A phenotypic taxonomy of hypertrophic cardiomyopathy
A phenotypic taxonomy of hypertrophic cardiomyopathy
Abstract BackgroundHypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous structural phenotypes but there is no systematic framework for classifying morphology or assessing associated risks. In this study we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression for automated patient stratification. MethodsAn observational, single-centre study enrolled 436 HCM patients (median age 60 years; 28.8% women) with clinical, genetic and imaging data. An independent cohort of 60 HCM patients from Singapore (median age 59 years; 11% women) and a normative reference population from UK Biobank (n = 16,691, mean age 55 years; 52.5% women) with equivalent data were also recruited. We used machine learning to analyse the three dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. ResultsThe prevalence of pathogenic or likely pathogenic variants for HCM (P/LP) was 24.6%, while 66% were genotype negative. Carriers of P/LP variants had lower left ventricular mass, but greater basal septal hypertrophy, with reduced lifespan (mean follow-up 9.9 years) compared to genotype negative individuals (hazard ratio: 2.66; 95% confidence interval [CI]: 1.42-4.96; P < 0.002). Four main phenotypic branches were identified using unsupervised learning of three dimensional shape: 1) non-sarcomeric hypertrophy with co-existing hypertension; 2) diffuse and basal asymmetric hypertrophy associated with outflow tract obstruction; 3) isolated basal hypertrophy; 4) milder non-obstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for P/LP variants: 2.18 [95% CI: 1.93-2.28, P = 0.0001]). Phenotypic variation and associated risks could be visualised as a continuous distribution across the taxonomic tree. The model was generalisable to an independent cohort (trustworthiness M1: 0.86-0.88). ConclusionsWe report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk and outcomes. This approach will be of value for developing personalized clinical profiles to guide diagnosis, surveillance and intervention in patients with HCM, and improve understanding of the drivers of heterogeneity.
Inglese Paolo、Bai Wenjia、de Marvao Antonio、Schiratti Pierre-Rapha?l、Li Surui、Pua Chee Jian、Theotokis Pantazis、Buchan Rachel J、Raphael Claire E、Baksi Arun John、Pantazis Antonis、Pennell Dudley J、Chin Calvin W L、O?ˉRegan Declan P、Halliday Brian P、Curran Lara、Cook Stuart A、Ware James S、McGurk Kathryn A、Jafari Mina、Prasad Sanjay K、Zheng Sean L、Clement Adam、Shah Mit
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusBiomedical Image Analysis Group, Department of Computing, Imperial College London||Department of Brain Sciences, Imperial College LondonMRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus||Department of Women and Children?ˉs Health, King?ˉs College London||British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King?ˉs College LondonMRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusMRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus||Biomedical Image Analysis Group, Department of Computing, Imperial College LondonDepartment of Brain Sciences, Imperial College LondonNational Heart and Lung Institute, Imperial College London||MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation Trust||MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation Trust||Mayo Clinic RochesterNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation TrustNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation TrustNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation TrustNational Heart Research Institute Singapore, National Heart Center Singapore||Department of Cardiology, National Heart Center Singapore||Cardiovascular Sciences ACP, Duke NUS Medical SchoolMRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation TrustNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation TrustMRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus||National Heart Research Institute Singapore, National Heart Center SingaporeNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation Trust||MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusNational Heart and Lung Institute, Imperial College London||MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusMRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusNational Heart and Lung Institute, Imperial College London||Royal Brompton & Harefield Hospitals, Guy?ˉs and St. Thomas?ˉ NHS Foundation TrustNational Heart and Lung Institute, Imperial College London||MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusMRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital CampusMRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus
内科学基础医学医学研究方法
Inglese Paolo,Bai Wenjia,de Marvao Antonio,Schiratti Pierre-Rapha?l,Li Surui,Pua Chee Jian,Theotokis Pantazis,Buchan Rachel J,Raphael Claire E,Baksi Arun John,Pantazis Antonis,Pennell Dudley J,Chin Calvin W L,O?ˉRegan Declan P,Halliday Brian P,Curran Lara,Cook Stuart A,Ware James S,McGurk Kathryn A,Jafari Mina,Prasad Sanjay K,Zheng Sean L,Clement Adam,Shah Mit.A phenotypic taxonomy of hypertrophic cardiomyopathy[EB/OL].(2025-03-28)[2025-06-28].https://www.medrxiv.org/content/10.1101/2023.03.11.23285908.点此复制
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