Pathophysiological analysis of serially measured plasma biomarkers, remote monitoring and clinical events, in symptomatic patients with moderate to severe chronic heart failure

Aims: To explore temporal patterns of serially measured cardiovascular-related biomarkers in patients with chronic heart failure (CHF), with the objective of identifying biomarker pathophysiological trajectories associated with clinical outcomes. These explorative analyses can generate hypotheses regarding underlying pathophysiological processes and the potential role of multi-biomarker approaches in chronic HF. Methods: The BioMEMS-study involved 334 patients with moderate to severe chronic HF in NYHA class III who received either standard of care or remote hemodynamic monitoring. Serial blood samples were collected at baseline, 3, 6, and 12 months, and biomarker levels were assessed using the Olink Cardiovascular-III panel. Joint modelling analyses were performed, integrating longitudinal biomarker trajectories and risk of the composite endpoint of all-cause mortality or HF hospitalization. Results: In multivariable-adjusted models, 15 biomarkers were consistently and significantly associated with the composite endpoint after adjustment for confounders and multiple testing. MMP-2, ST2, IGFBP-1, IGFBP-7, and NT-proBNP exhibited the strongest associations with the composite endpoint, with hazard ratios (95% CI) of 2.72 (1.87-4.03), 2.71 (2.00-3.80), 2.70 (1.81-4.27), 2.48 (1.81-3.45), and 2.28 (1.72-3.03), respectively. These findings were robust across sensitivity analyses correcting for clinical confounders and treatment groups. Temporal trajectories revealed higher biomarker levels in patients who experienced incident events, with biomarkers showing corresponding changes in levels preceding events. Conclusion: Serial biomarker measurements could provide additional insights in the pathophysiology of worsening HF. Specific biomarkers reflecting myocardial stress, cardiac remodelling and fibrosis show changes in levels over time as worsening HF approaches, which highlights possible involvement of these pathophysiological pathways.