Author + information
- Received April 2, 2020
- Revision received May 27, 2020
- Accepted June 1, 2020
- Published online July 27, 2020.
- Massimiliano Lorenzini, MD, PhDa,b,
- Gabrielle Norrish, MDb,c,
- Ella Field, BScb,c,
- Juan Pablo Ochoa, MDd,e,
- Marcos Cicerchia, MDd,e,
- Mohammed M. Akhtar, MDa,b,
- Petros Syrris, PhDb,
- Luis R. Lopes, MD, PhDa,b,
- Juan Pablo Kaski, MDb,c and
- Perry M. Elliott, MDa,b,∗ (, )@UCL_ICS
- aBarts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom
- bUniversity College London Institute of Cardiovascular Science, London, United Kingdom
- cCentre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, United Kingdom
- dHealth in Code S.L., Scientific Department, A Coruña, Spain
- eUniversidade da Coruña, GRINCAR (Cardiovascular Research Group), A Coruña, Spain
- ↵∗Address for correspondence:
Dr. Perry M. Elliott, UCL Institute for Cardiovascular Science, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6DD, United Kingdom.
Background Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM.
Objectives The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers.
Methods This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation.
Results The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3).
Conclusions Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening.
St. Bartholomew’s Hospital is a member of the European Reference Network for rare, low prevalence, and complex diseases of the heart. Drs. Lopes and Kaski are recipients of a Medical Research Council (MRC) Clinical Academic Research Partnership (CARP) award. Drs. Norish and Kaski are supported by the British Heart Foundation (BHF); Drs. Field and Kaski are supported by Max’s Foundation and Great Ormond Street Hospital Children’s Charity. Drs. Norish, Field, and Kaski work at Great Ormond Street Hospital, which received a proportion of funding from the UK Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme (NIHR GOSH BRC). All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received April 2, 2020.
- Revision received May 27, 2020.
- Accepted June 1, 2020.
- 2020 The Authors