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 origin

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.

Earlier detection and better treatment of atrial fibrillation, the most common cardiac arrhythmia in adults, is an important part of the cardiovascular disease research agenda that the Dutch Heart Foundatoin set in 2014, which funds the CUSTOM-AF 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. These efforts are aimed at strengthening collaboration and improving outcomes in AF and HF care across the participating regions.

Collaborators

Contact person:

MSc. A. de Bruin (Anja)

adebruin@nvvc.nl

Principal investigators

Dr. M.E.W. Hemels (Martin)

MHemels@Rijnstate.nl

Dr. R.G. Tieleman (Robert)

r.tieleman@gmail.com

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Pulmonary Hypertension (PH), particularly Pulmonary Arterial Hypertension (PAH), presents a fatal complication in chronic diseases, affecting 1 in 50,000 individuals, predominantly at a young age and more often in females. The underlying genetic link involves mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, disrupting BMP signaling. The PHAEDRA-IMPACT consortium aims to understand PH and PAH.
The Research
The research focuses on understanding PAH through the transforming growth factor-β (TGFβ) signaling pathway, particularly influenced by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, prevalent in heritable and some non-hereditary PAH cases. The PHAEDRA initiative identified compounds that modulate the TGFβ/BMP balance, showing efficacy in restoring endothelial function and reversing pulmonary vascular remodeling in preclinical models, though not curing PAH, making early detection crucial.
PHAEDRA has identified biomarkers for timely diagnosis and personalized treatment. PHAEDRA-IMPACT will enhance early detection using non-invasive risk assessments, imaging, and biomarker profiling to detect pre-capillary PH. Precision medicine will guide tailored therapies based on advanced imaging and biomarker analyses, addressing disease progression variability among predisposed individuals.
Additionally, patient-derived induced pluripotent stem (iPS) cells will be used in 3D culture models of lung and heart tissues to uncover PAH mechanisms and identify therapeutic targets. This comprehensive approach aims to advance our understanding of PAH pathogenesis, accelerate drug development, and enable personalized treatment and preventive strategies for individuals at risk or affected by PH.
Origin
This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation.

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GENIUS II

2018

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.

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