COVID@Heart

Sudden cardiac arrest (SCA) remains a significant public health challenge, accounting for nearly 20% of all deaths in developed nations and approximately half of all heart disease-related fatalities. A notable subset of SCA cases occurs in individuals without prior heart disease diagnosis, resulting in profound psychosocial impacts on affected families and society. Ventricular fibrillation (VF) is the primary arrhythmia leading to SCA, often occurring outside healthcare settings with survival rates ranging from 5% to 20%. Prevention is crucial, yet gaps in our understanding of SCA causes and mechanisms hinder effective prevention efforts. Various genetic and non-genetic factors, such as gender, age, comorbidities, and lifestyle, likely influence SCA risk, but their specific contributions remain unclear. The Focus The PREDICT2 initiative brings together leading Principal Investigators with expertise in epidemiology, clinical studies, genetics, and functional research to elucidate factors contributing to SCA, uncover underlying mechanisms, and develop strategies for prevention and treatment. The Research Building on foundational work from PREDICT1, which involved extensive patient characterization and preclinical model development, PREDICT2 focuses on inherited arrhythmia syndromes as models to understand the arrhythmogenic substrate in more common cardiac syndromes associated with SCA. Specifically, PREDICT2 aims to: Identify genetic and non-genetic factors that contribute to SCA risk and develop personalized risk prediction algorithms for individual patient assessment. Conduct functional studies to elucidate the mechanisms underlying SCA, enabling the development of novel risk stratification and therapeutic approaches. Implement clinical studies to evaluate risk prediction algorithms and therapeutic interventions, aiming to enhance the treatment and prevention of SCA. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation.

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 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 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 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 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. Origin 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 ARENA-PRIME programme (2018-2023), funded by the Dutch Heart Foundation, targets treatment-resistant HF forms, particularly in younger patients with dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). In 2023 ARIME-PRIME received a matching grant from the Dutch Heart Foundation to work on their research together with a private partners, so that they can achieve their ambitions and objectives more quickly.