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NWO-ZonMW VICI grant for Jolanda van der Velden (VUMC)

Tuesday, 17 April 2018

NWO-ZonMW has granted the VICI project (1.5 million euros) of Jolanda van der Velden entitled: Sarcomere inefficiency at the heart of hypertrophic cardiomyopathy (HCM).

Within the 5-year VICI project, van der Velden and her team will test the concept that sarcomere inefficiency is central in the initiation and progression of hypertrophic cardiomyopathy (HCM). HCM is a genetic heart disease affecting ~60,000 people in the Netherlands. Cardiomyopathy develops between 20 and 50 years of age. HCM is caused by mutations in genes encoding proteins of the sarcomere, the contractile building blocks of heart muscle. As the chain of events leading from mutation to disease is currently unknown, there is no specific treatment available.

Mutation

The VICI-program will define key pathomechanisms of HCM and thereby identify drug targets to treat disease. Recent studies funded by VIDI and FP7 grants revealed that 1) mutations resulting in altered sarcomere proteins cause inefficient contraction of the heart and 2) this cardiac inefficiency is already present in mutation carriers before onset of cardiomyopathy. Based on these important findings, van der Velden hypothesizes that the mutation-induced cardiac inefficiency triggers disease: it causes metabolic and mitochondrial abnormalities, which impair relaxation (diastolic dysfunction) and cause hypoperfusion of the heart before onset of hypertrophy. There is evidence that the early cellular pathomechanisms can be halted pharmacologically.

Approach & innovation

Van der Velden combines innovative in vivo imaging modalities with ex vivo tissue analyses in humans and mouse models to define the sequence of metabolic, mitochondrial and cardiovascular changes that lead from the mutation to disease. Basic studies using genetic and drug interventions in unique, human engineered heart tissue and HCM mouse models will establish causal relations between energy deficiency, mitochondrial dysfunction and impaired muscle relaxation. She will test the novel concept of intermittent drug-therapy as compared to chronic therapy using clinically available drugs in mouse models to translate basic findings to the clinic.

Impact

The team will (1) prove the new concept of sarcomere inefficiency in the propagation of HCM and provide a comprehensive understanding of the cellular events leading to cardiomyopathy. They will (2) identify targets for therapeutic interventions to treat HCM.

Collaboration

Within the VICI project (PI Jolanda van der Velden) investigators from different disciplines join forces to study the pathomechanisms of HCM. Imaging studies in mice and human are performed in closed collaboration with Gustav Strijkers (Department of Biomedical Engineering and Physics AMC), Coert Zuurbier (AMC, Anesthesiology), Bert van Rossum (Cardiology, VUmc) and Michelle Michels (Cardiology, Erasmus MC). While imaging studies are key in studying in vivo cardiac function, studies in engineered heart tissue (EHT) enable to study effects of mutations in a human-like heart tissue model (Figure). The engineered heart tissue is up and running at the Department of Physiology at VUmc (set-up by Paul Wijnker, post-doc at VUmc), and will be used to study mutation-induced cellular defects and test (novel) compounds. Engineered heart tissue is made from cardiomyocytes derived from inducible pluripotent stem cells (iPSC) carrying different sarcomere mutations. iPSC-derived cardiomyocytes will be made by the group of Robert Passier. As such, the VICI intensifies collaboration within hDMT, and aids in the establishment of a human-like cardiac muscle system to study genetic heart disease.

Dosis project

Van der Velden is coordinator of the CVON-project Dosis (together with Rudolf de Boer, UMCG), funded by the Netherlands heart foundation. Within Dosis (http://cvon-dosis.nl), we investigate additional (epi)genetic and environmental disease modifiers which, apart from ageing, perturb the balance between normal and mutant protein dose. The CVON project is complementary to the VICI-program, and results will strengthen both programs.

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