New treatment option for severe hypertrophic cardiomyopathy in children shows promise

Trametinib, a mitogen-activated protein kinase (MEK) inhibitor, reduces mortality and morbidity in children with severe hypertrophic cardiomyopathy (HCM) caused by pathogenic variants in the RAS/MAPK pathway, according to a study published today in JACC: Basic to Translational Science. The study provides strong evidence for personalized treatment targeting the underlying genetic causes of RASopathies, a group of rare disorders that often lead to life-threatening cardiac complications. 

“Our findings represent a breakthrough in the treatment of HCM in children, particularly those suffering from severe forms of the disease due to genetic variants in the RAS/MAPK pathway,” said Gregor Andelfinger, MD, PhD, co-author of the study and a cardiologist at CHU Saint-Justine in Montreal.  “The positive results we observed with trametinib are a promising step forward in addressing an urgent medical need for children whose condition has not responded to standard therapies.” 

HCM, a condition where the heart muscle thickens abnormally, is particularly dangerous in children and can lead to heart failure or premature death. About 20% of patients with RASopathies have HCM; RASopathy-associated HCM is often caused by genetic mutations in the RAS/MAPK signaling pathway, which regulates cell growth and development. It is often a more severe form of HCM and has a higher mortality rate. Until now, treatment options for severe cases of RASopathy-associated HCM (RAS-HCM) in pediatric patients have been limited. 

The study, which involved 61 children with severe RAS-HCM, compared 30 children receiving trametinib to 31 children receiving standard care. The results showed a significant reduction in the outcome of death, cardiac transplantation, or the need for cardiac surgery in the trametinib group. No life-threatening adverse events were observed, although dermatologic and mucous membrane side effects were common but manageable. 

“This study provides crucial evidence that targeted therapies like trametinib could dramatically improve the outlook for children suffering from severe HCM,” Andelfinger said. “It underscores the importance of developing genotype-specific therapies for RASopathies and other rare diseases.” 

“The paper by Andelfinger and colleagues provides exciting data with respect to treating ‘Rasopathies’ in children with HCM,” said Douglas Mann, MD, FACC, Editor-in-Chief of JACC: Basic to Translational Science. “Rasopathies are a group of rare genetic disorders that are caused by mutations in genes that regulate the Ras/mitogen-activated protein kinase (MAPK) signaling pathway.” 

“Given the rarity of this condition and the lack of existing therapies for these children, we felt it was important to publish this paper, with the hope that it will advance the field by providing a foundation for future randomized clinical trials to definitively evaluate the safety and efficacy of Trametinib in children with HCM,” Mann said. 

Study limitations include potential biases due to its design and incomplete data collection for the control group. Additionally, the trametinib group included patients with prior heart surgeries, which could affect the results. The shorter follow-up for the trametinib group may also underestimate long-term side effects. Lastly, the study does not determine the optimal dosing of trametinib for RAS-HCM. 

For embargoed copies of the study, please contact Olivia Walther, American College of Cardiology Media Relations Manager for JACC, at owalther@acc.org. 

The American College of Cardiology (ACC) is the global leader in transforming cardiovascular care and improving heart health for all. As the preeminent source of professional medical education for the entire cardiovascular care team since 1949, ACC credentials cardiovascular professionals in over 140 countries who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. Through its world-renowned family of JACC Journals, NCDR registries, ACC Accreditation Services, global network of Member Sections, CardioSmart patient resources and more, the College is committed to ensuring a world where science, knowledge and innovation optimize patient care and outcomes. Learn more at www.ACC.org or follow @ACCinTouch. 

The ACC’s JACC Journals rank among the top cardiovascular journals in the world for scientific impact. The flagship journal, the Journal of the American College of Cardiology (JACC) — and specialty journals consisting of JACC: Advances, JACC: Asia, JACC: Basic to Translational Science, JACC: CardioOncology, JACC: Cardiovascular Imaging, JACC: Cardiovascular Interventions, JACC: Case Reports, JACC: Clinical Electrophysiology and JACC: Heart Failure — pride themselves on publishing the top peer-reviewed research on all aspects of cardiovascular disease. Learn more at JACC.org.  

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