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Mavacamten improves energy balance in a pre-clinical model of RASopathy-associated hypertrophic cardiomyopathy
Andrea Ruiz-Velasco1, Charlène Jouve1, Lucille Deshayes1
1Université Paris Cité, Paris Cardiovascular Research Center, INSERM U970, Paris, France.
Insights
Mavacamten may treat RAS-associated hypertrophic cardiomyopathy (HCM). This study found mavacamten normalized energy use and mitochondrial function in a BRAF-mutant HCM model, suggesting it could be a therapeutic option for RAS-HCM patients.
Area of Science:
- Cardiovascular Research
- Genetics
- Mitochondrial Biology
Background:
- Activating RAS-MAPK pathway mutations cause ~20% of pediatric hypertrophic cardiomyopathy (HCM).
- RAS-associated HCM patients are excluded from current clinical trials.
- Mavacamten is approved for obstructive HCM but not RAS-associated HCM.
Purpose of the Study:
- To characterize functional and energetic disturbances in an in vitro RAS-HCM model.
- To evaluate mavacamten's therapeutic effects in this model.
Main Methods:
- Utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a BRAF (p.Thr599Arg) mutation.
- Assessed cell size, contractility, transcriptomics, and energetics (MitoStress, ATP imaging, NAD(P)H/FAD autofluorescence).
Main Results:
- BRAF-mutant hiPSC-CMs displayed hypertrophy, hypercontractility, and increased mitochondrial respiration.
- These cells showed ATP deficiency under rapid pacing, indicating mitochondrial inefficiency or high ATP demand.
- Mavacamten normalized mitochondrial respiration and ATP consumption, reducing the energetic burden.
Conclusions:
- BRAF-mutant hiPSC-CMs model key features of RAS-associated HCM.
- Mavacamten mitigates cardiac dysfunction and restores energetic balance under stress.
- Mavacamten shows potential as a therapeutic agent for RASopathy-associated HCM.
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.
