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.

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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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The RACE 9 Observe-AF

Until recently the standard approach of patients with recent-onset atrial fibrillation (AF) involved early cardioversion. In the latest ESC AF guidelines, a delayed cardioversion approach within 48 hours has been added to the recommendations. However, given the self-terminating and recurrent nature of AF, cardioversion may not always be necessary, and rate control medication could suffice to manage symptoms until spontaneous conversion to sinus rhythm occurs. The Focus The RACE 9 Observe-AF trial is a multicenter, prospective, randomized, open-label non-inferiority trial comparing a watchful waiting strategy (intervention) to routine care (control) for patients with recent-onset symptomatic AF. The Research The watchful waiting approach involves symptom reduction through rate control medication and monitoring for four weeks to await possible spontaneous conversion to sinus rhythm. Routine care consists of either early or delayed cardioversion within 48 hours. The primary endpoint of this non-inferiority study is the presence of sinus rhythm on the ECG after four weeks. Several stakeholders and potential end-users are closely involved in defining the study deliverables. An end-user expert committee has been established, consisting of seven patients with a history of arrhythmias, a psychiatrist, a privacy and legal advisor, a cardiologist, an AF nurse, a general practitioner, and two experts in hospital technology implementation. This committee was involved in piloting the device-based rate and rhythm infrastructure, providing feedback for optimization before the study commencement. Additionally, the committee meets regularly to advise investigators on implementing the device-based infrastructure into daily clinical practice post-study. The study will be conducted across multiple centers in the Netherlands, including UMC Groningen, Radboud UMC, Amsterdam UMC, Alrijne Hospital, VieCuri Medical Centre, Zuyderland Medical Centre, Elisabeth-TweeSteden Hospital, Rijnstate Hospital, Martini Hospital, St. Antonius Hospital, Antonius Hospital, Noordwest Hospitalgroup, Medisch Spectrum Twente, and Maastricht University Medical Center.
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