Abstract

Background Hypertrophic cardiomyopathy (HCM) is a clinically variable disease in terms of onset and progression. Pathogenic MYBPC3 variants account for a substantial proportion of HCM diagnoses. This study sought to identify protein biomarkers associated with HCM severity.

Methods Olink-assayed plasma proteins of 144 MYBPC3 pathogenic variant carriers were tested for associations with HCM severity based on HCM diagnostic criteria (unaffected, mildly, or severely affected). The UK Biobank was used to replicate the identified proteins through considering time to onset of HCM (67 cases), cardiomyopathy (156 cases),and associations with cardiac MRI derived left ventricular maximum wall thickness (6,492 participants). Replicated proteins were further prioritised based on cardiac tissue expression and druggability, and annotated using pathway enrichment and association with onset of: heart failure (HF), dilated cardiomyopathy (DCM), sudden cardiac arrest (SCA), and ventricular arrhythmias (VA).

Results Among pathogenic MYBPC3 variant carriers, we identified 27 proteins associated with HCM severity. We independently replicated 21 proteins in the UK Biobank. Of the five prioritised proteins (NT-proBNP, GDF-15, FGF-23, ADM, and NCAM1), all but NT-proBNP were targeted by drugs with repurposing potential. The replicated proteins additionally associated with the incidence of HF (n=5), DCM (n=4), SCA (n=4), and VA (n=4).

Conclusion This study replicated 21 and prioritised five proteins associated with HCM severity in pathogenic MYBPC3 variant carriers. Replication in unselected HCM suggests the prioritised proteins are associated with HCM independent of genotype, providing important leads for plasma-based markers for diagnoses, disease monitoring, and drug targets.

Competing Interest Statement

AFS has received funding from New Amsterdam Pharma for unrelated projects.

Funding Statement

MvV is supported by the postdoc talent grant from Amsterdam Cardiovascular Sciences. AFS is supported by the UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/ Z000211/1, BHF grant PG/22/10989, the UCL BHF Research Accelerator AA/18/6/34223, the UCL BHF Centre of Research Excellence RE/24/130013. This publication is part of the project "Computational medicine for cardiac disease" with file number 2025.027 of the research programme "Computing Time on National Computer Facilities" which is (partly) financed by the Dutch Research Council (NWO). This work was supported by the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (grant Dutch Cardiovascular Alliance 2020B005 DoubleDose), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, and an unrestricted grant from Bristol Meyers Squibb. ATR is funded by ZonMW grant (2024 Clinical Fellows; grant no. 09032232310042) and HORIZON cardiogenomics pathfinder IMPACT (grant no. 101115536).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was performed in accordance with the Helsinki declaration and was approved by the Medical Ethics Committee of the UMC Utrecht under registration number NL5588904115.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Both data and samples for BIO FOr CARE are available to external researchers through submission of an application to our data access board, which consists of investigators from each participating centre.

Non-standard abbreviations and acronymsCIconfidence intervalCMPcardiomyopathyCMRcardiac MRIDCMdilated cardiomyopathyHCMhypertrophic cardiomyopathyHFheart failureHRhazard ratioLVleft ventricularLVMWTLV maximum wall thicknessSCAsudden cardiac arrestUKBUK BiobankVAventricular arrhythmia