Perturbed Length-Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations

V Sequeira, PJM Wijnker, LLAM Nijenkamp, D Kuster, A Najafi, ER Witjas-Paalberends, JA Regan, N Boontje, Folkert ten Cate, T Germans, L Carrier, S Sadayappan, Marjon van Slegtenhorst, R Zaremba, DB Foster, AM Murphy, C Poggesi, C dos Remedios, GJM Stienen, CY HoMichelle Michels, J Velden

Research output: Contribution to journalArticleAcademicpeer-review

160 Citations (Scopus)


Rationale: High-myofilament Ca2+ sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca2+ sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. Objective: To investigate whether high myofilament Ca2+ sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. Methods and Results: Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca2+ sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca2+ sensitivity was similar (MYBPC3(mut) Conclusions: High-myofilament Ca2+ sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.
Original languageUndefined/Unknown
Pages (from-to)1491-+
JournalCirculation Research
Issue number11
Publication statusPublished - 2013

Research programs

  • EMC COEUR-09

Cite this