RECONNEXT

2021

Heart failure represents a significant healthcare challenge due to its high morbidity and mortality rates. Historically, the emphasis has been on heart failure with reduced ejection fraction characterized by left ventricular dilation. However, nearly half of heart failure patients involve diastolic dysfunction due to heart chamber stiffening, known as diastolic heart failure or HFpEF.

The Focus
Research conducted by our consortium indicates that impaired kidney function is an is a strong risk factor for HFpEF. Patients with chronic kidney disease are more prone to developing HFpEF and have higher mortality rates from associated complications. The specific mechanisms by which even slight declines in renal function worsen cardiovascular risk and impact the development and prognosis of HFpEF are not yet fully understood. Insights from RECONNECT highlight the pivotal role of systemic inflammation and microvasculature in this context.

The Research
RECONNEXT (Renal connection to microvascular disease and HFpEF: the next phase) is a multicenter consortium dedicated on advancing medical research on heart failure - particularly heart failure with preserved ejection fraction (HFpEF) - in relation to impaired kidney function.

Specific pre-clinical and clinical research objectives have been defined:

Identify renal drivers for HFpEF onset and progression in subgroups/clusters of HFpEF patients, taking patient-specific risk profiles into account.
Deepen our understanding of the mechanistic pathways involved in the pathogenic cross-talk between renal drivers, systemic inflammation, microvasculature, and cardiac cells leading to HFpEF, using dedicated ex vivo bioassays to assess patient material and in vivo small and large animal models.
Investigate the most promising therapeutic targets in newly developed and well-characterized state-of-the art rodent and porcine models of CKD-associated HFpEF, taking comorbidities into account.
Investigate the most promising therapeutic, diagnostic and prognostic candidate(s) in well-defined patient-groups by taking a stratified approach.

We expect that the results of this project will enhance our mechanistic insight in the renal drivers of HFpEF development and progression and will lead to the development of personalized diagnostic, prognostic and therapeutic solutions for HFpEF patients.

The origin

The RECONNECT consortium has provided fundamental knowledge on the connection between chronic kidney disease and HFpEF and established a translational pipeline for the discovery and evaluation of potential diagnostic, prognostic and therapeutic targets. RECONNEXT builds upon the success of RECONNECT, established in 2015 (see Figure 1 below), supported by CardioVasculair Onderzoek Nederland (CVON) and the Dutch Heart Foundation. The RECONNEXT consortium consists of nephrologists, cardiologists, general practitioners, and scientists from five leading academic centers in the Netherlands (UMC Utrecht, Erasmus MC, UMC Groningen, Amsterdam UMC, Leiden University) renowned for their expertise in heart failure, vascular biology, and chronic kidney disease.

Collaborators

Funded

Contact person:

info@heart-institute.nl

Principal investigators

Prof. dr. M.C. Verhaar (Marianne)

m.c.verhaar@umcutrecht.nl

Prof. dr. D.J.G.M. Duncker (Dirk-Jan)

d.duncker@erasmusmc.nl

See all investigators

Cardiovascular disease (CVD) and dementia are closely intertwined, often resulting in cognitive impairment among individuals with cardiovascular or cerebrovascular conditions. Approximately one-third of dementia cases are linked to vascular injury, emphasizing that vascular cognitive impairment (VCI) is a preventable aspect of cognitive decline.
The Focus
The Heart-Brain Connection Crossroads (HBCx) consortium investigates hemodynamic alterations as reversible contributors to VCI, seeking to enhance our understanding of the connection between cardiovascular health and cognitive function.
The Research
HBCx builds upon the foundation laid by HBC1 (CVON 2012-06), which established a national network dedicated to studying, diagnosing, and treating VCI. Clinical investigations within HBC1, focusing on patients with chronic heart failure (CHF), carotid occlusive disease (COD), and clinically evident VCI, emphasized the role of hemodynamics along the heart-brain axis in VCI. These findings underscored significant associations between heart-brain connections and VCI.
The HBCx program, launched in 2019, takes a comprehensive approach by investigating hemodynamics in key cardiac conditions such as atrial fibrillation and heart failure, while also exploring vascular factors and their interplay with amyloid pathology. Moreover, HBCx considers modulating factors like age and sex. The program aims to improve early detection, identify treatable targets, and integrate the Heart-Brain Connection approach into routine care. Ultimately, the long-term vision of HBCx is to reduce VCI prevalence among CVD patients through enhanced understanding and innovative treatment strategies.
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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