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Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease

Topriceanu, Constantin-Cristian; Moon, James C; Axelsson Raja, Anna; Captur, Gabriella; Ho, Carolyn Y; (2024) Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease. Circulation: Genomic and Precision Medicine , 17 (4) , Article e004580. 10.1161/CIRCGEN.124.004580.

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Abstract

Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular (LV) hypertrophy with LV wall thickness ≥15 mm in probands or ≥13 mm in at-risk relatives. Although LV hypertrophy is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of the disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, before diagnosis with HCM (G+/LV hypertrophy-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LV hypertrophy are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca2+ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including abnormal ECG, longer mitral valve leaflets, lower global E' velocities on Doppler echocardiography, and higher serum N-terminal propeptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and guide the development of novel treatment strategies aimed at influencing disease trajectory.

Type: Article
Title: Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease
Location: United States
DOI: 10.1161/CIRCGEN.124.004580
Publisher version: http://dx.doi.org/10.1161/circgen.124.004580
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: cardiomyopathy, hypertrophic, longitudinal studies, mitral valve, penetrance, sarcomere
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine > MRC Unit for Lifelong Hlth and Ageing
URI: https://discovery.ucl.ac.uk/id/eprint/10196655
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