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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> <p></p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>BRAF-mutant hiPSC-CMs exhibit hypertrophy, hypercontractility, and energetic imbalance under stress, reproducing pathological characteristics of RAS-HCM.</p> </ItemContent> <ItemContent> <p>Mitochondrial stress tests showed a higher basal respiration and maximal respiratory capacity, indicating that mitochondrial dysfunction is not the main cause of this imbalance.</p> </ItemContent> <ItemContent> <p>Mavacamten normalized basal mitochondrial respiration and ATP utilization under stress, indicating that hypercontractility represents a major energetic burden.</p> </ItemContent> <ItemContent> <p>The beneficial effects of mavacamten on BRAF-mutant hiPSC-CMs suggest therapeutic potential for treating RASopathy-associated HCM.</p> </ItemContent> </UnorderedList></p>

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Mavacamten improves energy balance in a pre-clinical model of RASopathy-associated hypertrophic cardiomyopathy

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Andrea Ruiz-Velasco,
  • Charlène Jouve,
  • Lucille Deshayes,
  • Michael Kohlhaas,
  • Christoph Maack,
  • Jean-Sébastien Hulot

摘要

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.

Impact

BRAF-mutant hiPSC-CMs exhibit hypertrophy, hypercontractility, and energetic imbalance under stress, reproducing pathological characteristics of RAS-HCM.

Mitochondrial stress tests showed a higher basal respiration and maximal respiratory capacity, indicating that mitochondrial dysfunction is not the main cause of this imbalance.

Mavacamten normalized basal mitochondrial respiration and ATP utilization under stress, indicating that hypercontractility represents a major energetic burden.

The beneficial effects of mavacamten on BRAF-mutant hiPSC-CMs suggest therapeutic potential for treating RASopathy-associated HCM.