Biobank-scale plasma proteomics identifies novel biomarkers in hypertrophic cardiomyopathy

Conference item

Background: Hypertrophic cardiomyopathy (HCM) is characterized by substantial heterogeneity in both clinical phenotype and risk of adverse outcomes including heart failure and sudden cardiac death. This highlights the need for robust biomarkers for risk stratification and while previous studies have identified the role of select plasma proteins, comprehensive large-scale proteomic analyses have been limited in HCM.

Methods: We performed case-control analysis of 2922 plasma proteins in 49,588 UK Biobank participants (100 HCM cases) to identify proteins associated with HCM. Additional datasets including All of Us and the HCM Registry (HCMR) enabled external validation and cross-phenotype association with cardiac magnetic resonance imaging-derived measures. Associations with adverse clinical outcomes were further identified and causal relationships evaluated using Mendelian randomisation. Relative biomarker importance was also assessed by joint modelling via machine learning.

Results: We confirmed the associations of established biomarkers (e.g. NTproBNP, troponins I and T) with HCM cases, cardiac imaging markers of disease severity, and adverse outcomes. Mendelian randomisation analyses supported a causal effect of HCM on increasing NTproBNP and troponin T levels. Novel protein associations (e.g. HRC, ACE2, ANGPT2 and LTBP2) were identified, with HRC also showing prognostic utility for heart failure-related outcomes in HCM cases.

Conclusions: This biobank-scale plasma proteomic study in HCM validated known biomarkers and identified novel candidates (e.g. HRC, ACE2) with potential diagnostic and prognostic utility. These findings highlight the potential for plasma proteomics to improve risk prediction and provide insight into HCM pathobiology, paving the way for future validation and mechanistic studies.

Authors: Chan, JH; Grace, C; Mazidi, M; Clarke, R; Ho, CY

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BMJ Publishing Group
• Journal: Heart
• Volume: 111
• Issue: S6
• Pages: A3
• Article number: P5
• Publication date: 2025-12-30
• Acceptance date: 2025-09-03
• Event title: 2025 Autumn Meeting of the British Society for Cardiovascular Research
• Event location: London, UK
• Event website: https://www.bscr.org/meetings/bscr2025a
• Event start date: 2025-09-03
• Event end date: 2025-09-04
• DOI: 10.1136/heartjnl-2025-bscr.7
• EISSN: 1468-201X
• ISSN: 1355-6037
• Language: English
• Keywords: hypertrophic cardiomyopathy; biomarker; biobank; troponin; disease; heart failure; cardiomyopathy