My research has focused on understanding molecular changes that underlie cardiac muscle function, hypertrophy and hypertrophic cardiomyopathy. As a PhD student, I studied changes in transcription factors that drive physiological and pathological hypertrophy in swine. After that I switched to the department of Physiology as a postdoc to focus on the function of cardiac myosin binding protein C (cMyBP-C). Combining biochemistry, mass-spectrometry and muscle mechanics, I identified a novel phosphorylation site on cMyBP-C, which was phosphorylated by GSK3β, and which increased the kinetics of contraction. Additionally, I identified an HCM-specific miRNA signature in HCM-patients with cMyBP-C mutations.
From 2012-2014, I worked in Dr Sadayappan’s laboratory at Loyola University Chicago. I worked on using cMyBP-C as a biomarker, and on the disease mechanism of the most common HCM-associated MYBPC3Δ25bp mutation. In 2013, I received the post-doctoral fellowship from the American Heart Association to work on the MYBPC3Δ25bp mutation.
My current research at the VUmc focuses on molecular changes in HCM mouse models and human patient samples. Combining biochemical and biophysical techniques with in vivo and in vitro measurements of cardiac/cardiomyocyte function, I aim to elucidate the still elusive HCM pathophysiology.
1. Najafi A, Sequeira V, Helmes M, Bollen IA, Goebel M, Regan JA, Carrier L, Kuster DW, Van Der Velden J. Selective phosphorylation of PKA targets after β-adrenergic receptor stimulation impairs myofilament function in Mybpc3-targeted HCM mouse model. Cardiovasc Res. 2016 110:200-214
2. Sequeira V, Najafi A, Wijnker PJ, Dos Remedios CG, Michels M, Kuster DW, van der Velden J. ADP-stimulated contraction: A predictor of thin-filament activation in cardiac disease. Proc Natl Acad Sci U S A. 2015 ;112(50):E7003-12.
3. Kuster DW, Govindan S, Springer TI, Martin JL, Finley NL, Sadayappan S. A hypertrophic cardiomyopathy-associated MYBPC3 mutation common in populations of South Asian descent causes contractile dysfunction. J Biol Chem. 2015 290:5855-67
4. Kuster DW, Sequeira V, Najafi A, Boontje NM, Wijnker PJ, Witjas-Paalberends ER, Marston SB, dos Remedios CG, Carrier L, Demmers JA, Redwood CS, Sadayappan S, van der Velden J. GSK3β phosphorylates newly identified site in the Pro-Ala rich region of cardiac myosin binding protein C and alters cross-bridge cycling kinetics in human. Circ Res 2013 112:633-9
5. Kuster DW, Mulders J, ten Cate FJ, Michels M, dos Remedios CG, da Costa Martins PA, van der Velden J, Oudejans CB. MicroRNA transcriptome profiling in cardiac tissue of hypertrophic cardiomyopathy patients with MYBPC3 mutations. J Mol Cell Cardiol 2013 65:59-66
Selection of funded projects:
I can see clearly now: small animal imaging to distinguish cause and effect in early HCM disease pathology. ACS out-of-the-box grant 2016-2018
Pathophysiology of Hypertrophic Cardiomyopathy Associated Cardiac Myosin Binding Protein-C Mutation. American Heart Association Post-doctoral fellowship grant (2013-2015)
PhD students (co-promotor)