The Double Dose-consortium aims to unravel the mechanism by which cardiomyopathy-causing mutations lead to ultrastructural changes in cardiomyocytes. The consortium is led by prof. dr. Jolanda van der Velden and prof. dr. Rudolf de Boer and combines experts in preclinical research, clinical genetics, health technology assessment and clinical researchers with a strong clinical focus on cardiomyopathy in children and adults.
Health care problem: Mutations in genes encoding the key components of the cardiac muscle cause diseases referred to as cardiomyopathies. Since the genetic defect is inheritable, cardiomyopathies affect several members of a family and may strike at a young age. Thereby, inherited cardiomyopathies pose an enormous economic and societal burden. The identification of the underlying gene defect early on may allow for the timely application of preventive and curative therapies. However, inherited cardiomyopathies are characterized by extreme clinical heterogeneity in their presentation. The mutation alone is not sufficient to predict clinical course. Recent research showed that cardiomyopathy-mutations induce metabolic stress and that secondary metabolic stress, such as obesity accelerates disease progression. This has led to the Double Dose hypothesis that metabolic stress represents the central pathomechanism of early and late cardiac dysfunction in inherited cardiac disease. Therapeutically targeting this may prevent or cure cardiomyopathies. Linking clinical data, patient samples and our experimental models we will define the mechanism of how obesity and muscle adiposity cause vascular and cardiac muscle dysfunction in mutation carriers. We will also unravel the mechanism by which cardiomyopathy-causing mutations lead to ultrastructural changes in cardiomyocytes. These changes cause impaired metabolism, contraction and relaxation defects, and disturbed communication with other cells in the heart.
Strength of biobanks & patient cohorts: Making use of our extensive patient cohorts and the findings from Dosis and we will optimize care for cardiomyopathy patients. We will quantify the cost-effectiveness of current diagnostics and clinical care from both patient and societal perspective. Furthermore, we will translate our findings that metabolic alterations are central to cardiomyopathies, by initiating at least one clinical trial based on treatment(s) that reduce metabolic stress. The Double Dose program will establish serum, tissue and iPSC-CMs biobanks from a large set of cardiomyopathy patients. We will provide mechanistic pre-clinical and clinical insight into the link between metabolic stress and cardiomyopathy pathophysiology, and translate these findings to optimize diagnosis and care of cardiomyopathy patients.
The Double Dose program is financed by the Netherlands Heart Foundation and Stichting Hartedroom. Our 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.
To strengthen and broaden the scope of their research, the DOUBLE-DOSE consortium has decided to make part of their talent budget available for a mini-consortium grant. This funding mechanism is designed to foster team science and provides unaffiliated scientists with the opportunity to join DOUBLE-DOSE. The project should be innovative and preferably designed to develop new techniques / provide pilot data to apply for future funding.
• Mini-consortium grant for early/mid-career scientists
• Budget: € 75.000 per project
• Deadline: March 1st 2023
• Start: Ultimately January 1st 2024
Please find the document with more information and applicationform via the downloads below.