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Protein biomarkers associated with left bundle branch block in patients with heart failure and reduced ejection
Karin Ljung1,2, Christian Vestman1,2, Ulrika Reistam1,2
1Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.
Insights
Left bundle branch block (LBBB) in heart failure with reduced ejection fraction (HFrEF) alters plasma proteins, including FGF2 and EGFR. This proteomic shift may drive cardiac remodelling in HFrEF patients with LBBB.
Area of Science:
- Cardiology
- Proteomics
- Biochemistry
Background:
- Left bundle branch block (LBBB) is prevalent in heart failure with reduced ejection fraction (HFrEF), causing cardiac dyssynchrony and accelerating remodelling.
- The underlying biological mechanisms of LBBB-associated cardiac remodelling are not fully understood.
Purpose of the Study:
- To investigate the plasma proteome in patients with HFrEF and LBBB compared to those with HFrEF without LBBB.
- To identify proteins and pathways dysregulated in HFrEF + LBBB, potentially contributing to cardiac remodelling.
Main Methods:
- A cohort of 4254 patients from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure was analyzed.
- 268 patients with HFrEF and LBBB (cases) were matched with 268 patients with HFrEF without LBBB (controls) using propensity score matching.
- Relative plasma concentrations of 364 proteins were compared between groups using proximity extension assay.
Main Results:
- 11% (41 out of 364) of assessed proteins showed altered expression in HFrEF + LBBB compared to HFrEF - LBBB.
- Key proteins with altered expression included decreased Fibroblast Growth Factor 2 (FGF2) and increased Epidermal Growth Factor Receptor (EGFR).
- Upregulated proteins were enriched in pathways related to immune response, cell signalling, and the mitogen-activated protein kinase (MAPK) pathway.
Conclusions:
- Left bundle branch block in HFrEF is associated with a distinct circulating proteome.
- Dysregulation of FGF2, EGFR, and the MAPK pathway may play a pathophysiological role in accelerated cardiac remodelling in HFrEF + LBBB.
- These findings provide a basis for identifying biomarkers and therapeutic targets for LBBB-related cardiac remodelling in HFrEF.
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.
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