The plasma proteome is linked to echocardiographic parameters and stages of diastolic dysfunction, across the ejection fraction spectrum

Introduction: This study investigates the interplay between the circulating plasma proteome and echocardiographic parameters in patients across the spectrum of heart failure (HF) (ranging from patients at risk of/with preserved (HFpEF) to reduced (HFrEF) ejection fraction). Methods: Data from two cohort studies, HELPFul and Bio-SHiFT, were analyzed. We measured 4210 circulating plasma proteins in a total of 750 patients using SomaScan® proteomics. Echocardiographic parameters in both studies included left ventricular ejection fraction (LVEF) and the ratio of the peak early left ventricular (LV) filling velocity and early diastolic mitral annular velocity (E/e’). In further analyses, we classified patients in left ventricular diastolic dysfunction (LVDD) groups according to the prevailing guidelines. Results: Out of the 4210 plasma proteins, 21 proteins were significantly associated with E/e’ in patients at risk of/with HFpEF, whereas 9 proteins were associated with LVEF. Approximately 43 % (n = 1822) of the proteins showed significant interactions between E/e’ and HF subtype. All of these proteins showed weaker associations with E/e’ in patients at risk of/with HFpEF compared to the ones with HFrEF. These proteins were related to the extracellular matrix, cellular processes, insulin-like growth factor (IGF) transport, metabolic and catabolic processes. Furthermore, comparisons between LVDD groups and those with normal diastolic function identified 40 proteins associated with grade 2 (top 5: Cystatin C, TMEDA, NT-proBNP, GDF-15 and PXDN) and 198 with grade 3 LVDD (top 5: NT-proBNP, Cystatin C, PXDN, RNasa1, and Factor D). Conclusion: In patients at risk of/with HFpEF, biological processes and pathways showed weaker associations with E/e’ compared to patients with HFrEF. Varying pathways identified through proteomics were associated with deterioration of LVDD across the ejection fraction spectrum. Our results are in line with the mechanistic frameworks currently thought to underlie the various types of HF.