Mavacamten improves energy balance in a pre-clinical model of RASopathy-associated hypertrophic cardiomyopathy
Abstract
Background: Activating mutations in the RAS-MAPK pathway account for ~20% of cases of pediatric hypertrophic cardiomyopathy (HCM) and are associated with poor outcomes. Mavacamten is approved for obstructive HCM; however, patients with RAS-associated HCM have not been included in the clinical trials so far. We aimed to characterize the functional and energetic disturbances in an in vitro RAS-HCM model and evaluate the therapeutic effects of mavacamten. Methods: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying a CRISPR-induced BRAF (p.Thr599Arg) mutation and their isogenic control were studied. Cell size, contractility, and transcriptomics were assessed, while energetics were determined using MitoStress assays, live ATP imaging, and NAD(P)H/FAD autofluorescence. Results: BRAF-mutant hiPSC-CMs showed hypertrophy, hypercontractility, increased mitochondrial cofactor pools, and enhanced maximal respiratory capacity. Despite this, they developed ATP deficiency in response to rapid pacing, suggesting mitochondrial inefficiencies or an overwhelming ATP demand. Mavacamten normalized mitochondrial respiration and excessive ATP consumption, partially restoring energetic balance and highlighting hypercontractility as a major burden in RAS-HCM. Conclusions: BRAF-mutant cardiomyocytes recapitulate the characteristics of HCM in vitro. Mavacamten mitigates dysfunctions and restores energetic balance under stress conditions, indicating it holds potential as a therapeutic option for RASopathy-associated HCM.
Related
- Tunable Magnetorheological Elastomer Substrates for Studying Mechano-Genetic Interactions in Hypertrophic Cardiomyopathy
- GPC6 Lipid Shielding Sustains WNT5A Gradients to Prevent a RASopathy-like Developmental State
- Sequence-aware genotyping improves the accuracy of molecular markers associated with cassava mosaic disease resistance loci
- Muscle stem cell treatment mitigates stress-associated multiorgan dysfunction in D-galactose-induced accelerated aging mice and improves behavior in naturally aged mice
- Phage intervention improves colitis and response to corticosteroids by attenuating virulence of Crohn’s disease–associated bacteria
BibTeX
@article{ruizvelasco2026mavacamten,
title = {{Mavacamten improves energy balance in a pre-clinical model of RASopathy-associated hypertrophic cardiomyopathy}},
author = {Andrea Ruiz-Velasco and Charlène Jouve and Lucille Deshayes and Michael Kohlhaas and Christoph Maack and Jean-Sébastien Hulot},
journal = {Pediatric Research},
year = {2026},
month = jun,
doi = {10.1038/s41390-026-05208-9},
url = {https://hal.science/hal-05775537v1},
note = {CC BY-NC-SA 4.0},
}
RIS
TY - JOUR
TI - Mavacamten improves energy balance in a pre-clinical model of RASopathy-associated hypertrophic cardiomyopathy
AU - Andrea Ruiz-Velasco
AU - Charlène Jouve
AU - Lucille Deshayes
AU - Michael Kohlhaas
AU - Christoph Maack
AU - Jean-Sébastien Hulot
PY - 2026
DA - 2026/06/22
JO - Pediatric Research
DO - 10.1038/s41390-026-05208-9
UR - https://hal.science/hal-05775537v1
AB - Background: Activating mutations in the RAS-MAPK pathway account for ~20% of cases of pediatric hypertrophic cardiomyopathy (HCM) and are associated with poor outcomes. Mavacamten is approved for obstructive HCM; however, patients with RAS-associated HCM have not been included in the clinical trials so far. We aimed to characterize the functional and energetic disturbances in an in vitro RAS-HCM model and evaluate the therapeutic effects of mavacamten. Methods: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying a CRISPR-induced BRAF (p.Thr599Arg) mutation and their isogenic control were studied. Cell size, contractility, and transcriptomics were assessed, while energetics were determined using MitoStress assays, live ATP imaging, and NAD(P)H/FAD autofluorescence. Results: BRAF-mutant hiPSC-CMs showed hypertrophy, hypercontractility, increased mitochondrial cofactor pools, and enhanced maximal respiratory capacity. Despite this, they developed ATP deficiency in response to rapid pacing, suggesting mitochondrial inefficiencies or an overwhelming ATP demand. Mavacamten normalized mitochondrial respiration and excessive ATP consumption, partially restoring energetic balance and highlighting hypercontractility as a major burden in RAS-HCM. Conclusions: BRAF-mutant cardiomyocytes recapitulate the characteristics of HCM in vitro. Mavacamten mitigates dysfunctions and restores energetic balance under stress conditions, indicating it holds potential as a therapeutic option for RASopathy-associated HCM.
SN - 0031-3998
SN - 1530-0447
ER -