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Article ; Online: Unexplored horizons on sex bias and progression of heart failure with preserved ejection fraction.

Benincasa, Giuditta / Napoli, Claudio

European heart journal. Cardiovascular pharmacotherapy

2023 Volume 9, Issue 6, Page(s) 502–504

MeSH term(s)	Humans ; Stroke Volume ; Sexism ; Heart Failure/diagnosis ; Hospitalization
Language	English
Publishing date	2023-07-22
Publishing country	England
Document type	Editorial ; Comment
ZDB-ID	2808613-2
ISSN	2055-6845 ; 2055-6837
ISSN (online)	2055-6845
ISSN	2055-6837
DOI	10.1093/ehjcvp/pvad050
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Article ; Online: Transgenerational Epigenetic Inheritance of Cardiovascular Diseases: A Network Medicine Perspective.

Benincasa, Giuditta / Napoli, Claudio / DeMeo, Dawn L

Maternal and child health journal

2024 Volume 28, Issue 4, Page(s) 617–630

Abstract: Introduction: The ability to identify early epigenetic signatures underlying the inheritance of cardiovascular risk, including trans- and intergenerational effects, may help to stratify people before cardiac symptoms occur.: Methods: Prospective and ... ...

Abstract	Introduction: The ability to identify early epigenetic signatures underlying the inheritance of cardiovascular risk, including trans- and intergenerational effects, may help to stratify people before cardiac symptoms occur. Methods: Prospective and retrospective cohorts and case-control studies focusing on DNA methylation and maternal/paternal effects were searched in Pubmed from 1997 to 2023 by using the following keywords: DNA methylation, genomic imprinting, and network analysis in combination with transgenerational/intergenerational effects. Results: Maternal and paternal exposures to traditional cardiovascular risk factors during critical temporal windows, including the preconceptional period or early pregnancy, may perturb the plasticity of the epigenome (mainly DNA methylation) of the developing fetus especially at imprinted loci, such as the insulin-like growth factor type 2 (IGF2) gene. Thus, the epigenome is akin to a "molecular archive" able to memorize parental environmental insults and predispose an individual to cardiovascular diseases onset in later life. Direct evidence for human transgenerational epigenetic inheritance (at least three generations) of cardiovascular risk is lacking but it is supported by epidemiological studies. Several blood-based association studies showed potential intergenerational epigenetic effects (single-generation studies) which may mediate the transmittance of cardiovascular risk from parents to offspring. Discussion: In this narrative review, we discuss some relevant examples of trans- and intergenerational epigenetic associations with cardiovascular risk. In our perspective, we propose three network-oriented approaches which may help to clarify the unsolved issues regarding transgenerational epigenetic inheritance of cardiovascular risk and provide potential early biomarkers for primary prevention.
MeSH term(s)	Male ; Pregnancy ; Female ; Humans ; Epigenesis, Genetic ; Cardiovascular Diseases/genetics ; Retrospective Studies ; Prospective Studies ; DNA Methylation
Language	English
Publishing date	2024-02-26
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1339905-6
ISSN	1573-6628 ; 1092-7875
ISSN (online)	1573-6628
ISSN	1092-7875
DOI	10.1007/s10995-023-03886-z
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Zs.A 6170: Show issues

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Article ; Online: Bioinformatic platforms for clinical stratification of natural history of atherosclerotic cardiovascular diseases.

Benincasa, Giuditta / Suades, Rosa / Padró, Teresa / Badimon, Lina / Napoli, Claudio

European heart journal. Cardiovascular pharmacotherapy

2023 Volume 9, Issue 8, Page(s) 758–769

Abstract: Although bioinformatic methods gained a lot of attention in the latest years, their use in real-world studies for primary and secondary prevention of atherosclerotic cardiovascular diseases (ASCVD) is still lacking. Bioinformatic resources have been ... ...

Abstract	Although bioinformatic methods gained a lot of attention in the latest years, their use in real-world studies for primary and secondary prevention of atherosclerotic cardiovascular diseases (ASCVD) is still lacking. Bioinformatic resources have been applied to thousands of individuals from the Framingham Heart Study as well as health care-associated biobanks such as the UK Biobank, the Million Veteran Program, and the CARDIoGRAMplusC4D Consortium and randomized controlled trials (i.e. ODYSSEY, FOURIER, ASPREE, and PREDIMED). These studies contributed to the development of polygenic risk scores (PRS), which emerged as novel potent genetic-oriented tools, able to calculate the individual risk of ASCVD and to predict the individual response to therapies such as statins and proprotein convertase subtilisin/kexin type 9 inhibitor. ASCVD are the first cause of death around the world including coronary heart disease (CHD), peripheral artery disease, and stroke. To achieve the goal of precision medicine and personalized therapy, advanced bioinformatic platforms are set to link clinically useful indices to heterogeneous molecular data, mainly epigenomics, transcriptomics, metabolomics, and proteomics. The DIANA study found that differential methylation of ABCA1, TCF7, PDGFA, and PRKCZ significantly discriminated patients with acute coronary syndrome from healthy subjects and their expression levels positively associated with CK-MB serum concentrations. The ARIC Study revealed several plasma proteins, acting or not in lipid metabolism, with a potential role in determining the different pleiotropic effects of statins in each subject. The implementation of molecular high-throughput studies and bioinformatic techniques into traditional cardiovascular risk prediction scores is emerging as a more accurate practice to stratify patients earlier in life and to favour timely and tailored risk reduction strategies. Of note, radiogenomics aims to combine imaging features extracted for instance by coronary computed tomography angiography and molecular biomarkers to create CHD diagnostic algorithms useful to characterize atherosclerotic lesions and myocardial abnormalities. The current view is that such platforms could be of clinical value for prevention, risk stratification, and treatment of ASCVD.
MeSH term(s)	Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/prevention & control ; Atherosclerosis/diagnosis ; Atherosclerosis/drug therapy ; Atherosclerosis/genetics ; Coronary Disease/drug therapy ; Computational Biology
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors
Language	English
Publishing date	2023-08-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2808613-2
ISSN	2055-6845 ; 2055-6837
ISSN (online)	2055-6845
ISSN	2055-6837
DOI	10.1093/ehjcvp/pvad059
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Article ; Online: Unsolved Issues on Beneficial Effects of Combination Therapy With Sotatercept in Pulmonary Arterial Hypertension.

Benincasa, Giuditta / Strozziero, Maria Grazia / Trama, Ugo / Napoli, Claudio

Heart, lung & circulation

2023 Volume 33, Issue 1, Page(s) 12–13

MeSH term(s)	Humans ; Pulmonary Arterial Hypertension/drug therapy ; Recombinant Fusion Proteins ; Familial Primary Pulmonary Hypertension
Chemical Substances	ACE-011 ; Recombinant Fusion Proteins
Language	English
Publishing date	2023-11-30
Publishing country	Australia
Document type	Editorial
ZDB-ID	2020980-0
ISSN	1444-2892 ; 1443-9506
ISSN (online)	1444-2892
ISSN	1443-9506
DOI	10.1016/j.hlc.2023.10.010
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Zs.A 4988: Show issues

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Article ; Online: Cardiovascular risk factors and molecular routes underlying endothelial dysfunction: Novel opportunities for primary prevention.

Benincasa, Giuditta / Coscioni, Enrico / Napoli, Claudio

Biochemical pharmacology

2022 Volume 202, Page(s) 115108

Abstract: One of the major challenges of cardiovascular primary prevention approach is the absence of early biomarkers of endothelial dysfunction which may be useful for identifying at-risk subjects. Endothelial dysfunction is a systemic disorder in which ... ...

Abstract	One of the major challenges of cardiovascular primary prevention approach is the absence of early biomarkers of endothelial dysfunction which may be useful for identifying at-risk subjects. Endothelial dysfunction is a systemic disorder in which traditional cardiovascular risk factors, such as aging, gender, hypertension, smoking, hyperglycemia, and dyslipidemia, as well as emerging risk determinants, such as fetal factors, gut microbiome alteration, clonal hematopoiesis, air pollution, and sleep disorders act synergistically to tip the endothelial balance in favor of vasoconstrictive, pro-inflammatory, and pro-thrombotic phenotypes. Endothelial dysfunction can start already in fetal life and may be regained once detrimental stimuli are removed. The hallmark of endothelial dysfunction is a marked reduction of nitric oxide (NO) bioavailability owing to epigenetic-sensitive dysregulation of the endothelial nitric oxide synthase (eNOS) gene and upregulation of reactive oxygen species (ROS) in endothelial cells (ECs). Advance in liquid-based assays and molecular biology tools are providing novel potential EC-specific biomarkers for prediction and diagnosis of endothelial dysfunction. Significant associations between clinically useful indexes of endothelial dysfunction, mainly brachial artery flow-mediated dilation (FMD), and increased number of endothelial microparticles (EMPs), increased levels of endoglin and endocan, as well as reduced levels of irisin were observed in subjects with one or more traditional risk factors. However, none entered in clinical practice yet. Smoking cessation, weight loss, physical exercise, and diet control are the milestones of cardiovascular primary prevention, and they may restore endothelial function via epigenetic-sensitive pathways able to reduce inflammation and oxidative stress and increase NO production . We briefly summarize well-known and novel molecular routes driving early endothelial dysfunction mainly in human ECs and related potential biomarkers which may add predictive or diagnostic value to the traditional non-invasive techniques. Also, we focus on clinical trials investigating lifestyle modifications and their impact on molecular routes involved in restoring endothelial function.
MeSH term(s)	Biomarkers/metabolism ; Cardiovascular Diseases/metabolism ; Endothelial Cells/metabolism ; Endothelium, Vascular/metabolism ; Heart Disease Risk Factors ; Humans ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Oxidative Stress ; Primary Prevention ; Risk Factors ; Vascular Diseases/metabolism
Chemical Substances	Biomarkers ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase Type III (EC 1.14.13.39)
Language	English
Publishing date	2022-05-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2022.115108
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Zs.A 19: Show issues

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Article ; Online: "Transplantomics" for predicting allograft rejection: real-life applications and new strategies from Network Medicine.

Benincasa, Giuditta / Viglietti, Mario / Coscioni, Enrico / Napoli, Claudio

Human immunology

2022 Volume 84, Issue 2, Page(s) 89–97

Abstract: Although decades of the reductionist approach achieved great milestones in optimizing the immunosuppression therapy, traditional clinical parameters still fail in predicting both acute and chronic (mainly) rejection events leading to higher rates across ... ...

Abstract	Although decades of the reductionist approach achieved great milestones in optimizing the immunosuppression therapy, traditional clinical parameters still fail in predicting both acute and chronic (mainly) rejection events leading to higher rates across all solid organ transplants. To clarify the underlying immune-related cellular and molecular mechanisms, current biomedical research is increasingly focusing on "transplantomics" which relies on a huge quantity of big data deriving from genomics, transcriptomics, epigenomics, proteomics, and metabolomics platforms. The AlloMap (gene expression) and the AlloSure (donor-derived cell-free DNA) tests represent two successful examples of how omics and liquid biopsy can really improve the precision medicine of heart and kidney transplantation. One of the major challenges in translating big data in clinically useful biomarkers is the integration and interpretation of the different layers of omics datasets. Network Medicine offers advanced bioinformatic-molecular strategies which were widely used to integrate large omics datasets and clinical information in end-stage patients to prioritize potential biomarkers and drug targets. The application of network-oriented approaches to clarify the complex nature of graft rejection is still in its infancy. Here, we briefly discuss the real-life clinical applications derived from omics datasets as well as novel opportunities for establishing predictive tests in solid organ transplantation. Also, we provide an original "graft rejection interactome" and propose network-oriented strategies which can be useful to improve precision medicine of solid organ transplantation.
MeSH term(s)	Humans ; Transplantation, Homologous ; Genomics ; Proteomics ; Biomarkers/metabolism ; Allografts/metabolism ; Graft Rejection/diagnosis ; Graft Rejection/genetics ; Graft Rejection/pathology
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-11-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	801524-7
ISSN	1879-1166 ; 0198-8859
ISSN (online)	1879-1166
ISSN	0198-8859
DOI	10.1016/j.humimm.2022.11.004
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Zs.A 1597: Show issues

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Article ; Online: An evidence-based debate on epigenetics and immunosenescence in COVID-19.

Napoli, Claudio / Coscioni, Enrico / Trama, Ugo / Strozziero, Maria Grazia / Benincasa, Giuditta

Current research in immunology

2023 Volume 4, Page(s) 100069

Abstract: Immunosenescence contributes to the decline of immune function leading to a reduced ability to respond to severe coronavirus disease 2019 (COVID-19) in elderly patients. Clinical course of COVID-19 is widely heterogeneous and guided by the possible ... ...

Abstract	Immunosenescence contributes to the decline of immune function leading to a reduced ability to respond to severe coronavirus disease 2019 (COVID-19) in elderly patients. Clinical course of COVID-19 is widely heterogeneous and guided by the possible interplay between genetic background and epigenetic-sensitive mechanisms underlying the immunosenescence which could explain, at least in part, the higher percentage of disease severity in elderly individuals. The most convincing evidence regards the hypomethylation of the angiotensin-converting enzyme 2 (
Language	English
Publishing date	2023-09-26
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	2590-2555
ISSN (online)	2590-2555
DOI	10.1016/j.crimmu.2023.100069
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Article ; Online: Epigenetics and outcome prediction in heart transplantation after circulatory death: A clinical perspective.

Benincasa, Giuditta / Donatelli, Francesco / Strozziero, Maria Grazia / Miceli, Antonio / Coscioni, Enrico / Napoli, Claudio

Clinical transplantation

2023 Volume 37, Issue 12, Page(s) e15154

MeSH term(s)	Humans ; Heart Transplantation ; Cardiovascular System ; Prognosis ; Epigenesis, Genetic ; Tissue Donors ; Tissue and Organ Procurement ; Death
Language	English
Publishing date	2023-10-06
Publishing country	Denmark
Document type	Letter
ZDB-ID	639001-8
ISSN	1399-0012 ; 0902-0063
ISSN (online)	1399-0012
ISSN	0902-0063
DOI	10.1111/ctr.15154
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Zs.A 2204: Show issues

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Article ; Online: Epigenetic challenges on the horizon of chimeric antigen receptor-T.

Benincasa, Giuditta / Strozziero, Maria Grazia / Di Pastena, Maria Assunta / Criscuolo, Clelia / Cetani, Giusy / Trama, Ugo / Napoli, Claudio

Cytotherapy

2024 Volume 26, Issue 5, Page(s) 411–412

MeSH term(s)	Humans ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; Epigenesis, Genetic ; Immunotherapy, Adoptive/methods ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes/immunology
Chemical Substances	Receptors, Chimeric Antigen ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2024-03-02
Publishing country	England
Document type	Journal Article ; Editorial
ZDB-ID	2039821-9
ISSN	1477-2566 ; 1465-3249
ISSN (online)	1477-2566
ISSN	1465-3249
DOI	10.1016/j.jcyt.2024.02.016
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Zs.A 5601: Show issues

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Article ; Online: Pursuing functional biomarkers in complex disease: Focus on pulmonary arterial hypertension.

Benincasa, Giuditta / Napoli, Claudio / Loscalzo, Joseph / Maron, Bradley A

American heart journal

2022 Volume 258, Page(s) 96–113

Abstract: A major gap in diagnosis, classification, risk stratification, and prediction of therapeutic response exists in pulmonary arterial hypertension (PAH), driven in part by a lack of functional biomarkers that are also disease-specific. In this regard, ... ...

Abstract	A major gap in diagnosis, classification, risk stratification, and prediction of therapeutic response exists in pulmonary arterial hypertension (PAH), driven in part by a lack of functional biomarkers that are also disease-specific. In this regard, leveraging big data-omics analyses using innovative approaches that integrate network medicine and machine learning correlated with clinically useful indices or risk stratification scores is an approach well-positioned to advance PAH precision medicine. For example, machine learning applied to a panel of 48 cytokines, chemokines, and growth factors could prognosticate PAH patients with immune-dominant subphenotypes at elevated or low-risk for mortality. Here, we discuss strengths and weaknesses of the most current studies evaluating omics-derived biomarkers in PAH. Progress in this field is offset by studies with small sample size, pervasive limitations in bioinformatics, and lack of standardized methods for data processing and interpretation. Future success in this field, in turn, is likely to hinge on mechanistic validation of data outputs in order to couple functional biomarker data with target-specific therapeutics in clinical practice.
MeSH term(s)	Humans ; Pulmonary Arterial Hypertension/diagnosis ; Biomarkers ; Machine Learning ; Precision Medicine ; Risk Factors
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-12-22
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80026-0
ISSN	1097-6744 ; 0002-8703
ISSN (online)	1097-6744
ISSN	0002-8703
DOI	10.1016/j.ahj.2022.12.009
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