Sen-Martín, LauraFernández-Trasancos, ÁngelLópez-Unzu, Miguel ÁBak, AgataZafra-Castellano, MagdalenaSrikantharajah, RajivenPathak, DivyaKlotz, AnnikaKuehn, Michel NFerrarini, AlessiaLabrador-Cantarero, VerónicaSánchez-Ortiz, DavidPricolo, María RosariaVicente, NataliaVelázquez-Carreras, DianaSánchez-García, LucíaSicilia, JonNicolás-Ávila, José ÁngelSánchez-Díaz, MaríaSchlossarek, SaskiaCussó, LorenaDesco, ManuelVillalba-Orero, MaríaGuzmán-Martínez, GabrielaCalvo, EnriqueBarriales-Villa, RobertoVázquez, JesúsSánchez-Cabo, FátimaHidalgo, Andrésde Tombe, Pieter PCarrier, LucieSpudich, James ARuppel, Kathleen MWeinberger, FlorianCazorla, OlivierHessel, Anthony LAlegre-Cebollada, Jorge2026-07-162026-07-162026-07Nat Cardiovasc Res. 2026 Jul;5(7):638-657.https://hdl.handle.net/20.500.12105/27597Mavacamten 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.J.A.-C. acknowledges funding from the Ministerio de Ciencia, Innovación y Universidades (MICIU, MICIU/AEI /10.13039/501100011033) through grants PID2020-120426GB-I00, PID2023-147683NB-I00 (European Regional Development Fund, ERDF) and RED2022-134242-T, the Regional Government of Madrid (grants Tec4Bio S2018/NMT-4443, 50% co-financed by the ERDF for the programming period 2014-2020, and grant TecNanoBio TEC-2024/TEC-158, Bases Reguladoras 2402/2024; Convocatoria 3177/2024), MICIU’s Severo Ochoa Program SEV-2015-0505 through a CNIC intramural grant 03-2016 IGP, and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. [101002927]). F.W. acknowledges grant PID2023-147006OB-I00 from MICIU (ERDF). J.V. acknowledges grants PID2021-122348NB-I00 from MICIU (ERDF), PLEC2022-009298, PLEC2022-009235 and EQC2021-007053-P from MICIU and from ‘European Union NextGenerationEU/PRTR’, S2022/BMD-7333-CM (INMUNOVAR-CM) from the Regional Government of Madrid and LCF/PR/HR22/52420019 from ‘la Caixa’ Foundation. L. Cussó is supported by MICIU/AEI /10.13039/501100011033 and by FSE+ under grant RYC2023-043775-I. M.D. acknowledges grant PT23/00027 from ISCIII and co-funded by the European Union. L. Carrier is supported by the German Centre for Cardiovascular Research (DZHK), the German Ministry of Research Education (BMBF) and by the Leducq Foundation (grant 20CVD01). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICIU and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU). L.S.-M. acknowledges funding from Boehringer Ingelheim Fonds. L.S.-M. is the recipient of an FPI predoctoral fellowship (PRE2021-097336 funded by MICIU). M.Á.L.-U. is the recipient of a Juan de la Cierva – Formación postdoctoral grant (FJC 047055-I funded by MICIU). L.S.-G is supported by grant PTA2020-019067-I funded by MICIU/ AEI/10.13039/501100011033. R.S. is the recipient of a fellowship by the German Heart Foundation.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 International42414613NATURE CARDIOVASCULAR RESEARCHopen access