Inflammatory and adipokine-associated proteomic signatures of heart failure progression by body mass index: insights from the EXAMINE trial
A Wahhab, G Zhang, M Maurice-Ventouris, H Issa, F Kahles, J Ferreira, F Zannad, N Girerd, A SharmaAbstract
Background
Obesity is a well-established risk factor for heart failure (HF) and is strongly associated with hospitalisation for HF (HFH). However, whether obesity modifies the biological pathways underlying HF decompensation remains incompletely understood. We hypothesized that circulating biomarkers exhibit body mass index (BMI)-dependent associations with HFH, reflecting obesity-related heterogeneity in HF biology.
Purpose
To determine whether obesity is associated with distinct proteomic profiles linked to HFH.
Methods
We conducted a secondary analysis of the EXAMINE trial, which enrolled patients with type 2 diabetes (T2D) following acute coronary syndrome. Among 5,379 participants, adjudicated HFH events and associated time to HFH events were identified. Participants were stratified by BMI definition of obesity ≥30 (N = 2208; HFH events = 94) or <30 kg/m² (N = 3171; HFH events = 101). Plasma proteomic data generated using the Olink Cardiovascular II panel were analysed. Differential protein expression and functional pathway enrichment analyses compared participants with and without HFH by obesity status. Fine-Gray competing risk regression was used to evaluate the association between individual proteomic biomarkers and the cumulative incidence of HFH, accounting for the competing risk of death and stratified by obesity status.
Results
Twenty-two proteomic biomarkers were upregulated in both obese (BMI≥30) and non-obese (BMI<30) groups, reflecting shared HF-related pathways involving neurohormonal activation, vascular stress, and pro-inflammatory signalling mediated by interleukin-6 and interleukin-8. In contrast, 17 proteins were uniquely dysregulated in participants with obesity, with enrichment of pathways related to lipid metabolism, adipokine signalling, and interleukin-6/interleukin-10 immune regulation. Network analyses indicated a chronic inflammation-associated signalling profile in obesity. Using Fine-Gray competing risks regression, 12 proteomic biomarkers demonstrated significant BMI interactions for HFH risk (e.g., IL1RL2, OSCAR), while 9 biomarkers were significantly associated with HFH across both obese and non-obese groups (e.g., IL6, SPON2).
Conclusion
In patients with T2D following acute coronary syndrome, HF progression is associated with shared neurohormonal and inflammatory pathways across the spectrum of BMI groups; however, obesity is characterised by additional immune, metabolic, and adipokine-associated dysregulation. Among patients with obesity, HFH was associated with concurrent interleukin-6 and interleukin-10 signalling, alongside enrichment of proteomic markers linked to adipokine-related signaling (e.g., CCL3, CXCL1, FGF21). Several biomarkers showed BMI-dependent or BMI-independent associations with HFH. Together, these findings suggest that inflammation and adipokine-associated signalling represent key features of obesity-associated HF progression and may inform improved risk stratification.Proteomic Network of HFH BiomarkersFor image description, please refer to the figure legend and surrounding text.BMI-Dependent Biomarker Risk of HFHFor image description, please refer to the figure legend and surrounding text.