Low LDL-Cholesterol and Hemorrhagic Risk: Mechanistic Insights and Clinical Perspectives.

Low-density lipoprotein cholesterol (LDL-C) plays a central role in lipid metabolism and is a well-established therapeutic target for the prevention of atherosclerotic cardiovascular diseases (CVDs). In recent years, increasingly aggressive lipid-lowering strategies have been adopted to achieve ultra-low LDL-C concentrations (<55 mg/dL or even <30 mg/dL) in high-risk patients. While the benefits of LDL-C reduction in lowering the incidence of myocardial infarction and ischemic stroke are well documented, emerging clinical evidence has raised concerns about a potential association between very low LDL-C levels and an increased risk of bleeding, particularly hemorrhagic stroke and gastrointestinal hemorrhage.

Mediator complex: update of key insights into transcriptional regulation of ancestral framework and its role in cardiovascular diseases.

Transcriptional regulation plays a pivotal role in coordinating the complex morphogenetic and molecular events involved in heart development and function. In the early stages of cardiovascular diseases (CVDs), the Mediator complex (MED) performs a variety of essential functions. While initial studies focused on correlating MED components with specific CVDs, more recent research has shifted toward a deeper exploration of the MED's role in the early pathogenesis of these diseases.

DNA hypermethylation of MED1 and MED23 as early diagnostic biomarkers for unsolved issues in atrial fibrillation.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. Much effort was spent to identify biomarkers useful to stratify AF patients. Mediator complex (MED) is an ancestral regulator of transcriptional mechanisms.

Familial Dilated Cardiomyopathy: A Novel MED9 Short Isoform Identification.

Familial dilated cardiomyopathy (DCM) is among the leading indications for heart transplantation. DCM alters the transcriptomic profile. The alteration or activation/silencing of physiologically operating transcripts may explain the onset and progression of this pathological state.

Mediator complex in neurological disease.

Neurological diseases, including traumatic brain injuries, stroke (haemorrhagic and ischemic), and inherent neurodegenerative diseases cause acquired disability in humans, representing a leading cause of death worldwide. The Mediator complex (MED) is a large, evolutionarily conserved multiprotein that facilities the interaction between transcription factors and RNA Polymerase II in eukaryotes. Some MED subunits have been found altered in the brain, although their specific functions in neurodegenerative diseases are not fully understood.

Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage.

Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells.

Association Between Circulating CD4 T Cell Methylation Signatures of Network-Oriented SOCS3 Gene and Hemodynamics in Patients Suffering Pulmonary Arterial Hypertension.

Pathogenic DNA methylation changes may be involved in pulmonary arterial hypertension (PAH) onset and its progression, but there is no data on potential associations with patient-derived hemodynamic parameters. The reduced representation bisulfite sequencing (RRBS) platform identified N = 631 differentially methylated CpG sites which annotated to N = 408 genes (DMGs) in circulating CD4 T cells isolated from PAH patients vs. healthy controls (CTRLs).

De novo DNA methylation induced by circulating extracellular vesicles from acute coronary syndrome patients.

Background And Aims: DNA methylation is associated with gene silencing, but its clinical role in cardiovascular diseases (CVDs) remains to be elucidated. We hypothesized that extracellular vesicles (EVs) may carry epigenetic changes, showing themselves as a potentially valuable non-invasive diagnostic liquid biopsy. We isolated and characterized circulating EVs of acute coronary syndrome (ACS) patients and assessed their role on DNA methylation in epigenetic modifications.

MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia.

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP.

Machine Learning and Bioinformatics Framework Integration to Potential Familial DCM-Related Markers Discovery.

Objectives: Dilated cardiomyopathy (DCM) is characterized by a specific transcriptome. Since the DCM molecular network is largely unknown, the aim was to identify specific disease-related molecular targets combining an original machine learning (ML) approach with protein-protein interaction network.

Methods: The transcriptomic profiles of human myocardial tissues were investigated integrating an original computational approach, based on the Custom Decision Tree algorithm, in a differential expression bioinformatic framework.

and DNA methylation as potential epigenetic-sensitive targets in acute coronary syndrome network analysis.

Acute coronary syndrome (ACS) is the most severe clinical manifestation of coronary heart disease.We performed an epigenome-wide analysis of circulating CD4 and CD8 T cells isolated from ACS patients and healthy subjects (HS), enrolled in the DIANA clinical trial, by reduced-representation bisulphite sequencing (RRBS). In CD4 T cells, we identified 61 differentially methylated regions (DMRs) associated with 57 annotated genes (53% hyper- and 47% hypo-methylated) by comparing ACS patients HS.

Soft drinks and sweeteners intake: Possible contribution to the development of metabolic syndrome and cardiovascular diseases. Beneficial or detrimental action of alternative sweeteners?

The rapid increase in obesity, metabolic syndrome, and cardiovascular diseases (CVDs) has been related to the rise in sugar-added foods and sweetened beverages consumption. An interesting approach has been to replace sugar with alternative sweeteners (AS), due to their impact on public health. Preclinical and clinical studies, which analyze the safety of AS intake, are still limited.

The human aortic endothelium undergoes dose-dependent DNA methylation in response to transient hyperglycemia.

Background: Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming.

DNA methylation profiling of CD04/CD08 T cells reveals pathogenic mechanisms in increasing hyperglycemia: PIRAMIDE pilot study.

Background: DNA methylation can play a pathogenic role in the early stages of hyperglycemia linking homeostasis imbalance and vascular damage.

Material And Methods: We investigated DNA methylome by RRBS in CD04 and CD08 T cells from healthy subjects (HS) to pre-diabetics (Pre-Diab) and type 2 diabetic (T2D) patients to identify early biomarkers of glucose impairment and vascular damage. Our cross-sectional study enrolled 14 individuals from HS state to increasing hyperglycemia (pilot study, PIRAMIDE trial, NCT03792607).

Integrated analysis of DNA methylation profile of HLA-G gene and imaging in coronary heart disease: Pilot study.

Aims: Immune endothelial inflammation, underlying coronary heart disease (CHD) related phenotypes, could provide new insight into the pathobiology of the disease. We investigated DNA methylation level of the unique CpG island of HLA-G gene in CHD patients and evaluated the correlation with cardiac computed tomography angiography (CCTA) features.

Methods: Thirty-two patients that underwent CCTA for suspected CHD were enrolled for this study.

Differential DNA Methylation Encodes Proliferation and Senescence Programs in Human Adipose-Derived Mesenchymal Stem Cells.

Adult adipose tissue-derived mesenchymal stem cells (ASCs) constitute a vital population of multipotent cells capable of differentiating into numerous end-organ phenotypes. However, scientific and translational endeavors to harness the regenerative potential of ASCs are currently limited by an incomplete understanding of the mechanisms that determine cell-lineage commitment and stemness. In the current study, we used reduced representation bisulfite sequencing (RRBS) analysis to identify epigenetic gene targets and cellular processes that are responsive to 5'-azacitidine (5'-AZA).

Epigenetic-sensitive pathways in personalized therapy of major cardiovascular diseases.

The complex pathobiology underlying cardiovascular diseases (CVDs) has yet to be explained. Aberrant epigenetic changes may result from alterations in enzymatic activities, which are responsible for putting in and/or out the covalent groups, altering the epigenome and then modulating gene expression. The identification of novel individual epigenetic-sensitive trajectories at single cell level might provide additional opportunities to establish predictive, diagnostic and prognostic biomarkers as well as drug targets in CVDs.

Strengths and Opportunities of Network Medicine in Cardiovascular Diseases.

Network medicine can advance current medical practice by arising as response to the limitations of a reductionist approach focusing on cardiovascular (CV) diseases as a direct consequence of a single defect. This molecular-bioinformatic approach integrates heterogeneous "omics" data and artificial intelligence to identify a chain of perturbations involving key components of multiple molecular networks that are closely related in the human interactome. The clinical view of the network-based approach is greatly supported by the general law of molecular interconnection governing all biological complex systems.

Blood transfusions and adverse acute events: a retrospective study from 214 transfusion-dependent pediatric patients comparing transfused blood components by apheresis or by whole blood.

Introduction: Blood transfusion is a lifesaving procedure for patients affected by hematological diseases or hemorrhage risk.

Aim: This retrospective study was aimed to evaluate clinical safety of pediatric transfusions by comparing the frequency of adverse events caused by apheretic blood components vs whole blood.

Methods: From 2011 to 2015, 214 patients (blood malignancy patients, n = 144 and thalassemic patients, n = 70) received 12 531 units of blood components.

Differential epigenetic factors in the prediction of cardiovascular risk in diabetic patients.

Hyperglycaemia can strongly alter the epigenetic signatures in many types of human vascular cells providing persistent perturbations of protein-protein interactions both in micro- and macro-domains. The establishment of these epigenetic changes may precede cardiovascular (CV) complications and help us to predict vascular lesions in diabetic patients. Importantly, these epigenetic marks may be transmitted across several generations (transgenerational effect) and increase the individual risk of disease.

Non-nutritional sweeteners effects on endothelial vascular function.

Aim: Hyperglycemia status induces endothelial dysfunction, although the underlying pathogenic mechanisms are not fully understood. There are several studies connecting sugar/sweetened beverages to the cardiovascular disease. Currently, many sweeteners have been extensively introduced into lifestyle to normalize blood glucose levels without altering the sweet taste.