Predicting remission and recovery in patients with heart failure

Hypothesis: Heart failure with improved ejection fraction (HFiEF) is a distinct HF phenotype with good prognosis and a characteristic omic biomarker pattern that may indicate the biological pathways involved in reverse remodelling of the heart. These pathways may represent novel biotargets for therapeutic design.

Experimental Methods and Research Plan: Fifty patients with HFiEF will be matched with 50 patients with HFrEF whose EF remained<40% throughout the observation period (matching will be performed for age, sex, renal function, comorbidities). Plasma samples on admission will be prepared for proteomic studies using previously published methods for depletion of high-abundant proteins and using solid phase extraction on calcium silicate matrix4,5,6. Tryptic digests of proteins will be analysed using reverse phase liquid chromatography high-definition mass spectrometry HDMSE, with ion mobility to enable peptide separation according to collisional cross-sectional area4. Raw data files will be processed using Progenesis QI (Non-linear dynamics, Waters Corp.) to provide absolute quantification of proteins from the spiked-in S.Cerevisiae alcohol dehydrogenase standard. The high-dimensional data will be mined using statistical and bioinformatics packages to reveal the most differentially expressed proteins. These will then be verified using parallel reaction monitoring with appropriately labelled peptides. The discovery study is powered at 80% to detect a standardised difference of 0.5 at p=0.01. Models for predicting HFiEF will be built using these differentially expressed proteins and those revealed independently on Olink platform panels, which employ a multiplexed targeted approach using a proprietary proximity extension assay technology. The combined omic signature will be subject to pathway analysis to reveal relevant biological processes which could be biotargets for therapy6, and could be tested as a prognostic marker in the BIOSTAT-CHF validation cohort.

Expected outcomes and Impact: On completion of this project, an omic signature for HFiEF will be generated which will enable stratification of HF patients into those who do not improve and those who are likely to show reverse cardiac remodelling. Identification of this subgroup of HFiEF is the first step towards defining patients who will recover fully from HF, and may also reveal relevant pathophysiological pathways that could be targeted to achieve this.