Warnaar 2023 Abstract IOC160

Warnaar V, Nassar A, Nollet E, Michels M, Kuster D, Ochala J, Buikema JW, van der Velden J (2023) Effect of Mavacamten on the myofilament-mitochondrial axis in hypertrophic cardiomyopathy with and without sarcomere mutation. Mitochondr Physiol Network 28.01.

Link: IOC160

Warnaar Vincent, Nassar Ali, Nollet Edgar, Michels Michelle, Kuster Diederik, Ochala Julien, Buikema Jan W, van der Velden Jolanda (2023)

Event: IOC160

Hypertrophic cardiomyopathy (HCM) is the most common autosomal dominant inherited form of cardiomyopathies. A lack of knowledge about the key regulators that are involved in the disease onset and progression results in limited therapeutic strategies to prevent or cure HCM. This study focuses on the role of mitochondrial (dys)function in the pathophysiology of HCM, and test the effect of the myosin inhibitor Mavacamten (MAVA). Previous research has shown that MAVA corrects the so-called Super Relaxed (SRX) / Disorded-relaxed (DRX) ratio of myosin. MAVA shifts myosin heads from the high energy consuming DRX to an energy-saving SRX state. To define both the acute and chronic effect of MAVA treatment studies in cardiac tissue slices from HCM patients, stem-cell derived engineered heart tissue (EHT) and an established HCM mouse model will be combined.

To study MAVA-mediated PREVENTIVE effects we will set up a human in vitro model for HCM. Therefore, we will generate EHTs from human induced pluripotent stem cell lines with Crispr/Cas9-induced MYBPC3 (c.2373insG) founder mutation, the isogenic control line and two patient-derived cell lines. Next, ex vivo tissue slices, of cardiac samples from HCM patients, will be kept in culture to study the REVERSIBILITY of the altered myofilament-mitochondrial axis by chronic MAVA treatment. To proof the effects of MAVA treatment on the heart an in vivo mouse model with the same Dutch founder mutation is used to link the in vitro data on the myofilament-mitochondrial axis with in-depth in vivo characterization of the heart. Functional readouts such as contraction and relaxation parameters are obtained and subsequent analyses include mitochondrial function, SRX/DRX ratio analyses. It is expected that MAVA reduces ATP demand and improves mitochondrial function by normalizing the SRX/DRX ratio. Subsequent improved mitochondrial function, and the coincident reduced oxidative stress, exerts positive effects on cardiac remodeling.

• Bioblast editor: Plangger M • O2k-Network Lab: NL Amsterdam Nollet E

Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cardiovascular, Myopathy

HRR: Oxygraph-2k

Affiliations and support

Vincent Warnaar¹, Ali Nassar¹, Edgar Nollet¹, Michelle Michels², Diederik Kuster¹, Julien Ochala³, Jan W. Buikema^1,4, Jolanda van der Velden¹

Amsterdam Cardiovascular Sciences, Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
Heart Center, Department of Cardiology, Amsterdam UMC, Amsterdam, The Netherlands

Funding was provided by BMS and NWO-VICI.