Protein biomarkers associated with left bundle branch block in patients with heart failure and reduced ejection fraction

Abstract

Introduction: Left bundle branch block (LBBB) is common in heart failure with reduced ejection fraction (HFrEF) and causes dyssynchrony, which accelerates cardiac remodelling. The biological mechanisms behind LBBB-associated remodelling remain largely unknown. Therefore, we used an omics approach to test the hypothesis that LBBB is associated with plasma protein dysregulation aiming at defining a proteome that contributes to the specific disease driving phenotype in dyssynchronopathy.

Methods: Patients were selected from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure database (n = 4254). Patients with HFrEF and LBBB (HFrEF + LBBB) served as cases (n = 268) and a matched control group (n = 268) with HFrEF without LBBB (HFrEF - LBBB) was selected using propensity score matching. We compared relative plasma concentrations of 364 proteins between the two groups using proximity extension assay.

Results: HFrEF + LBBB was associated with up- or downregulation of 41 proteins out of 364 assessed, 11%, compared with HFrEF - LBBB. Fibroblast growth factor 2 (FGF2) decreased, epidermal growth factor receptor (EGFR) increased, and several cytokines and proteins involved in extracellular matrix processing changed expression. Gene ontology pathways enriched among upregulated proteins were mainly involved in immune response and cell signalling and included the mitogen-activated protein kinase (MAPK) pathway.

Conclusion: In HFrEF, LBBB was associated with an altered circulating proteome. FGF2 and EGFR were highly dysregulated between the groups and the MAPK signalling pathway was affected, all of which may be pathophysiologically involved in the accelerated cardiac remodelling observed in these patients. These findings constitute a foundation for future studies of relevant LBBB-related biomarkers, treatment targets, and mechanisms behind the cardiac remodelling observed when LBBB is superimposed on HFrEF.

Keywords: Biomarkers; Dyssynchrony; Heart failure; Left bundle branch block; Proteomics; Remodelling.