Characterising the heterogeneity of heart failure with preserved ejection fraction: moving beyond subgroups and distinguishing disease from risk.
Year: 2026
Type: article
Study design: Observational Study
Abstract: AIMS: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome commonly hypothesised to comprise discrete subtypes. This study aimed to characterise HFpEF heterogeneity using advanced data science techniques applied to deeply phenotyped, multi-modal cohorts. METHODS AND RESULTS: 902 patients with HF and a left ventricular ejection fraction ≥ 50% were prospectively recruited and underwent detailed clinical, imaging, and genetic profiling. Clustering algorithms were first applied to derive discrete subgroups. To overcome rigid subgroup assignment, DDRTree was applied to map continuous phenotypic and outcome variation onto a two-dimensional tree. Genome-wide association studies (GWAS) identified variants associated with tree dimensions. Internal validation assessed stability, and external validation was conducted in a UK Biobank HFpEF cohort (n=148). Sensitivity analyses included patients with mildly reduced ejection fraction (n=1154). Logistic regression compared HFpEF with comorbidity-matched controls (n=902). Whilst conventional clustering did not identify meaningful subgroups, DDRTree revealed a stable, interpretable tree structure, capturing continuous variation in cardiac structure and function, biomarkers and comorbidities. Over a median follow-up of 6.8 years, phenotypic complexes demonstrated differing risks of cardiovascular death, HF hospitalisation, adverse renal outcome, and infection hospitalisation. GWAS revealed a locus near CRACD associated with tree dimension one. Findings were reproducible in external and sensitivity analyses. A profile of cardiac and systemic characteristics that distinguish HFpEF from its associated comorbidities were identified. CONCLUSIONS: HFpEF risk and disease course reflect a variable interplay of pathophysiological processes in each individual. This study provides a biologically plausible framework to guide a more personalised approach to HFpEF.
Source: Apollo (University of Cambridge)
Authors: Soltani, Fardad, Black, Nicholas, Bradley, Joshua, Priestner, Lucy, Ko Ko, Naing, Glasse, Hannah, Milner, Isabelle, Kreppel, Sarah, Schmitt, Matthias, Nucifora, Gaetano, Petrie, Mark C, Al-Mohammad, Abdallah, McCann, Gerry P, Lumbers, R Thomas, Beezer, Janine, Paton, Maria F, Robinson, Shaun, Hyland, Rebecca, Hartshorne-Evans, Nick, Humphreys-Davies, Laurence, Raisi-Estabragh, Zahra, Petersen, Steffen E, Newman, William G, McDonagh, Theresa, Mayet, Jamil, Williams, Simon G, Jenkins, David A, Morris, Andrew P, Peek, Niels, Miller, Christopher A
Institutions: Manchester Academic Health Science Centre, University of Manchester, Manchester University NHS Foundation Trust, Northern Care Alliance NHS Foundation Trust, Lancashire Teaching Hospitals NHS Foundation Trust, University of Glasgow, University of Sheffield, University of Leicester, NIHR Leicester Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, University College London, Sunderland Royal Hospital, University of Leeds, Leeds Teaching Hospitals NHS Trust, Imperial College Healthcare NHS Trust, British Society for Heart Failure, National Health Service, St Bartholomew's Hospital, Queen Mary University of London, Barts Health NHS Trust, William Harvey Research Institute, King's College Hospital NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, University of Cambridge
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Boston Scientific Corporation, Queen Mary University of London, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, University College London, Novo Nordisk, Sheffield Hospitals Charity, St George's University Hospitals NHS Foundation Trust, Barts Health NHS Trust, National Institutes of Health, Manchester Biomedical Research Centre, Medical Research Council, NIHR Imperial Biomedical Research Centre, NIHR Leicester Biomedical Research Centre, THIS Institute, University of Cambridge
Awards: Is myocardial fibrosis a key mechanism and prognostic indicator in early heart failure?, G1173971013, UK HFpEF: a national resource to accelerate therapeutic innovation in HFpEF, G1483213741, G1798610363, G3449402819, G402563391, Precision medicine to improve the outcome of patients with heart failure with preserved ejection fraction, G5209516035, G573552857, G5908284888, G5974926870, Discovery and Characterization of Rare Variant Effects in Dilated Cardiomyopathy via Large-Scale Biobank Analysis, G7219166070, G7272929574, Targeting the extracellular matrix to improve the outcome of patients with heart failure, G880270018, G8814686486
OpenAlex ID: W7128941903
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