Carolyn Y Ho1, Allison L Cirino1, Neal K Lakdawala1, John Groarke1, Anne Marie Valente2, Christopher Semsarian3, Steven D Colan2, E John Orav4. 1. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. 2. Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA. 3. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, University of Sydney, and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia. 4. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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