Rare Cardiovascular Diseases Research Articles

A brief review on recent advances in diagnostic and therapeutic applications of extracellular vesicles in cardiovascular disease

Extracellular vesicles (EVs) are important mediators of intercellular communication within the cardiovascular system, playing essential roles in physiological homeostasis and contributing to the pathogenesis of various cardiovascular diseases (CVDs). However, their potential as diagnostic biomarkers and therapeutic agents in rare cardiovascular diseases, such as valvular heart disease (VHD) and cardiomyopathies, remains largely unexplored. This review comprehensively emphasizes recent advancements in extracellular vesicle research, explicitly highlighting their growing significance in diagnosing and potentially treating rare cardiovascular diseases, with a particular focus on valvular heart disease and cardiomyopathies. We highlight the potential of extracellular vesicle-based liquid biopsies as non-invasive tools for early disease detection and risk stratification, showcasing specific extracellular vesicle-associated biomarkers (proteins, microRNAs, lipids) with diagnostic and prognostic value. Furthermore, we discussed the therapeutic promise of extracellular vesicles derived from various sources, including stem cells and engineered extracellular vesicles, for cardiac repair and regeneration through their ability to modulate inflammation, promote angiogenesis, and reduce fibrosis. By integrating the findings and addressing critical knowledge gaps, this review aims to stimulate further research and innovation in extracellular vesicle-based diagnostics and therapeutics of cardiovascular disease.

Large-scale phosphoproteomics reveals activation of the MAPK/GADD45β/P38 axis and cell cycle inhibition in response to BMP9 and BMP10 stimulation in endothelial cells

BackgroundBMP9 and BMP10 are two major regulators of vascular homeostasis. These two ligands bind with high affinity to the endothelial type I kinase receptor ALK1, together with a type II receptor, leading to the direct phosphorylation of the SMAD transcription factors. Apart from this canonical pathway, little is known. Interestingly, mutations in this signaling pathway have been identified in two rare cardiovascular diseases, hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension.MethodsTo get an overview of the signaling pathways modulated by BMP9 and BMP10 stimulation in endothelial cells, we employed an unbiased phosphoproteomic-based strategy. Identified phosphosites were validated by western blot analysis and regulated targets by RT-qPCR. Cell cycle analysis was analyzed by flow cytometry.ResultsLarge-scale phosphoproteomics revealed that BMP9 and BMP10 treatment induced a very similar phosphoproteomic profile. These BMPs activated a non-canonical transcriptional SMAD-dependent MAPK pathway (MEKK4/P38). We were able to validate this signaling pathway and demonstrated that this activation required the expression of the protein GADD45β. In turn, activated P38 phosphorylated the heat shock protein HSP27 and the endocytosis protein Eps15 (EGF receptor pathway substrate), and regulated the expression of specific genes (E-selectin, hyaluronan synthase 2 and cyclooxygenase 2). This study also highlighted the modulation in phosphorylation of proteins involved in transcriptional regulation (phosphorylation of the endothelial transcription factor ERG) and cell cycle inhibition (CDK4/6 pathway). Accordingly, we found that BMP10 induced a G1 cell cycle arrest and inhibited the mRNA expression of E2F2, cyclinD1 and cyclinA1.ConclusionsOverall, our phosphoproteomic screen identified numerous proteins whose phosphorylation state is impacted by BMP9 and BMP10 treatment, paving the way for a better understanding of the molecular mechanisms regulated by BMP signaling in vascular diseases.

Abstract 430: Epigenome Editing Of The AGT Gene As A Therapeutic Approach For Cardiovascular Disorders

Overactivation of the renin-angiotensin system contributes to many common and rare cardiovascular diseases such as hypertension, atherosclerosis, and genetic thoracic aortopathies. Current pharmacologic therapies that target this pathway have been proven safe and effective, yet they require individuals with these conditions to adhere to daily medications. CRISPR-Cas9-mediated hepatic inactivation of the angiotensinogen ( AGT ) gene, the precursor of all angiotensin peptides, could be a promising “one and done” therapeutic approach for these disorders. However, disruption of AGT by Cas9 nuclease would result in irreversible changes to the genome and would likely have negative consequences if targeted to organs outside of the liver. CRISPRoff is a CRISPR-based epigenome editing tool consisting of catalytically inactive Cas9 fused to a DNA methyltransferase, as well as a guide RNA (gRNA) designed to target a genomic promoter of interest. Targeting to a gene promoter can result in DNA methylation and subsequent silencing of gene expression, a phenomenon that has the potential to be reversed by CRISPRon, a catalytically inactive Cas9 fused to a demethylase that could be targeted to the same site using the same gRNA. We hypothesized that CRISPRoff can be used to efficiently and durably silence AGT expression by methylation of the AGT promoter. To test this, we screened HuH-7 hepatoma cells with CRISPRoff and either individual gRNAs or dual combinations of gRNAs targeting the AGT promoter. We measured AGT mRNA expression by RT-qPCR and selected the two combinations of gRNAs that resulted in the greatest decrease in AGT expression for methylation analysis. We found that AGT expression was decreased by ≈50% in treated cells, and this correlated with substantially increased methylation throughout the AGT promoter. A long-term in vitro study to assess the durability of this methylation is underway. We are also generating a humanized AGT mouse model to test whether these CRISPRoff gRNAs can silence the human AGT gene in vivo. These results provide a proof of concept of CRISPRoff for silencing of AGT expression as a therapeutic approach for common and rare cardiovascular disorders.

Cardiovascular Magnetic Resonance Imaging Patterns in Rare Cardiovascular Diseases

Rare cardiovascular diseases (RCDs) have low incidence but major clinical impact. RCDs' classification includes Class I-systemic circulation, Class II-pulmonary circulation, Class III-cardiomyopathies, Class IV-congenital cardiovascular diseases (CVD), Class V-cardiac tumors and CVD in malignancy, Class VI-cardiac arrhythmogenic disorders, Class VII-CVD in pregnancy, Class VIII-unclassified rare CVD. Cardiovascular Magnetic Resonance (CMR) is useful in the diagnosis/management of RCDs, as it performs angiography, function, perfusion, and tissue characterization in the same examination. Edema expressed as a high signal in STIRT2 or increased T2 mapping is common in acute/active inflammatory states. Diffuse subendocardial fibrosis, expressed as diffuse late gadolinium enhancement (LGE), is characteristic of microvascular disease as in systemic sclerosis, small vessel vasculitis, cardiac amyloidosis, and metabolic disorders. Replacement fibrosis, expressed as LGE, in the inferolateral wall of the left ventricle (LV) is typical of neuromuscular disorders. Patchy LGE with concurrent edema is typical of myocarditis, irrespective of the cause. Cardiac hypertrophy is characteristic in hypertrophic cardiomyopathy (HCM), cardiac amyloidosis (CA) and Anderson-Fabry Disease (AFD), but LGE is located in the IVS, subendocardium and lateral wall in HCM, CA and AFD, respectively. Native T1 mapping is increased in HCM and CA and reduced in AFD. Magnetic resonance angiography provides information on aortopathies, such as Marfan, Turner syndrome and Takayasu vasculitis. LGE in the right ventricle is the typical finding of ARVC, but it may involve LV, leading to the diagnosis of arrhythmogenic cardiomyopathy. Tissue changes in RCDs may be detected only through parametric imaging indices.

Is There a Role for Genetic Testing in Patients With Myocarditis?

HomeCirculation: Genomic and Precision MedicineVol. 15, No. 5Is There a Role for Genetic Testing in Patients With Myocarditis? No AccessArticle CommentaryRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialNo AccessArticle CommentaryRequest AccessFull TextIs There a Role for Genetic Testing in Patients With Myocarditis? Emanuele Monda and Giuseppe Limongelli Emanuele MondaEmanuele Monda https://orcid.org/0000-0001-9304-988X Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy (E.M., G.L.). Search for more papers by this author and Giuseppe LimongelliGiuseppe Limongelli Correspondence to: Giuseppe Limongelli, MD, PhD, FESC Inherited and Rare Cardiovascular Disease Clinic Department of Translational Medical Sciences University of Campania “Luigi Vanvitelli” Via L. Bianchi 1 c/o Monaldi Hospital, AORN Colli Naples, 80131 Italy. Email E-mail Address: [email protected] https://orcid.org/0000-0002-8291-9517 Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy (E.M., G.L.). Institute of Cardiovascular Sciences, University College of London and St. Bartholomew’s Hospital, London, United Kingdom (G.L.). Search for more papers by this author Originally published29 Sep 2022https://doi.org/10.1161/CIRCGEN.122.003824Circulation: Genomic and Precision Medicine. 2022;15FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCGEN.122.003824For Sources of Funding and Disclosures, see page 478.Correspondence to: Giuseppe Limongelli, MD, PhD, FESC Inherited and Rare Cardiovascular Disease Clinic Department of Translational Medical Sciences University of Campania “Luigi Vanvitelli” Via L. Bianchi 1 c/o Monaldi Hospital, AORN Colli Naples, 80131 Italy. Email [email protected]it

The Elusive Hearts Study: Seeking Genetic Diagnoses in Gene-elusive Cases of Rare Monogenic Cardiovascular Diseases

The Elusive Hearts Study: Seeking Genetic Diagnoses in Gene-elusive Cases of Rare Monogenic Cardiovascular Diseases

Human-induced pluripotent stem cells as models for rare cardiovascular diseases: from evidence-based medicine to precision medicine.

Rare cardiovascular diseases (RCDs) refer to those cardiovascular diseases that display a low prevalence as well as morbidity. Due to the vast variety of underlying genetic mutations and the relatively low patient population, RCDs present additional challenges for diagnosis. Precision medicine may offer opportunities for designing patient-specific therapies in particular for carriers of variants with undetermined significance. Moreover, precision medicine strategies provide benefit to patients with "common" symptoms but carry in rare genetic variants. Induced pluripotent stem cells (iPSCs) present a state-of-the-art precision medicine approach which recently made contributions to the study of RCDs via patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Human iPSC-CMs are derived from a patient's somatic cells and thus recapitulate a personalized genomics background, serving as patient-specific disease models. In light of these advantages, iPSC-CMs evolved as an effective tool for modeling cardiac disease phenotypes and accurately evaluating the toxicity of potential therapeutic compounds. This review covers approaches for studying RCDs and iPSC-CM models generated so far for different RCDs, such as long QT syndrome (LQT), short QT syndrome (SQT), Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC), and other rare diseases accomplished by cardiac-related syndromes like Fabry disease (FD) and Marfan syndrome (MFS). This overview aims to aid better understanding of the utility of iPSC-CM models, their various features, and future prospects.

Is maternal obesity a risk factor for rare childhood cardiovascular diseases?

Is maternal obesity a risk factor for rare childhood cardiovascular diseases?

Journal of Rare Cardiovascular Diseases now included in Directory of Open Access Journals (DOAJ)!

Journal of Rare Cardiovascular Diseases now included in Directory of Open Access Journals (DOAJ)!

New clinical classification of rare cardiovascular diseases and disorders: relevance for cardiovascular research.

New clinical classification of rare cardiovascular diseases and disorders: relevance for cardiovascular research.

Prevalence and clinical presentation of myocardial bridge on the basis of the National Polish Percutaneous Interventions Registry and the Classification of Rare Cardiovascular Diseases.

BACKGROUND A myocardial bridge (MB) is defined as a congenital anomaly, in which a segment of an epicardial coronary artery takes an intramuscular course. AIMS The aim of the study was to evaluate the prevalence of MB in coronary arteries among patients who were diagnosed using coronary angiography. METHODS Data were obtained from the National Polish Percutaneous Interventions Registry for patients hospitalized between January 1, 2014, and December 31, 2016, in invasive cardiology departments in Poland and divided into groups with and without MB. RESULTS The study included 298 558 patients. The non‑MB group comprised 296 133 patients (99.19%; women, 38.01%), while the MB group included 2425 patients (0.81%; women, 39.98%). The most frequent location of MB was the left anterior descending artery (n = 2355; 97.11% of patients). The MB group less often had diabetes (14.68% vs 21.63%), previous stroke (1.61% vs 2.96%), previous myocardial infarction (10.97% vs 21.97%), kidney disease (2.8% vs 5.04%), previous coronary artery bypass graft (1.03% vs 5.64%), previous percutaneous coronary intervention (13.20% vs 25.86%) than the non‑MB group (P <0.0001). The incidence of acute coronary syndromes was lower in the MB group (P <0.0001), while smoking was more common (18.76% vs 16.87%, P <0.01). CONCLUSIONS Patients with MB were younger and had fewer comorbidities and risk factors for atherosclerosis than patients without MB. The condition was more common among patients with stable coronary artery disease. Smoking and female sex appeared to be associated with a more clinically symptomatic presentation of MB.

Clinical classification of rare cardiac arrhythmogenic and conduction disorders, and rare arrhythmias.

INTRODUCTION Rare cardiovascular diseases and disorders (RCDDs) constitute an important clinical problem, and their proper classification is crucial for expanding knowledge in the field of RCDDs. OBJECTIVES The aim of this paper is to provide an updated classification of rare arrhythmogenic and conduction disorders, and rare arrhythmias (RACDRAs). METHODS We performed a search for RACDRAs using the Orphanet inventory of rare diseases, which includes diseases with a prevalence of no more than 5 per 10 000 in the general population. We supplemented this with a search of PubMed and Scopus databases according to a wider definition proposed by the European Parliament and the Council of the European Union. RESULTS RACDRAs are categorized into 2 groups, primary electrical disorders of the heart and arrhythmias in specific clinical settings. The first group is further divided into subgroups of major clinical presentation: disorders predisposing to supraventricular tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and others. The second group includes iatrogenic arrhythmias or heart rhythm disturbances related to medical treatment, arrhythmias associated with metabolic disorders, and others. We provide a classification of RACDRAs and supplement them with respective RCDDs codes. CONCLUSION The clinical classification of RACDRAs may form a basis to facilitate research and progress in clinical practice, both in diagnostic and therapeutic approaches.

More on the 2018 update of “Clinical classification of rare cardiovascular diseases and disorders”

More on the 2018 update of “Clinical classification of rare cardiovascular diseases and disorders”

Classification of rare cardiovascular diseases and disorders: challenges in categorisation of different diseases

Classification of rare cardiovascular diseases and disorders: challenges in categorisation of different diseases

Inherited heart diseases and storage diseases with cardiac involvement

Rare diseases mostly have agenetic cause. Many rare cardiovascular diseases also have agenetic cause. For target-oriented cardiogenetic diagnostics, expert knowledge in human genetics as well as in clinical cardiology is needed. In recent years, the genetic cause of a number of heart diseases have been, at least in part, elucidated. Especially, certain arrhythmias and cardiomyopathy forms have amonogenetic cause. Anearly genetic diagnosis means that patients can be treated more effectively. Rare storage diseases also usually have agenetic cause and can manifest themselves in the heart; prominent examples are Fabry disease and amyloidosis. As patients with Fabry disease or amyloidosis suffer from adiverse and variable symptomatology, the correct diagnosis is often difficult.

JRCD in the European Heart Journal

We present to you the fourth and final issue of Journalof Rare Cardiovascular Diseases (JRCD) for 2017.

Clinical Classification of Rare Cardiovascular Diseases and Disorders: 2018 Update

Rare diseases and disorders constitute important clinical problems. There are many concerns among physicians while planning the diagnostic and treatment process of such a heterogenous group of patients. These concerns arise not only from the rarity of cases, but also from multiple gaps in knowledge on the management of patients with rare diseases and disorders. The commonly accepted prevalence of rare diseases and disorders is 1 per 2 000 in the general population or less. Incidental prevalence and multiplicity of comorbidities result in an inability to gather enough experience at any single centre. Thus, cooperation and the exchange of ideas is important for the management of patients with rare diseases. Classification of rare cardiovascular diseases and disorders (RCDD) is crucial for expanding knowledge in the field of RCDD. It consists of an overview of RCDD, facilitates clinical approaches to patients and makes the creation of registries and databases easier. We hope that the updated RCDD classification will aid medical practice through the contribution to progress in diagnostics and therapy. It also serves as a summary of scientific achievements in the field of RCDD. Without the grouping of specific disorders, it is very difficult to create diagnostic and therapeutic algorithms. The Classification of RCDD was published for the first time in the Journal of Rare Cardiovascular Diseases (JRCD) in 2013 [1]. RCDD classification was discussed during the 2013 European Society of Cardiology Congress held in Amsterdam (www.crcd.eu/?p=2800) and in international journals, including a recent publication of the European Heart Journal [2, 3]. Clinical classification of RCDD takes into account major clinical symptoms and pathologies and is based on common clinical and/or anatomical features.

JRCD is now an open-access journal and also accepts high-quality papers beyond the field of rare cardiovascular diseases and disorders

JRCD is now an open-access journal and also accepts high-quality papers beyond the field of rare cardiovascular diseases and disorders

The Application and Future of Big Database Studies in Cardiology: A Single-Center Experience.

As medical research techniques and quality have improved, it is apparent that cardiovascular problems could be better resolved by more strict experiment design. In fact, substantial time and resources should be expended to fulfill the requirements of high quality studies. Many worthy ideas and hypotheses were unable to be verified or proven due to ethical or economic limitations. In recent years, new and various applications and uses of databases have received increasing attention. Important information regarding certain issues such as rare cardiovascular diseases, women's heart health, post-marketing analysis of different medications, or a combination of clinical and regional cardiac features could be obtained by the use of rigorous statistical methods. However, there are limitations that exist among all databases. One of the key essentials to creating and correctly addressing this research is through reliable processes of analyzing and interpreting these cardiologic databases.

“A rare day to put rare diseases in the spotlight!” “With research possibilities are limitless”

Mottos of the Rare Disease Day Dear Readers, Just few days ago, on 28th February, the tenth edition of Rare Disease Day was launched by EURORDIS and its Council for National Alliances to attract thousands people all over the world to come together to advocate for more research on rare diseases. Rare Disease Day goes globally, where all stakeholders, including patients and families, patient organizations, politicians, carers, medical professionals, researchers and industry come together to raise awareness of rare diseases through thousands of events all over the world. Among many topics, patients’ involvement in research is getting momentum. Thanks to patients’ actions, such as advocacy for research, funding research, governance of research, and last but not least participate in research, actually resulted in more research. It has been numerously underlined that research in rare diseases is a key factor as it brings hope to the millions of people living with rare disease across the world and their families. There are numerous types of research and frameworks that are important to rare disease community, including: infrastructures such as registries (databases of patients with their clinical and genetic information) and biobanks (catalogues of human biological samples), basic research to identify the cause and mechanisms of rare diseases, translational research, which focuses on using the conclusions of basic research to develop therapeutics for patients living with a rare disease, clinical research, when medicinal products are tested in humans through clinical trials, and finally research into quality of life, working conditions, social needs, integration at school, as well as multidisciplinary education of social service providers. Hopefully, all those noble initiatives will move the field forward for the good of all patients and their families. In this first issue of the Journal in 2017, we start with an interesting Review on cardiac sarcoidosis. The Original paper comes from the study group involving several centers, specializing in the treatment of pulmonary hypertension (PH) and is about non-invasive assessment of hemodynamics in PH. Then, as usual, we have several clinical cases of rare cardiovascular diseases with informative discussions and overview of the problems. Finally, there is a report from the annual meeting of the European Association of Cardiovascular Imaging (EACVI) – EuroEcho.