2026-07-25T03:51:31Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/275972026-07-17T00:17:42Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Sen-Martín, Laura author Fernández-Trasancos, Ángel author López-Unzu, Miguel Á author Bak, Agata author Zafra-Castellano, Magdalena author Srikantharajah, Rajiven author Pathak, Divya author Klotz, Annika author Kuehn, Michel N author Ferrarini, Alessia author Labrador-Cantarero, Verónica author Sánchez-Ortiz, David author Pricolo, María Rosaria author Vicente, Natalia author Velázquez-Carreras, Diana author Sánchez-García, Lucía author Sicilia, Jon author Nicolás-Ávila, José Ángel author Sánchez-Díaz, María author Schlossarek, Saskia author Cussó, Lorena author Desco, Manuel author Villalba-Orero, María author Guzmán-Martínez, Gabriela author Calvo, Enrique author Barriales-Villa, Roberto author Vázquez, Jesús author Sánchez-Cabo, Fátima author Hidalgo, Andrés author de Tombe, Pieter P author Carrier, Lucie author Spudich, James A author Ruppel, Kathleen M author Weinberger, Florian author Cazorla, Olivier author Hessel, Anthony L author Alegre-Cebollada, Jorge author 2026-07 Mavacamten is a targeted treatment for hypertrophic cardiomyopathy, a disease caused by genetic variants affecting mainly sarcomeric myosin and its regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here we generate knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which unlike carriers of cMyBP-C truncations, develop pathogenic myocardial remodeling with preserved cMyBP-C levels and localization. Mechanistically, R502W reduces cMyBP-C-myosin affinity and generates sarcomere hypercontractility due to increased Ca sensitivity and a favored ON structural state of myosin. Even though these pathomechanisms do not overlap with those triggered by truncating MYBPC3 variants, mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient hearts, correlating with the drug's ability to restore OFF myosin in R502W sarcomeres. In R502W human engineered heart tissues, mavacamten also opposes hypercontractility. Hence, our results indicate that mavacamten is effective in treating hypertrophic cardiomyopathy caused by both truncating and missense MYBPC3 variants regardless of their primary pathomechanisms. Nat Cardiovasc Res. 2026 Jul;5(7):638-657. NATURE CARDIOVASCULAR RESEARCH 42414613 https://hdl.handle.net/20.500.12105/27597 Mavacamten shows broad benefit in human and mouse models of MYBPC3-related hypertrophic cardiomyopathy.