who underwent coronary angiography for acute coronary syndromes in the ISACS-TC (International Survey of Acute Coronary Syndromes in Transitional Countries; Clini​calTr​ials.gov, NCT01218776) registry from 2010 to 2019. The main outcome measure was the association between traditional risk factors and severity of CAD and its relationship with 30-day mortality. Relative risk (RR) ratios and 95% CIs were calculated from the ratio of the absolute risks of women versus men using inverse probability of weighting. Estimates were compared by test of interaction on the log scale. Severity of CAD was categorized as obstructive (≥50% stenosis) versus nonobstructive CAD. The RR ratio for obstructive CAD in women versus men among people without diabetes mellitus was 0.49 (95% CI, 0.41-0.60) and among those with diabetes mellitus was 0.89 (95% CI, 0.62-1.29), with an interaction by diabetes mellitus status of =0.002. Exposure to smoking shifted the RR ratios from 0.50 (95% CI, 0.41-0.61) in nonsmokers to 0.75 (95% CI, 0.54-1.03) in current smokers, with an interaction by smoking status of =0.018. There were no significant sex-related interactions with hypercholesterolemia and hypertension. Women with obstructive CAD had higher 30-day mortality rates than men (RR, 1.75; 95% CI, 1.48-2.07). No sex differences in mortality were observed in patients with nonobstructive CAD. Conclusions Obstructive CAD in women signifies a higher risk for mortality compared with men. Current smoking and diabetes mellitus disproportionally increase the risk of obstructive CAD in women. Achieving the goal of improving cardiovascular health in women still requires intensive efforts toward further implementation of lifestyle and treatment interventions. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT01218776.
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http://dx.doi.org/10.1161/JAHA.120.017235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792418PMC
October 2020

ESC Advocacy (2018-2020): contributing to the ESC mission of reducing the burden of cardiovascular disease.

Authors:
Lina Badimon

Cardiovasc Res 2020 Oct;116(12):e169-e170

European Society of Cardiology Advocacy Committee Chair and Director Cardiovascular Program-ICCC, IR-Hospital de la Santa Creu i Sant Pau, CiberCV, Barcelona, Spain.

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http://dx.doi.org/10.1093/cvr/cvaa237DOI Listing
October 2020

The European Heart Journal: leading the fight to reduce the global burden of cardiovascular disease.

Eur Heart J 2020 09;41(33):3113-3116

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK Copenhagen, Denmark.

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http://dx.doi.org/10.1093/eurheartj/ehaa674DOI Listing
September 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

The cancer patient and cardiology.

Eur J Heart Fail 2020 12 2;22(12):2290-2309. Epub 2020 Oct 2.

Campus Bio-Medico University School of Medicine, Rome, Italy.

Advances in cancer treatments have improved clinical outcomes, leading to an increasing population of cancer survivors. However, this success is associated with high rates of short- and long-term cardiovascular (CV) toxicities. The number and variety of cancer drugs and CV toxicity types make long-term care a complex undertaking. This requires a multidisciplinary approach that includes expertise in oncology, cardiology and other related specialties, and has led to the development of the cardio-oncology subspecialty. This paper aims to provide an overview of the main adverse events, risk assessment and risk mitigation strategies, early diagnosis, medical and complementary strategies for prevention and management, and long-term follow-up strategies for patients at risk of cancer therapy-related cardiotoxicities. Research to better define strategies for early identification, follow-up and management is highly necessary. Although the academic cardio-oncology community may be the best vehicle to foster awareness and research in this field, additional stakeholders (industry, government agencies and patient organizations) must be involved to facilitate cross-discipline interactions and help in the design and funding of cardio-oncology trials. The overarching goals of cardio-oncology are to assist clinicians in providing optimal care for patients with cancer and cancer survivors, to provide insight into future areas of research and to search for collaborations with industry, funding bodies and patient advocates. However, many unmet needs remain. This document is the product of brainstorming presentations and active discussions held at the Cardiovascular Round Table workshop organized in January 2020 by the European Society of Cardiology.
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http://dx.doi.org/10.1002/ejhf.1985DOI Listing
December 2020

Frail older adults show a distinct plasma microvesicle profile suggesting a prothrombotic and proinflammatory phenotype.

J Cell Physiol 2021 Mar 4;236(3):2099-2108. Epub 2020 Aug 4.

Cardiovascular Program ICCC, Institut de Recerca Hospital Santa Creu i Sant Pau; IIB-Sant Pau, Barcelona, Spain.

In a global context of advanced aging, geriatric diseases such as frailty syndrome face challenges in the search for biomarkers and preventive strategies. Frailty has been associated with atherothrombotic pathologies. Circulating microvesicles (cMVs), phospholipid-rich vesicles with a size of 0.1-1.0 μm, have been shown to participate in atherothrombosis onset and progression. We have hypothesized that cMVs from platelets, and vascular and immune cells, are increased in frail older adults. To verify this, a prevalent-case control study was designed with 28 frail older and 27 nonfrail older adults older than 64 years. Frailty was defined by Fried's phenotype. Total cMVs, annexin V positive (AV+)-cMVs, and annexin V negative (AV )-cMVs derived from blood and vascular cells were measured by flow cytometry. In the analysis of total cMVs, the frail group presented higher levels of CD14 /CD142 (p = .042), CD41a /CD142 (p = .041), and CD56 (p = .025), CD14 cMVs (p = .043), and CD16 /CD14 (p = .019) cMVs levels. Within the phosphatidylserine-exposing cMVs (AV ), the frail group showed higher CD14 /AV (p = .044), CD9 /AV (p = .031), P2RY12 /AV (p = .028), and CD235a /AV (p = .043) cMVs concentrations. Finally, within AV cMVs, the frail group showed higher CD142 /CD41a /AV cMVs concentrations originated from platelets (p = .027), CD56 /AV originated from natural killer cells (p = .022), and CD34 /AV cMVs from hematopoietic stem cells (p = .037). In summary, frail older adults present higher concentrations of platelet-, leukocyte-, and hematopoietic cell-derived cMVs compared to robust age-matched older adults. These cMVs may be involved in the deregulation of the immune system, endothelial damage, and increased risk of thrombosis associated with frailty.
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http://dx.doi.org/10.1002/jcp.29996DOI Listing
March 2021

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

Prior Beta-Blocker Therapy for Hypertension and Sex-Based Differences in Heart Failure Among Patients With Incident Coronary Heart Disease.

Hypertension 2020 09 13;76(3):819-826. Epub 2020 Jul 13.

From the Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy (R.B., O.M., E.C.).

The usefulness of β-blockers has been questioned for patients who have hypertension without a prior manifestation of coronary heart disease or heart failure. In addition, sex-based differences in the efficacy of β-blockers for prevention of heart failure during acute myocardial ischemia have never been evaluated. We explored whether the effect of β-blocker therapy varied according to the sex among patients with hypertension who have no prior history of cardiovascular disease. Data were drawn from the ISACS (International Survey of Acute Coronary Syndromes)-Archives. The study population consisted of 13 764 patients presenting with acute coronary syndromes. There were 2590 patients in whom hypertension was treated previously with β-blocker (954 women and 1636 men). Primary outcome measure was the incidence of heart failure according to Killip class classification. Subsidiary analyses were conducted to estimate the association between heart failure and all-cause mortality at 30 days. Outcome rates were assessed using the inverse probability of treatment weighting and logistic regression models. Estimates were compared by test of interaction on the log scale. Among patients taking β-blockers before admission, there was an absolute difference of 4.6% between women and men in the rate of heart failure (Killip ≥2) at hospital presentation (21.3% versus 16.7%; relative risk ratio, 1.35 [95% CI, 1.10-1.65]). On the opposite, the rate of heart failure was approximately similar among women and men who did not receive β-blockers (17.2% versus 16.1%; relative risk ratio, 1.09 [95% CI, 0.97-1.21]). The test of interaction identified a significant (=0.034) association between sex and β-blocker therapy. Heart failure was predictive of mortality at 30-day either in women (odds ratio, 7.54 [95% CI, 5.78-9.83]) or men (odds ratio, 9.62 [95% CI, 7.67-12.07]). In conclusion, β-blockers use may be an acute precipitant of heart failure in new-onset coronary heart disease among women, but not men. Heart failure increases the risk of death. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT04008173.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15323DOI Listing
September 2020

An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.

Eur Heart J 2020 10;41(37):3504-3520

Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute, Queen Mary University of London and Barts Heart Centre, London, UK.

This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA). Angina pectoris affects approximately 112 million people globally. Up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease, more common in women than in men, and a large proportion have INOCA as a cause of their symptoms. INOCA patients present with a wide spectrum of symptoms and signs that are often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment. INOCA can result from heterogeneous mechanism including coronary vasospasm and microvascular dysfunction and is not a benign condition. Compared to asymptomatic individuals, INOCA is associated with increased incidence of cardiovascular events, repeated hospital admissions, as well as impaired quality of life and associated increased health care costs. This consensus document provides a definition of INOCA and guidance to the community on the diagnostic approach and management of INOCA based on existing evidence from research and best available clinical practice; noting gaps in knowledge and potential areas for further investigation.
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http://dx.doi.org/10.1093/eurheartj/ehaa503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577516PMC
October 2020

An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.

EuroIntervention 2021 Jan;16(13):1049-1069

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University and Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.

This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA). Angina pectoris affects approximately 112 million people globally. Up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease, more common in women than in men, and a large proportion have INOCA as a cause of their symptoms. INOCA patients present with a wide spectrum of symptoms and signs that are often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment. INOCA can result from heterogeneous mechanism including coronary vasospasm and microvascular dysfunction and is not a benign condition. Compared to asymptomatic individuals, INOCA is associated with increased incidence of cardiovascular events, repeated hospital admissions, as well as impaired quality of life and associated increased health care costs. This consensus document provides a definition of INOCA and guidance to the community on the diagnostic approach and management of INOCA based on existing evidence from research and best available clinical practice; noting gaps in knowledge and potential areas for further investigation.
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http://dx.doi.org/10.4244/EIJY20M07_01DOI Listing
January 2021

A simple score to select patients for manual thrombectomy in emergent percutaneous coronary interventions: the DDTA score.

J Cardiovasc Med (Hagerstown) 2020 Aug;21(8):595-602

Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid.

Background: The objective of manual thrombectomy is the removal of occlusive thrombus to improve the results of primary angioplasty. The better understanding of the factors associated with successful manual thrombectomy may provide relevant information regarding thrombus formation and resolution.

Methods: Observational study of all consecutive patients remitted for emergent percutaneous coronary intervention (PCI) in a single centre. Successful manual thrombectomy was considered when TIMI 3 was achieved after using the device and a score to predict successful manual thrombectomy was designed.

Results: We included 618 patients, 65.1% treated with manual thrombectomy. No relevant differences in clinical features or time delays were observed between patients treated with vs. without manual thrombectomy, but manual thrombectomy treated patients received more often dual antiplatelet treatment (DAPT) before PCI. Final TIMI flow 3 was achieved in most patients and more frequently in manual thrombectomy treated patients (94.8 vs. 86.6%; P < 0.01). The successful manual thrombectomy rate was 81.3% and it was higher in patients pretreated with DAPT (89.0 vs. 73.3%; P < 0.01). The time delay to first medical contact was not related to the final TIMI 3, but it was significantly and negatively related to successful manual thrombectomy. According to the multivariate analysis, we designed the DDTA score: DAPT pretreatment (2), delay less than 2 h (3) or 2-4 h (2), TIMI flow improvement after wiring the lesion (2) and age less than 55 years (3). Patients with DDTA score at least 4 had lower no-reflow, mortality and major cardiovascular complications incidence.

Conclusion: The DDTA score (DAPT pretreatment, time delays, TIMI flow improvement after wiring the lesion and age) identifies patients who benefit mostly from manual thrombectomy.
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http://dx.doi.org/10.2459/JCM.0000000000000992DOI Listing
August 2020

Relationship of adverse events to quality of anticoagulation control in atrial fibrillation patients with diabetes: real-world data from the FANTASIIA Registry.

Ann Med 2020 09 17;52(6):300-309. Epub 2020 Jun 17.

Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, CIBERCV, Murcia, Spain.

Background: Atrial fibrillation (AF) patients with diabetes (DM) have high risk of cardiovascular events.

Purpose: To compare clinical characteristics, adverse outcomes and quality of anticoagulation in AF patients regarding DM status.

Methods: AF patients from FANTASIIA registry were included. Baseline characteristics and comorbidities were recorded. After 2-years follow-up, the association between adverse events and DM was evaluated.

Results: 1956 patients (mean age 73.8 ± 9.5 years, 56% male) were analyzed; 574 (29.3%) had DM. Diabetic patients had also high prevalence of hypertension (90.6% vs 76.1%;  < .001) or renal disease (21.4% vs 15.9%;  < .001). After median follow-up of 1077 days (IQR 766-1113 days), diabetic patients had high total mortality (16.9%/year vs 11.4%/year;  < .001), cardiovascular mortality (9.1%/year vs 3.9%/year;  < .001) and MACE (12.9%/year vs 6.8%/year;  < .001). DM patients had poor anticoagulation control (time in therapeutic range: 58.52 ± 24.37% vs 62.68 ± 25.31%;  = .002). DM with lower TTR showed higher cardiovascular death and MACE. Multivariate analysis showed an independent association between DM and cardiovascular mortality [HR 1.73 (IC95% 1.07-2.80);  = .024].

Conclusion: AF Diabetic patients have higher comorbidities and poorer TTR than nondiabetic patients. Low TTR was associated with adverse events. The risk of cardiovascular outcomes was higher in DM patients, with independent association between DM and mortality risk.
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http://dx.doi.org/10.1080/07853890.2020.1778176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877972PMC
September 2020

Implementing the new European Regulations on medical devices-clinical responsibilities for evidence-based practice: a report from the Regulatory Affairs Committee of the European Society of Cardiology.

Eur Heart J 2020 07;41(27):2589-2596

Cardiovascular Program and CiberCV, IR-Hospital de la Santa Creu i Sant Pau, Convent-ICCC, C/ Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.

The new European Union (EU) law governing the regulatory approval of medical devices that entered into force in May 2017 will now take effect from 26 May 2021. Here, we consider how it will change daily practice for cardiologists, cardiac surgeons, and healthcare professionals. Clinical evidence for any high-risk device must be reported by the manufacturer in a Summary of Safety and Clinical Performance (SSCP) that will be publicly available in the European Union Database on Medical Devices (Eudamed) maintained by the European Commission; this will facilitate evidence-based choices of which devices to recommend. Hospitals must record all device implantations, and each high-risk device will be trackable by Unique Device Identification (UDI). Important new roles are envisaged for clinicians, scientists, and engineers in EU Expert Panels-in particular to scrutinize clinical data submitted by manufacturers for certain high-risk devices and the evaluations of that data made by notified bodies. They will advise manufacturers on the design of their clinical studies and recommend to regulators when new technical specifications or guidance are needed. Physicians should support post-market surveillance by reporting adverse events and by contributing to comprehensive medical device registries. A second law on In Vitro Diagnostic Medical Devices will take effect from 2022. We encourage all healthcare professionals to contribute proactively to these new systems, in order to enhance the efficacy and safety of high-risk devices and to promote equitable access to effective innovations. The European Society of Cardiology will continue to advise EU regulators on appropriate clinical evaluation of high-risk devices.
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http://dx.doi.org/10.1093/eurheartj/ehaa382DOI Listing
July 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