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.