The DCVA brings partners together to deliver in breakthrough science in consortia to develop new cardiovascular solutions

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ARENA-PRIME

2018
The former CVON-ARENA programme (2012-2017) advanced understanding of cardiac RNA species in heart failure (microRNAs, lncRNAs and circular RNAs).The CVON-ARENA programme (2012-2017) advanced understanding of cardiac RNA species, such as microRNAs, lncRNAs, and circular RNAs, in various forms of heart failure (HF). This subsequent DCVA-ARENA-PRIME programme (2018-2023) targets treatment-resistant HF forms, particularly in younger patients with dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). The Focus In preceding decades, conventional therapies have notably enhanced the survival rates of heart failure (HF) patients. However, a subset of individuals, particularly younger patients afflicted with dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM), still confront disease progression despite these treatments. This underscores the necessity for innovative approaches. The DCVA-ARENA-PRIME initiative aims to address this gap by focusing on the development of novel gene therapies tailored to the specific disease mechanisms underlying DCM, attributed to mutations in the RBM20 and LMNA genes, as well as ACM, and associated with mutations in the DSGL2 and PKP2 genes. The goal is to progress towards first-in-human clinical trials, particularly focusing on LMNA disease, and to establish preclinical proof-of-concept for ACM therapies targeting DSGL2 and PKP2. The Research The DCVA-ARENA-PRIME researchers utilize insights from previous programmes on cardiac gene therapies (e.g., inhibitory RNAs such as allele-specific short hairpin RNAs, antimiRs, etc.) and gene editing technologies (e.g., base- and prime editing) to develop novel treatments for dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). This effort is supplemented by advanced research on adeno-associated viral vectors and the integration of heart tissue collections with cutting-edge sequencing technologies (like single-cell sequencing) to further explore disease mechanisms. At the beginning of the DCVA-ARENA-PRIME programme, a (end-) user committee has been established, making sure that (end-)users are closely involved in the design of the studies and the implementation of the co-created studies and deliverables. This committee meets annually alongside the program's research meetings to provide guidance to investigators on optimizing the program's outcomes for (end-) users. It addresses all feedback, inquiries, and recommendations, whether requested or spontaneous. This committee meets once per year in conjunction with the programme’s research meetings and advises the investigators about the course of the programme and what actions need to be taken in order to maximise the probability that the (end-) users will be able to utilize and/or benefit from the results. This committee addresses any comments, remarks, questions and advice they may have, solicited or otherwise. The members of the DCVA-ARENA-PRIME user committee include cardiomyopathy patients and their relatives, clinicians (e.g. cardiologists), representatives from related research programs (e.g., RegMedXB, H2020-TRAIN-HEART), and industry stakeholders including biotech and pharma company representatives and venture capitalists. Supporting Young Investigators The programme prioritizes attracting and nurturing young talent, providing hands-on training and fellowship awards to facilitate their career development. Over 20 young investigators participate, benefiting from exposure to collaborative research environments. To further support this career development, five fellowship awards of 50.000€ have been granted the past three years to junior postdoctoral researchers in the laboratories of the Hubrecht Institute, University Medical Center Utrecht, Amsterdam UMC (location VUmc and AMC) and Maastricht University.
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COVID@Heart

About 10% of the COVID-19 affected patients develop critical illness with a high mortality rate. This critical illness appears to be strongly linked with cardiovascular disease, as the prevalence of cardiovascular comorbidities and risk factors (such as diabetes and obesity) are often found among hospitalized COVID-19 patients. The consortium COVID@Heart believes that mitigating this cardiovascular burden of Covid-19 should start early, while patients are (still) outside the hospital. The Research COVID@Heart has three core activities: Develop a tool to identify high-risk cardiovascular patients with COVID-19 in a home environment, before the critical illness emerges. This tool will allow general practitioners to better notify high-risk patients, monitor them more closely (e.g. by using home saturation measurements), prescribe preventive cardiovascular medication earlier ('moon shot') and refer them to a hospital promptly when needed. Create a diagnostic tool to improve early differentiation between COVID-19 and a myocardial infarction, addressing the challenge of overlapping symptoms faced by general practitioners. Design a questionnaire supplemented by select biomarkers and blood tests to enhance the detection of cardiovascular disease in COVID-19 survivors experiencing prolonged symptoms of fatigue and shortness of breath, as these symptoms are potentially linked to accelerated subclinical cardiovascular disease.
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CUSTOM-AF

2020
Individuals with atrial fibrillation are at increased risk of an ischemic stroke. Active detection of atrial fibrillation (AF) and optimal referral and treatment of patients could prevent an estimated 1500 ischemic strokes annually. Effective collaboration between primary and secondary care professionals is essential for achieving this goal of stroke prevention attributed to AF. This is the primary objective of the implementation consortium known as CUSTOM-AF. The CUSTOM-AF was founded in June 2020 and restarted in 2022. CUSTOM-AF implementation consortium aims to share successful practice examples with regional networks and develop guidelines for organizing active detection and integrated care within a network. Additionally, consortium partners seek innovative methods for general practitioners to detect and manage AF without necessitating hospital referrals. With this consortium, the Dutch Heart Foundation, NVVC Connect, Harteraad, and the Dutch CardioVascular Alliance, all work together towards optimal care for patients with AF. The Dutch College of General Practitioners (NHG) serves as a key advisor to the consortium. The Research The scope of the consortium has been expanded to include two disorders: heart failure and AF. The consortium has undertaken significant initiatives over the past two years (2020-2022) to advance its objectives: Guideline Development: The consortium developed the "Screening and Treatment Optimization for AF" guideline, designed to facilitate early detection of AF within regional healthcare systems. Cost-Effectiveness Analysis: A comprehensive analysis conducted to assess various screening scenarios for AF, evaluating the economic feasibility of different approaches. Thematic Collaboration: In early 2022, a thematic collaboration titled "Juiste Hartzorg op de Juiste Plek" was established in partnership with the Heart Foundation and ZonMw. This collaboration secured funding for 22 regions to support transmural collaboration on AF and HF, with a focus on early detection and treatment optimization. Moving forward from September 2022, NVVC Connect will intensify support for the regions by emphasizing continuous improvement through the PDCA cycle, facilitating knowledge sharing, and implementing innovative approaches such as Check@home. These efforts are aimed at strengthening collaboration and improving outcomes in AF and HF care across the participating regions.
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DECISION

Digoxin is the oldest, market-authorized drug for heart failure (HF), and very cheap. A large trial with digoxin, the DIG trial, executed in the early nineties revealed a highly significant reduction in HF hospitalizations, but no effect on mortality. A post-hoc analysis of the DIG trial suggests that low serum concentrations of digoxin may not only improve HF hospitalizations but also mortality in chronic HF patients. To validate these findings, a prospective, randomized, placebo-controlled trial is required to redefine the role of digoxin in modern HF treatment. The Focus The primary objective of this study is to investigate whether low-level digoxin (targeting serum concentrations of 0.5-0.9 ng/mL), compared to a placebo, reduces (repeated) HF hospitalizations, (repeated) urgent HF hospital visits, and cardiovascular mortality when added to standard guideline-recommended therapies in chronic HF patients with reduced or mid-range ejection fractions (LVEF ≤50%). The Research This proposed trial is a national, multicenter, randomized, double-blind, placebo-controlled clinical trial involving 982 chronic HF patients aged ≥18 years, classified as NYHA II to ambulatory IV, LVEF ≤50%, and specific serum NT-proBNP concentrations based on rhythm and recent HF hospitalization status. Patients must also be on guideline-recommended therapies. The study population includes at least one-third with atrial fibrillation (AF) and one-third women to represent the real-life HF population. Patients were randomized to receive either a low-level digoxin or a placebo in a double-blinded manner. Digoxin Teva will be administered orally, starting at doses of 0.2mg or 0.1mg (based on age, renal function, and concomitant medication). No loading dose is given to the placebo group. After 4 weeks of evaluating medication (digoxin or placebo), concentrations will be measured. Dose adjustments will be made if needed to reach the target serum digoxin concentration range of 0.5-0.9ng/mL. The outcomes in reducing adverse cardiovascular events in patients with chronic heart failure of low-dose digoxin will be compared to the outcomes of the placebo.
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DEFENCE

2021
Currently, it is largely unknown to what extent the heart is involved in COVID-19. The aim of this project is to assess the incidence and consequences of cardiac damage in patients who have experienced COVID-19. How often does COVID-19 lead to myocardial damage? What are the short- and long-term consequences of this damage and what can we do to prevent it from occurring? These are the central questions that will be answered within the DEFENCE consortium. The Research The DEFENCE consortium integrates several national studies initiated at the onset of the COVID-19 pandemic, encompassing diverse patient groups as part of the COPP study, ranging from elite athletes (COMMIT study) and individuals recovering at home (COVID@Heart study) to hospitalized patients (CAPACITY-COVID registry and CAPACITY 2 study) and children with post-infection inflammatory syndromes affecting the heart (MIS-C). By harmonizing these initiatives, a unique cohort spanning the entire spectrum of COVID-19 severity has been established. The ongoing studies are extended at multiple levels within the DEFENCE project. This includes: Standardized Healthcare Pathway Implementation: Implementing and evaluating a standardized healthcare pathway to assess cardiac damage occurrence within 6 months post-hospitalization for COVID-19. Serial Cardiac Magnetic Resonance (CMR) Imaging: Performing serial CMR imaging to determine the prevalence and reversibility of myocardial damage, with all scans assessed in a core lab. Evaluation of Cardiovascular Symptoms: Assessing the incidence of cardiovascular symptoms such as chest pain and palpitations in the post-acute phase through patient questionnaires. Linking Data to National Datasets: Linking study data to national datasets at Statistics Netherlands to analyze long-term cardiovascular morbidity and mortality. To evaluate whether cardiovascular disease is a characteristic feature of COVID-19, a comparison with other respiratory tract infections, including seasonal influenza will be made.
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DOUBLE DOSE

Cardiomyopathies, caused by genetic mutations affecting cardiac muscle components, pose significant economic and societal burdens due to their hereditary nature and early onset. Despite known genetic defects, predicting disease progression remains challenging due to extreme clinical variability. Recent research indicates that cardiomyopathy mutations induce metabolic stress, exacerbated by factors like obesity, which can accelerate disease progression. The Double Dose hypothesis suggests that targeting metabolic stress may offer preventive or curative strategies for these conditions. The Focus The Double Dose Consortium aims to understand how cardiomyopathy-causing mutations lead to structural changes in cardiomyocytes. This interdisciplinary effort combines experts in preclinical research, clinical genetics, health technology assessment, and clinical care focused on cardiomyopathy in both children and adults. The Research The consortium combines experts in preclinical research, clinical genetics, health technology assessment and clinical researchers with a strong clinical focus on cardiomyopathy in children and adults. These experts investigate how obesity and muscle adiposity contribute to vascular and cardiac muscle dysfunction in mutation carriers through the analysis of clinical data, patient samples, and experimental models. They will also study the mechanisms underlying ultrastructural changes in cardiomyocytes caused by these mutations, leading to impaired metabolism, contraction, relaxation defects, and disrupted cellular communication within the heart. Utilizing extensive patient cohorts and ongoing studies, the consortium aims to optimize care for cardiomyopathy patients by assessing the cost-effectiveness of diagnostics and clinical interventions. They plan to translate findings on metabolic alterations into clinical trials targeting treatments that reduce metabolic stress. The Double Dose program will establish biobanks containing serum, tissue, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to provide mechanistic insights into cardiomyopathy pathophysiology and improve diagnosis and care. DCVA iPSC-CM Journal Club iPSC-CMs are increasingly being used as alternatives for testing animals to investigate mechanisms of disease. Do you work with induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)? Join the DCVA iPSC-CM Journal Club: a journal club that unites six institutes in the Netherlands working on iPSC-CMs. With the DCVA iPSC-CM Journal Club we establish a platform that combines forces to advance the use of stem cells for cardiovascular research in the Netherlands. The DCVA iPSC-CM Journal Club was founded in October 2020 by scientists from the Double Dose consortium. In this monthly journal club, we discuss the latest developments in the field, share protocols and exchange ideas on standardization in order to improve the quality of our own scientific studies. We host national and international experts from the field who discuss the main challenges of iPSC-CMs, but also remain accessible for young researchers to ask their questions. For more information or to apply, contact Birgit Goversen (b.goversen@amsterdamumc.nl). DOUBLE-DOSE mini-consortium The DOUBLE-DOSE consortium has allocated a portion of its talent budget for a mini-consortium grant to enhance and expand the scope of their research. This funding initiative aims to promote team science and offers independent scientists the opportunity to collaborate with DOUBLE-DOSE. Projects should be innovative and ideally focused on developing new techniques or generating pilot data to support future funding applications. In short: • Mini-consortium grant for early/mid-career scientists • Budget: € 75.000 per project • Deadline: March 1st, 2023 • Start: Ultimately January 1st, 2024 Please find the document with more information and an application form via the downloads below.
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