Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy

Aine Lynch; Mark Tatangelo; Sachin Ahuja; Chun-Po Steve Fan; Sandar Min; Myriam Lafreniere-Roula; Tanya Papaz; Vivian Zhou; Kathryn Armstrong; Peter F Aziz; Lee N Benson; Ryan Butts; Andreea Dragulescu; Letizia Gardin; Justin Godown; Aamir Jeewa; Paul F Kantor; Beth D Kaufman; Ashwin K Lal; John J Parent; Marc 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 Rossano; Robert G Weintraub; Seema Mital

doi:10.1016/j.jacc.2023.01.012

Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy

J Am Coll Cardiol. 2023 Mar 21;81(11):1035-1045. doi: 10.1016/j.jacc.2023.01.012.

Authors

Aine Lynch¹, Mark Tatangelo², Sachin Ahuja³, Chun-Po Steve Fan², Sandar Min⁴, Myriam Lafreniere-Roula⁵, Tanya Papaz⁶, Vivian Zhou⁴, Kathryn Armstrong⁷, Peter F Aziz⁸, Lee N Benson¹, Ryan Butts⁹, Andreea Dragulescu¹, Letizia Gardin¹⁰, Justin Godown¹¹, Aamir Jeewa¹, Paul F Kantor¹², Beth D Kaufman¹³, Ashwin K Lal¹⁴, John J Parent¹⁵, Marc Richmond¹⁶, Mark W Russell¹⁷, Seshadri Balaji¹⁸, Elizabeth A Stephenson¹, Chet Villa¹⁹, John L Jefferies²⁰, Robert Whitehill²¹, Jennifer Conway²², Taylor S Howard²³, Stephanie J Nakano²⁴, Joseph Rossano²⁵, Robert G Weintraub²⁶, Seema Mital²⁷

Affiliations

¹ Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto Ontario, Canada.
² Ted Rogers Computational Program, Ted Rogers Centre for Heart Research, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
³ Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁴ Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Applied Health Research Centre, St Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada.
⁶ Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada.
⁷ Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.
⁸ Department of Pediatrics, Cleveland Clinic Children's Hospital, Cleveland, Ohio, USA.
⁹ Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA.
¹⁰ Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
¹¹ Department of Pediatrics, Monroe Carrell Jr Children's Hospital at Vanderbilt University, Nashville, Tennessee, USA.
¹² Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA.
¹³ Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Palo Alto, California, USA.
¹⁴ Department of Pediatrics, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.
¹⁵ Department of Pediatrics, Riley Children's Hospital, Indianapolis, Indiana, USA.
¹⁶ Department of Pediatrics, Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, New York, USA.
¹⁷ Department of Pediatrics, University of Michigan Health System, Ann Arbor, Michigan, USA.
¹⁸ Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA.
¹⁹ Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
²⁰ Department of Pediatrics, University of Tennessee Health Sciences Centre, Memphis, Tennessee, USA.
²¹ Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
²² Department of Pediatrics, Stollery Children's Hospital, Edmonton, Alberta, Canada.
²³ Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA.
²⁴ Department of Pediatrics, Children's Hospital Colorado, Aurora, Colorado, USA.
²⁵ Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
²⁶ Department of Cardiology, The Royal Children's Hospital of Melbourne, Melbourne, Victoria, Australia.
²⁷ Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto Ontario, Canada; Ted Rogers Computational Program, Ted Rogers Centre for Heart Research, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada. Electronic address: seema.mital@sickkids.ca.

PMID: 36922089
DOI: 10.1016/j.jacc.2023.01.012

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.

Keywords: Noonan syndrome; RASopathy; hypertrophic cardiomyopathy; implantable cardioverter-defibrillator; pediatric; sudden cardiac death.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cardiomyopathy, Hypertrophic* / complications
Cardiomyopathy, Hypertrophic* / diagnosis
Cardiomyopathy, Hypertrophic* / genetics
Cohort Studies
Death, Sudden, Cardiac / epidemiology
Death, Sudden, Cardiac / etiology
Defibrillators, Implantable* / adverse effects
Heart Failure* / complications
Humans
Risk Assessment
Risk Factors

Grants and funding

CIHR/Canada