Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy

Authors

• Aine Lynch, The Hospital for Sick Children
• Mark Tatangelo, Peter Munk Cardiac Centre
• Sachin Ahuja, Schulich School of Medicine & Dentistry
• Chun Po Steve Fan, Peter Munk Cardiac Centre
• Sandar Min, The Hospital for Sick Children
• Myriam Lafreniere-Roula, St. Michael's Hospital, Toronto
• Tanya Papaz, The Hospital for Sick Children
• Vivian Zhou, The Hospital for Sick Children
• Kathryn Armstrong, BC​ Children​'​​s Hospital
• Peter F. Aziz, Cleveland Clinic Foundation
• Lee N. Benson, The Hospital for Sick Children
• Ryan Butts, UT Southwestern Medical School
• Andreea Dragulescu, The Hospital for Sick Children
• Letizia Gardin, Children's Hospital of Eastern Ontario, Ottawa
• Justin Godown, Monroe Carell Jr. Children's Hospital at Vanderbilt
• Aamir Jeewa, The Hospital for Sick Children
• Paul F. Kantor, Children's Hospital Los Angeles
• Beth D. Kaufman, Lucile Packard Children's Hospital Stanford
• Ashwin K. Lal, University of Utah School of Medicine
• John J. Parent, Riley Children's Hospital
• Marc Richmond, Columbia University Irving Medical Center
• Mark W. Russell, Michigan Medicine
• Seshadri Balaji, Doernbecher Children's Hospital
• Elizabeth A. Stephenson, The Hospital for Sick Children
• Chet Villa, Cincinnati Children's Hospital Medical Center
• John L. Jefferies, University of Tennessee Health Science Center
• Robert Whitehill, Children's Healthcare of Atlanta
• Jennifer Conway, Stollery Children's Hospital

Abstract

Background: Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood. Objectives: The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients. Methods: In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray's tests, and age-related hazard of all-cause mortality was determined. Results: RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years [IQR: 0.2-5.0 years] vs 9.8 years [IQR: 2.0-13.9 years], respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative incidence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respectively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence. Conclusions: RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM.

Publication Title

Journal of the American College of Cardiology

Recommended Citation

Lynch, A., Tatangelo, M., Ahuja, S., Steve Fan, C., Min, S., Lafreniere-Roula, M., Papaz, T., Zhou, V., Armstrong, K., Aziz, P., Benson, L., Butts, R., Dragulescu, A., Gardin, L., Godown, J., Jeewa, A., Kantor, P., Kaufman, B., Lal, A., Parent, J., Richmond, M., Russell, M., Balaji, S., Stephenson, E., Villa, C., Jefferies, J., Whitehill, R., & Conway, J. (2023). Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology, 81 (11), 1035-1045. https://doi.org/10.1016/j.jacc.2023.01.012