Publications
238 results found
Zuber V, Lewin A, Levin MG, et al., 2023, Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes, American Journal of Human Genetics, Vol: 110, Pages: 1177-1199, ISSN: 0002-9297
The existing framework of Mendelian randomization (MR) infers the causal effect of one or multiple exposures on one single outcome. It is not designed to jointly model multiple outcomes, as would be necessary to detect causes of more than one outcome and would be relevant to model multimorbidity or other related disease outcomes. Here, we introduce multi-response Mendelian randomization (MR2), an MR method specifically designed for multiple outcomes to identify exposures that cause more than one outcome or, conversely, exposures that exert their effect on distinct responses. MR2 uses a sparse Bayesian Gaussian copula regression framework to detect causal effects while estimating the residual correlation between summary-level outcomes, i.e., the correlation that cannot be explained by the exposures, and vice versa. We show both theoretically and in a comprehensive simulation study how unmeasured shared pleiotropy induces residual correlation between outcomes irrespective of sample overlap. We also reveal how non-genetic factors that affect more than one outcome contribute to their correlation. We demonstrate that by accounting for residual correlation, MR2 has higher power to detect shared exposures causing more than one outcome. It also provides more accurate causal effect estimates than existing methods that ignore the dependence between related responses. Finally, we illustrate how MR2 detects shared and distinct causal exposures for five cardiovascular diseases in two applications considering cardiometabolic and lipidomic exposures and uncovers residual correlation between summary-level outcomes reflecting known relationships between cardiovascular diseases.
Avolio E, Srivastava PK, Ji J, et al., 2023, Murine studies and expressional analyses of human cardiac pericytes reveal novel trajectories of SARS-CoV-2 Spike protein-induced microvascular damage, Signal Transduction and Targeted Therapy, Vol: 8, ISSN: 2095-9907
Emanueli C, Schmidt AM, Golledge J, 2023, Unveiling Intriguing Links Between Limb Ischemia, Systemic Inflammation, and Progressive Atherosclerosis: A Tangled and Interconnected Web., Arterioscler Thromb Vasc Biol, Vol: 43, Pages: 907-909
Spinetti G, Mutoli M, Greco S, et al., 2023, Cardiovascular complications of diabetes: role of non-coding RNAs in the crosstalk between immune and cardiovascular systems., Cardiovasc Diabetol, Vol: 22
Diabetes mellitus, a group of metabolic disorders characterized by high levels of blood glucose caused by insulin defect or impairment, is a major risk factor for cardiovascular diseases and related mortality. Patients with diabetes experience a state of chronic or intermittent hyperglycemia resulting in damage to the vasculature, leading to micro- and macro-vascular diseases. These conditions are associated with low-grade chronic inflammation and accelerated atherosclerosis. Several classes of leukocytes have been implicated in diabetic cardiovascular impairment. Although the molecular pathways through which diabetes elicits an inflammatory response have attracted significant attention, how they contribute to altering cardiovascular homeostasis is still incompletely understood. In this respect, non-coding RNAs (ncRNAs) are a still largely under-investigated class of transcripts that may play a fundamental role. This review article gathers the current knowledge on the function of ncRNAs in the crosstalk between immune and cardiovascular cells in the context of diabetic complications, highlighting the influence of biological sex in such mechanisms and exploring the potential role of ncRNAs as biomarkers and targets for treatments. The discussion closes by offering an overview of the ncRNAs involved in the increased cardiovascular risk suffered by patients with diabetes facing Sars-CoV-2 infection.
Sopic M, Robinson EL, Emanueli C, et al., 2023, Integration of epigenetic regulatory mechanisms in heart failure., Basic Res Cardiol, Vol: 118
The number of "omics" approaches is continuously growing. Among others, epigenetics has appeared as an attractive area of investigation by the cardiovascular research community, notably considering its association with disease development. Complex diseases such as cardiovascular diseases have to be tackled using methods integrating different omics levels, so called "multi-omics" approaches. These approaches combine and co-analyze different levels of disease regulation. In this review, we present and discuss the role of epigenetic mechanisms in regulating gene expression and provide an integrated view of how these mechanisms are interlinked and regulate the development of cardiac disease, with a particular attention to heart failure. We focus on DNA, histone, and RNA modifications, and discuss the current methods and tools used for data integration and analysis. Enhancing the knowledge of these regulatory mechanisms may lead to novel therapeutic approaches and biomarkers for precision healthcare and improved clinical outcomes.
Heys R, Angelini GD, Joyce K, et al., 2023, Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: A protocol for a randomised controlled study (ProMPT2), PERFUSION-UK, ISSN: 0267-6591
Rudge MVC, Alves FCB, Hallur RLS, et al., 2023, Consequences of the exposome to gestational diabetes mellitus, BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, Vol: 1867, ISSN: 0304-4165
Ben-Aicha S, Caporali A, Srivastava P, et al., 2023, Role of MicroRNAs in Vascular Remodeling and Repair, MicroRNA in Regenerative Medicine, Second Edition, Pages: 453-488, ISBN: 9780128207222
Vascular remodeling can occur after a traumatic cardiovascular event or in the presence of comorbidities as well as aging. This remodeling is a complex network of stimulus including temporal gene expression coordinated by microRNAs (miRNAs). In the setting of cardiovascular regeneration, miRNAs could play a role in the generation of new functional cardiomyocytes and therapeutic angiogenesis whose implication remains as a key goal in cell therapy for vascular and cardiovascular diseases. In this later regard, cell differentiation elicits a complex concerto of precise miRNA expression for controlling cell fate decisions, function, and engraftment into the host. Despite promising results, limited improvements in animal models of ischemic disease using progenitor cell types have been shown in diseases, such as chronic angina, acute MI, and heart failure. To progress to the clinic, a better understanding of the transcriptional control of lineage commitment is warranted. This chapter describes the role of miRNAs in vascular remodeling and in cell therapy strategies for treating ischemic diseases.
Caporali A, Emanueli C, 2022, Unraveling the epitranscriptome of small non-coding RNAs in vascular cells, MOLECULAR THERAPY-NUCLEIC ACIDS, Vol: 30, Pages: 477-478, ISSN: 2162-2531
Sophocleous F, De Garate E, Bigotti MG, et al., 2022, A Segmental Approach from Molecular Profiling to Medical Imaging to Study Bicuspid Aortic Valve Aortopathy, CELLS, Vol: 11
Harries I, Biglino G, Ford K, et al., 2022, Prospective multiparametric CMR characterization and MicroRNA profiling of anthracycline cardiotoxicity: A pilot translational study, IJC HEART & VASCULATURE, Vol: 43
Ji J, Anwar M, Petretto E, et al., 2022, PPMS: a framework to profile primary microRNAs from single-cell RNA-sequencing datasets, Briefings in Bioinformatics, Vol: 23, Pages: 1-7, ISSN: 1467-5463
Motivation:Single-cell/nuclei RNA sequencing (scRNA-seq) technologies can simultaneously quantify gene expression in thousands of cells across the genome. However, the majority of the non-coding RNAs, such as microRNAs (miRNAs), cannot currently be profiled at the same scale. MiRNAs are a class of small non-coding RNAs and play an important role in gene regulation. MiRNAs originate from the processing of primary transcripts, known as primary-microRNAs (pri-miRNAs). The pri-miRNA transcripts, independent of their cognate miRNAs, can also function as long non-coding RNAs, code for micropeptides or even interact with DNA, acting like enhancers. Therefore, it is apparent that the significance of scRNA-seq pri-miRNA profiling expands beyond using pri-miRNA as proxies of mature miRNAs. However, there are no computational methods that allow profiling and quantification of pri-miRNAs at the single-cell type resolution.Results:We have developed a simple yet effective computational framework to Profile Pri-MiRNAs from Single-cell RNA-sequencing datasets (PPMS). Based on user input, PPMS can profile pri-miRNAs at cell-type resolution. PPMS can be applied to both newly produced and publicly available datasets obtained via single cell or single nuclei RNA-seq. It allows users to (i) investigate the distribution of pri-miRNAs across cell types and cell states and (ii) establish a relationship between the number of cells/reads sequenced and the detection of pri-miRNAs. Here, to demonstrate its efficacy, we have applied PPMS to publicly available scRNA-seq data generated from (a) individual chambers (ventricles and atria) of the human heart, (b) human pluripotent stem cells during their differentiation into cardiomyocytes (the heart beating cells) and (c) hiPSCs-derived cardiomyocytes infected with SARS-CoV2 virus. Availability and implementation:PPMS is free to use under a GNU license and is available to download from (GitHub link: https://github.com/SrivastavaLab-ICL/PPMS)
Skeffington KL, Moscarelli M, Abdul-Ghani S, et al., 2022, Pathology-related changes in cardiac energy metabolites, inflammatory response and reperfusion injury following cardioplegic arrest in patients undergoing open-heart surgery, Frontiers in Cardiovascular Medicine, Vol: 9, Pages: 1-14, ISSN: 2297-055X
Introduction: Changes in cardiac metabolites in adult patients undergoing open-heart surgery using ischemic cardioplegic arrest have largely been reported for non-ventricular tissue or diseased left ventricular tissue, with few studies attempting to assess such changes in both ventricular chambers. It is also unknown whether such changes are altered in different pathologies or linked to the degree of reperfusion injury and inflammatory response. The aim of the present work was to address these issues by monitoring myocardial metabolites in both ventricles and to establish whether these changes are linked to reperfusion injury and inflammatory/stress response in patients undergoing surgery using cold blood cardioplegia for either coronary artery bypass graft (CABG, n = 25) or aortic valve replacement (AVR, n = 16).Methods: Ventricular biopsies from both left (LV) and right (RV) ventricles were collected before ischemic cardioplegic arrest and 20 min after reperfusion. The biopsies were processed for measuring selected metabolites (adenine nucleotides, purines, and amino acids) using HPLC. Blood markers of cardiac injury (Troponin I, cTnI), inflammation (IL- 6, IL-8, Il-10, and TNFα, measured using Multiplex) and oxidative stress (Myeloperoxidase, MPO) were measured pre- and up to 72 hours post-operatively.Results: The CABG group had a significantly shorter ischemic cardioplegic arrest time (38.6 ± 2.3 min) compared to AVR group (63.0 ± 4.9 min, p = 2 x 10−6). Cardiac injury (cTnI release) was similar for both CABG and AVR groups. The inflammatory markers IL-6 and Il-8 were significantly higher in CABG patients compared to AVR patients. Metabolic markers of cardiac ischemic stress were relatively and significantly more altered in the LV of CABG patients. Comparing diabetic and non-diabetic CABG patients shows that only the RV of diabetic patients sustained major ischemic stress during reperfusion and that diabetic patients had a significantly
Abdul-Ghani S, Skeffington KL, Kim M, et al., 2022, Effect of cardioplegic arrest and reperfusion on left and right ventricular proteome/phosphoproteome in patients undergoing surgery for coronary or aortic valve disease, International Journal of Molecular Medicine, Vol: 49, Pages: 1-14, ISSN: 1107-3756
Our earlier work has shown inter‑disease and intra‑disease differences in the cardiac proteome between right (RV) and left (LV) ventricles of patients with aortic valve stenosis (AVS) or coronary artery disease (CAD). Whether disease remodeling also affects acute changes occuring in the proteome during surgical intervention is unknown. This study investigated the effects of cardioplegic arrest on cardiac proteins/phosphoproteins in LV and RV of CAD (n=6) and AVS (n=6) patients undergoing cardiac surgery. LV and RV biopsies were collected during surgery before ischemic cold blood cardioplegic arrest (pre) and 20 min after reperfusion (post). Tissues were snap frozen, proteins extracted, and the extracts were used for proteomic and phosphoproteomic analysis using Tandem Mass Tag (TMT) analysis. The results were analysed using QuickGO and Ingenuity Pathway Analysis softwares. For each comparision, our proteomic analysis identified more than 3,000 proteins which could be detected in both the pre and Post samples. Cardioplegic arrest and reperfusion were associated with significant differential expression of 24 (LV) and 120 (RV) proteins in the CAD patients, which were linked to mitochondrial function, inflammation and cardiac contraction. By contrast, AVS patients showed differential expression of only 3 LV proteins and 2 RV proteins, despite a significantly longer duration of ischaemic cardioplegic arrest. The relative expression of 41 phosphoproteins was significantly altered in CAD patients, with 18 phosphoproteins showing altered expression in AVS patients. Inflammatory pathways were implicated in the changes in phosphoprotein expression in both groups. Inter‑disease comparison for the same ventricular chamber at both timepoints revealed differences relating to inflammation and adrenergic and calcium signalling. In conclusion, the present study found that ischemic arrest and reperfusion trigger different changes in the proteomes and phosphoproteomes of LV and RV of
Davidson SM, Boulanger CM, Aikawa E, et al., 2022, Methods for the identification and characterization of extracellular vesicles in cardiovascular studies: from exosomes to microvesicles, CARDIOVASCULAR RESEARCH, ISSN: 0008-6363
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- Citations: 14
Ben-Aicha S, Buchanan J, Punjabi P, et al., 2022, Efficacy of treatments tested in COVID-19 patients with cardiovascular disease. A meta-analysis, Perfusion (United Kingdom), Pages: 1-11, ISSN: 1477-111X
BackgroundThe COVID-19 pandemic has spread globally infecting and killing millions. Those with cardiovascular disease (CVD) are at higher risk of increased disease severity and mortality. We performed a systematic review and meta-analysis to estimate the rate of in-hospital mortality following different treatments on COVID-19 in patients with CVD.MethodsPertinent articles were identified from the PubMed, Google Scholar, Ovid MEDLINE, and Ovid EMBASE databases. This study protocol was registered under PROSPERO with the identifier CRD42020183057.ResultsOf the 1673 papers scrutinized, 46 were included in the review. Of the 2553 patients (mean age 63.9 ± 2.7 years/o; 57.2% male), the most frequent CVDs were coronary artery disease (9.09%) and peripheral arterial disease (5.4%) and the most frequent cardiovascular risk factors were hypertension (86.7%) and diabetes (23.7%). Most patients were on multiple treatments. 14 COVID-19 treatments were compared with controls. The pooled event rate for in-hospital mortality was 20% (95% confidence interval (CI): 11–33%); certain heterogeneity was observed across studies.ConclusionsCOVID-19 is associated with a high in-hospital mortality rate in patients with CVD. This study shows that previous CVD determines mortality, regardless of the type of COVID-19 administered therapy. Treatments for at-risk patients should be administered carefully and monitored closely until further data are available.
Posadino AM, Erre GL, Cossu A, et al., 2022, NADPH-derived ROS generation drives fibrosis and endothelial-to-mesenchymal transition in systemic sclerosis: Potential cross talk with circulating miRNAs., Biomol Concepts, Vol: 13, Pages: 11-24
Systemic sclerosis (SSc) is an immune disorder characterized by diffuse fibrosis and vascular abnormalities of the affected organs. Although the etiopathology of this disease is largely unknown, endothelial damage and oxidative stress appear implicated in its initiation and maintenance. Here, we show for the first time that circulating factors present in SSc sera increased reactive oxygen species (ROS) production, collagen synthesis, and proliferation of human pulmonary microvascular endothelial cells (HPMECs). The observed phenomena were also associated with endothelial to mesenchymal transition (EndMT) as indicated by decreased von Willebrand factor (vWF) expression and increased alpha-smooth muscle actin, respectively, an endothelial and mesenchymal marker. SSc-induced fibroproliferative effects were prevented by HPMECs exposition to the NADPH oxidase inhibitor diphenyleneiodonium, demonstrating ROS's causative role and suggesting their cellular origin. Sera from SSc patients showed significant changes in the expression of a set of fibrosis/EndMT-associated microRNAs (miRNA), including miR-21, miR-92a, miR-24, miR-27b, miR-125b, miR-29c, and miR-181b, which resulted significantly upregulated as compared to healthy donors sera. However, miR29b resulted downregulated in SSc sera, whereas no significant differences were found in the expression of miR-29a in the two experimental groups of samples. Taking together our data indicate NADPH oxidase-induced EndMT as a potential mechanism of SSc-associated fibrosis, suggesting fibrosis-associated miRNAs as potentially responsible for initiating and sustaining the vascular alterations observed in this pathological condition.
Abdulrazzak H, Ruiz-Lozano P, Emanueli C, 2022, Epicardium-derived extracellular vesicles: a promising avenue for cardiac regeneration, CARDIOVASCULAR RESEARCH, Vol: 118, Pages: 350-352, ISSN: 0008-6363
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- Citations: 1
Robinson EL, Emanueli C, Martelli F, et al., 2021, Leveraging non-coding RNAs to fight cardiovascular disease: the EU-CardioRNA network, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 4881-4883, ISSN: 0195-668X
Floriano JF, Emanueli C, Vega S, et al., 2021, Pro-angiogenic approach for skeletal muscle regeneration, BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, Vol: 1866, ISSN: 0304-4165
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- Citations: 3
Vanhaverbeke M, Attard R, Bartekova M, et al., 2021, Peripheral blood RNA biomarkers for cardiovascular disease from bench to bedside: a position paper from the EU-CardioRNA COST action CA17129, CARDIOVASCULAR RESEARCH, Vol: 118, Pages: 3183-3197, ISSN: 0008-6363
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- Citations: 4
Scott A, Ballesteros LS, Bradshaw M, et al., 2021, In Vivo Characterization of Endogenous Cardiovascular Extracellular Vesicles in Larval and Adult Zebrafish, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 41, Pages: 2454-2468, ISSN: 1079-5642
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- Citations: 10
Abdulrazzak H, Ruiz-Lozano P, Emanueli C, 2021, Epicardium-derived extracellular vesicles: a promising avenue for cardiac regeneration (vol 118, pg 350, 2022), CARDIOVASCULAR RESEARCH, Vol: 118, Pages: 1611-1611, ISSN: 0008-6363
Robinson EL, Baker AH, Brittan M, et al., 2021, Dissecting the transcriptome in cardiovascular disease, CARDIOVASCULAR RESEARCH, Vol: 118, Pages: 1004-1019, ISSN: 0008-6363
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- Citations: 5
Sweaad WK, Stefanizzi FM, Chamorro-Jorganes A, et al., 2021, Relevance of N6-methyladenosine regulators for transcriptome: Implications for development and the cardiovascular system, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 160, Pages: 56-70, ISSN: 0022-2828
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- Citations: 1
Aday S, Hazan-Halevy I, Chamorro-Jorganes A, et al., 2021, Bioinspired artificial exosomes based on lipid nanoparticles carrying let-7b-5p promote angiogenesis in vitro and in vivo, Molecular Therapy, Vol: 29, Pages: 2239-2252, ISSN: 1525-0016
MicroRNAs (miRNAs) regulate gene expression by post-transcriptional inhibition of target genes. Proangiogenic small extracellular vesicles (sEVs; popularly identified with the name "exosomes") with a composite cargo of miRNAs are secreted by cultured stem cells and present in human biological fluids. Lipid nanoparticles (LNPs) represent an advanced platform for clinically approved delivery of RNA therapeutics. In this study, we aimed to (1) identify the miRNAs responsible for sEV-induced angiogenesis; (2) develop the prototype of bioinspired "artificial exosomes" (AEs) combining LNPs with a proangiogenic miRNA, and (3) validate the angiogenic potential of the bioinspired AEs. We previously reported that human sEVs from bone marrow (BM)-CD34+ cells and pericardial fluid (PF) are proangiogenic. Here, we have shown that sEVs secreted from saphenous vein pericytes and BM mesenchymal stem cells also promote angiogenesis. Analysis of miRNA datasets available in-house or datamined from GEO identified the let-7 family as common miRNA signature of the proangiogenic sEVs. LNPs with either hsa-let-7b-5p or cyanine 5 (Cy5)-conjugated Caenorhabditis elegans miR-39 (Cy5-cel-miR-39; control miRNA) were prepared using microfluidic micromixing. let-7b-5p-AEs did not cause toxicity and transferred functionally active let-7b-5p to recipient endothelial cells (ECs). let-7b-AEs also improved EC survival under hypoxia and angiogenesis in vitro and in vivo. Bioinspired proangiogenic AEs could be further developed into innovative nanomedicine products targeting ischemic diseases.
Chamorro-Jorganes A, Sweaad WK, Katare R, et al., 2021, METTL3 Regulates Angiogenesis by Modulating let-7e-5p and miRNA-18a-5p Expression in Endothelial Cells, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 41, Pages: E325-E337, ISSN: 1079-5642
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- Citations: 15
Badimon L, Robinson EL, Jusic A, et al., 2021, Cardiovascular RNA markers and artificial intelligence may improve COVID-19 outcome: a position paper from the EU-CardioRNA COST Action CA17129, CARDIOVASCULAR RESEARCH, Vol: 117, Pages: 1823-1840, ISSN: 0008-6363
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- Citations: 9
Bollini S, Emanueli C, 2021, To serve and protect: a new heart patrolling and recycling role for macrophages, CARDIOVASCULAR RESEARCH, Vol: 117, Pages: E17-E20, ISSN: 0008-6363
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- Citations: 1
Moscarelli M, Angelini GD, Emanueli C, et al., 2021, Remote ischemic preconditioning in isolated valve intervention. A pooled meta-analysis, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 324, Pages: 146-151, ISSN: 0167-5273
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- Citations: 1
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