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

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Cardiomyopathies, caused by genetic mutations affecting cardiac muscle components, pose significant economic and societal burdens due to their hereditary nature and early onset. Despite known genetic defects, predicting disease progression remains challenging due to extreme clinical variability. Recent research indicates that cardiomyopathy mutations induce metabolic stress, exacerbated by factors like obesity, which can accelerate disease progression. The Double Dose hypothesis suggests that targeting metabolic stress may offer preventive or curative strategies for these conditions.
The Focus
The Double Dose Consortium aims to understand how cardiomyopathy-causing mutations lead to structural changes in cardiomyocytes. This interdisciplinary effort combines experts in preclinical research, clinical genetics, health technology assessment, and clinical care focused on cardiomyopathy in both children and adults.
The Research
The consortium combines experts in preclinical research, clinical genetics, health technology assessment and clinical researchers with a strong clinical focus on cardiomyopathy in children and adults. These experts investigate how obesity and muscle adiposity contribute to vascular and cardiac muscle dysfunction in mutation carriers through the analysis of clinical data, patient samples, and experimental models. They will also study the mechanisms underlying ultrastructural changes in cardiomyocytes caused by these mutations, leading to impaired metabolism, contraction, relaxation defects, and disrupted cellular communication within the heart.
Utilizing extensive patient cohorts and ongoing studies, the consortium aims to optimize care for cardiomyopathy patients by assessing the cost-effectiveness of diagnostics and clinical interventions. They plan to translate findings on metabolic alterations into clinical trials targeting treatments that reduce metabolic stress. The Double Dose program will establish biobanks containing serum, tissue, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to provide mechanistic insights into cardiomyopathy pathophysiology and improve diagnosis and care.
Origin
This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation, together with Stichting Hartedroom. The consortium is a continuation of the Dosis consortium, in which the interaction between mutation and external factors was investigated. They found that cardiomyopathy-mutations induce metabolic stress and that secondary metabolic stress, such as obesity accelerates disease progression.
 

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The eCG Family Clinic

2020

Inherited cardiovascular diseases often run in families, with a 50% chance of passing on the disease-causing genetic defect to children. When a genetic mutation is found in the first family member diagnosed (called the proband), other relatives can get tested to see if they have the same mutation and – when they are carrier - be monitored and timely treated if needed. Unfortunately, less than half of the at-risk relatives don't seek genetic counseling in the first years of the proband's diagnosis. The eCG (electronic Cardiovascular Genetics) Family Clinic was created to stimulate families to test themselves after the diagnosis of the proband by making this process easier and more accessible.
The Research 
In the eCG Family Clinic consortium, a team of software experts, doctors, and specialists in ethics, law, economics, communication, and psychology work together to develop and implement a virtual clinic that offers personalized information and support through a virtual assistant, allowing relatives to make informed decisions about testing and treatment.
Because this consortium believes that involving all possible affected stakeholders is crucial for its success, it frequently consults with probands, family members, healthcare professionals, and advocates to understand their needs. The prototype is designed while keeping the important economic, ethical, and legal aspects of this new approach in mind. The prototype of the eCG Family Clinic is tested in real healthcare settings to see how well it works compared to current practices
Origin
This project is funded within the Innovative Medical Devices Initiative (IMDI) program 'Heart for Sustainable Care'. The focus of this program is the development of medical technology for the earlier detection, monitoring, and better treatment of cardiovascular diseases to ensure accessible healthcare and sufficient staffing. The program has been developed en funded by the Dutch Heart Foundation, ZonMw and NWO, who collaborate within the Dutch CardioVascular Alliance.

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