Objective The early natural history of sarcomere mutations and the evolution to hypertrophic cardiomyopathy (HCM) are poorly characterised. To describe phenotypic progression, we compared mutation carriers who developed HCM to those who did not during prospective longitudinal investigation.
Methods Sarcomere mutation carriers without baseline left ventricular hypertrophy (LVH) were studied during participation in a pilot clinical trial testing diltiazem versus placebo. 38 participants (mean±SD age 15.8±8.6 years) were followed for a median of 2.9 years (range 1.0–5.1 years) with imaging and biomarker analysis. 4 participants (mean baseline age 13.8±3.9 years) developed HCM and were compared to those without phenotypic progression.
Results Participants who developed HCM were all children/adolescents and members of families with more highly penetrant mutations. At baseline, participants who developed HCM had a higher left ventricular (LV) ejection fraction (74±2% vs 69±1%, p=0.02), lower global E′ velocity (11.2±0.5 vs 14.8±0.4 cm/s, p<0.0001), higher N terminal pro peptide of B-type natriuretic peptide (NT-proBNP) values (208±72 vs 57±13 pg/mL, p=0.04), longer posterior mitral leaflets, and more prevalent ECG abnormalities. During follow-up, these parameters and cardiac troponin values continued to diverge in participants who developed HCM, although LV wall thickness stabilised.
Conclusions LV relaxation, ECG changes, mitral leaflet length, and serum NT-proBNP concentrations appeared more prominently abnormal at baseline in preclinical sarcomere mutation carriers who imminently progressed to HCM. LVH appears to stabilise within 2 years of onset. Further investigation is needed to improve our understanding of the evolution of this disease.
Trial registration number NCT00319982; Post-results.
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Contributors CYH planned the study, drafted the manuscript, and is responsible for the overall content. ALC coordinated the study, and collected and analysed the data. EJO conducted the statistical analyses. NKL, SDC and CS assisted in study planning and provided critical comments. AMV performed CMR analyses. JG performed mitral valve analyses.
Funding This study was funded by the National Institutes of Health (K23 HL078901 to CYH) with additional support provided by the Arthur L. Lenahan Sr. Family Foundation (to CYH). Neither the NIH nor the Foundation played any role in the design or analysis of this study.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Partners Healthcare Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.