DEFENCE

The GENIUS II (Generating Evidence-Based Pharmaceutical Targets and Drugs for Atherosclerosis) consortium is dedicated to studying atherosclerosis, the primary pathological condition underlying cardiovascular diseases. The consortium aims to translate identified druggable targets for atherosclerosis intervention into clinical applications. Gender specificity is a key consideration in all our studies. Our consortium's talent program is structured to provide young researchers with insights into the opportunities and challenges of cardiovascular drug development. The Research GENIUS II research integrates knowledge of dyslipidemia and associated immune responses. Our work is organized into distinct work packages that correspond to the logical steps in drug development. Each selected target from GENIUS I is strategically incorporated into this framework. Our investigations encompass in vitro and in vivo analyses to understand mechanisms, druggability, and effects on atherosclerosis. In addition to building upon GENIUS I drug targets and leads, we leverage recent innovative advancements to identify new druggable targets within male and female atherosclerotic lesions, as well as in circulating cells. State-of-the-art molecular biology techniques, including single cell sequencing and immunophenotyping, are actively employed to dissect immunometabolic processes within atherosclerotic plaques and patients. These studies will enable us to monitor the presence of drug targets at disease sites, expediting drug design and potentially identifying gender-specific biomarkers to aid disease progression monitoring and diagnosis. Subsequent studies involve testing the efficacy of small molecules, monoclonal antibodies, and siRNA against pre-selected targets from GENIUS I. We have identified small molecules and monoclonal antibodies for five targets, which will undergo toxicity and proof-of-pharmacology studies to progress towards drug development for cardiovascular patients. We have also identified three drugs affecting primary targets from GENIUS I and are assessing their potential to reduce atherosclerotic parameters in First-In-Human clinical trials. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation. The GENIUS II consortium builds on the most promising targets identified in the GENIUS I consortium, with the goal of advancing these targets towards clinical application.

Atrial fibrillation (AF) is not benign. It commonly progresses from paroxysmal AF (PAF) to permanent AF. AF progression is associated with major adverse cardiovascular/cerebral events (MACCE). Cardiovascular risk factors and comorbidities (CVR) are present long before the first AF episode, causing a progressive atrial cardiomyopathy (ACM). The mechanisms of ACM vary between patients hindering effective AF management. The EmbRACE network now aims to unravel the diversity of mechanisms underlying ACM, identify simple diagnostic tools to identify them, and develop a therapeutic approach to prevent ACM progression. The Research Early rhythm-control therapy is one promising intervention to potentially interfere with ACM progression next to CVR management. For a sustained impact we aim to develop care pathways to prevent ACM and AF progression and MACCE. Therefore, we will identify and validate relevant cellular and molecular determinants of ACM and AF and their clinical surrogate parameters; develop an in-silico platform to simulate identified mechanisms of ACM and AF and their effects on AF progression and, based on these data, make suggestions for future refinement of ACM therapy; explore the variety of temporal patterns of PAF as markers of ACM subtypes, demonstrate their prognostic relevance and identify surrogate markers available in clinical practice, based on AI and machine learning; test in a randomized trial stratified for sex the hypothesis that early AF ablation and optimal CVR management in AF patients with ACM delays ACM progression and reduces MACCE; explore whether lifestyle management reduces ACM progression, whereas with only rate control ACM progresses; validate the RACE V AF progression score in real life cohorts and translate this and other knowledge into novel care pathways for AF. The origin Atrial fibrillation is the most common cardiac arrhythmia and can lead to a variety of complications, such as stroke. Currently, there are limited treatment options for this cardiac arrhythmia. Moreover, the disease is often noticed late, which makes proper treatment even more difficult. Therefore, the Dutch Heart Foundation funded the RACE V consortium. Afterwards, the Dutch Heart Foundation guided an exploration to form a national consortium as a follow-up around this theme. This led to the EmbRACE consortium, which is a national network of six university medical centers, UMC Groningen, Maastricht UMC+, UMC Utrecht, Amsterdam UMC and LUMC and Erasmus MC, and hospitals in Arnhem and Eindhoven. The Dutch Heart Foundation funds the research.