Clinical and Proteomic Risk Profiles of New-Onset Heart Failure in Men and Women.

Background: Previous studies have examined clinical predictors of incident heart failure (HF) in men and women. However, potential mechanisms through which these clinical predictors relate to the onset of HF remain to be established.
Objectives: The authors studied the association between clinical and proteomic risk profiles of new-onset HF in men and women.
Methods: Incident HF was studied in 478,479 participants from the UK Biobank. The association between new-onset HF and 8 common modifiable traditional risk factors, including obesity, smoking status, socioeconomic status, atrial fibrillation, type 2 diabetes, hypertension, hyperlipidemia, and history of myocardial infarction, was assessed in men and women. Proteomics data (2,923 unique proteins, Olink) was available in 22,695 men and 27,421 women. Pathway over-representation analyses were performed to identify biological pathways in men and women with and without new-onset HF. Principal component analyses were performed to extract weighted scores for each pathway. Subsequently, weighted scores were used in mediation analyses to investigate how the pathways mediated the association between risk factors and new-onset HF.
Results: During a median follow-up time of 12 years, HF incident rate was 3.60 per 1,000 person-years in men and 1.72 per 1,000 person-years in women (P < 0.001). The strongest risk factor for future HF was a history of myocardial infarction (HR: 2.61; 95% CI: 2.46-2.77) in men and atrial fibrillation (HR: 4.10; 95% CI: 3.58-4.71) in women. When a risk factor was present in women, it conferred a higher risk of new-onset HF compared with the presence of the same risk factor in men. Both in men and women, the population-attributable risk was highest for hypertension (25% in men, 29% in women) and obesity (16% in men, 21% in women). Pathway analyses of protein profiles indicated several inflammatory pathways, and neutrophil degranulation in particular, to be activated both in men and women who developed HF. These inflammatory pathways modestly (22% in men and 24% in women) contributed to the association between hypertension and new-onset HF, but showed a stronger contribution (33% in men and 47% in women) to the association between obesity and new-onset HF.
Conclusions: In men and women, the most prominent risk factors for new-onset HF were hypertension and obesity, but they conferred a greater risk of new-onset HF in women. New-onset HF in both men and women was associated with pathophysiological pathways related to neutrophil degranulation and immunomodulation; and these pathways partly mediated the association between hypertension, obesity, and new-onset HF.
Competing Interests: Funding Support and Author Disclosures Dr Qin is supported by a joint fellowship from the China Scholarship Council and University Medical Centre Groningen (number 202008440347). Dr Tromp is supported by the National University of Singapore Start-up grant, the tier 1 grant from the Ministry of Education, and the CS-IRG New Investigator Grant from the National Medical Research Council; has received research support from AstraZeneca; has received consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche Diagnostics, and Us2.ai; and owns patent US-10702247-B2 unrelated to the present work. Dr ter Maaten is supported by the Dutch Heart Foundation and Netherlands Organization for Research; and has received speaker fees to her institution from Boehringer Ingelheim and Novartis. Dr André de la Rambelje is supported by PRIME-CKD consortium of the European Commission. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and has served as co-founder and non–executive director of Us2.ai. Dr Voors has received consultancy and/or research fees from Anacardio, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, Cytokinetics, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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