Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy
Áine Lynch, Mark Tatangelo, Sachin Ahuja, Chun‐Po Steve Fan, Sandar Min, Myriam Lafrenière‐Roula, Tanya Papaz, Vivian Zhou, Kathryn Armstrong, Peter F. Aziz, Lee Benson, Ryan J. Butts, Andréea Dragulescu, Letizia Gardin, Justin Godown, Aamir Jeewa, Paul F. Kantor, Beth D. Kaufman, Ashwin K. Lal, John J. Parent, Marc E. Richmond, Mark W. Russell, Seshadri Balaji, Elizabeth A. Stephenson, Chet Villa, John L. Jefferies, Robert Whitehill, Jennifer Conway, Taylor S. Howard, Stephanie J. Nakano, Joseph W. Rossano, Robert G. Weintraub, Seema Mital
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.