Blood protein profile of left ventricular diastolic function

Abstract Background Left ventricular diastolic dysfunction inducing heart failure carries a large global burden of disease, yet the mechanisms behind the condition are poorly understood. Few studies have previously investigated the link between proteomics and diastolic echocardiographic parameters. Purpose To get insight into pathophysiological mechanisms of diastolic dysfunction by investigating relationships between a large set of proteins and indices of diastolic function in population-based studies. Methods Cardiovascular-related plasma proteins (92 proteins measured by proximity extension assay, CVD-panel, Olink) and echocardiography were assessed in the population-based studies Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS), (n = 1016, men all aged 70) and Prospective Investigation of Obesity, Energy and Metabolism (POEM) (n = 502, men all aged 50). PIVUS was used as discovery and Benjamini-Hochberg correction was applied for false discovery rate correction 0.05. POEM was used as the replication sample. The protein panel was compared to three diastolic echocardiographic parameters: the ratio of early and late diastolic filling of the left ventricle (E/A-ratio), isovolumic relaxation time (IVRT), and left atrium size (LA-size. In addition, 1322 proteins were examined in POEM (Explorer-panel) and related to indices of diastolic function. In the latter analysis, Bonferroni-correction was applied. Results A total of 7 of 92 proteins could be replicated regarding a significant relationship to the E/A-ratio. These proteins were: CD40 ligand (CD40-L), proto-oncogene tyrosine-protein kinase src (SRC), heat shock protein 27 (HSP-27), epidermal growth factor (EGF), TNF superfamily member 14 (TNFSFL14), vascular endothelial growth factor D (VEGF-D), and endothelial cell-specific molecule 1 (ESM-1). No proteins were related to IVRT or LA-size. Using the larger protein panel in POEM, an additional 10 proteins showed significant relations to the E/A-ratio. The 7 and 10 proteins and their correlation to the E/A-ratio are displayed in Table I. Two proteins showed significant relationship to LA-size: stem cell factor (SCF) and receptor for advanced glycation endproducts (RAGE). No proteins were significantly related to IVRT. Conclusion Key pathways linked to diastolic dysfunction were signal transduction, metabolism, and immune system-pathways. The study enhances understanding of the pathophysiology of diastolic dysfunction, offering potential for drug development in the future.