Key result
HFrEF biomarkers link to metabolism and proliferation while HFpEF profiles associate with inflammation and matrix remodeling.
Why the study?
Information on the pathophysiological differences between HFrEF versus HFpEF is needed.
What are the distinct pathophysiological mechanisms and biological pathways differentiating HFrEF from HFpEF based on biomarker network analysis?
Observational (n=2,348)
What are the distinct pathophysiological mechanisms and biological pathways differentiating HFrEF from HFpEF based on biomarker network analysis?
Network analysis of biomarkers reveals distinct pathophysiological pathways in heart failure, with HFrEF driven by cellular proliferation and metabolism, and HFpEF driven by inflammation and extracellular matrix reorganization.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“This combination of greater precision medicine tools and the growing statistical implausibility of sequential negative heart failure trials has led to a breaking point realization: perhaps the fault lies in our current approach to heart failure rather than deficiencies in prior therapeutic strategies.”
Highlights divergent HFrEF/HFpEF pathways; hypothesis-generating and requires prospective validation before clinical translation.
BACKGROUND Information on the pathophysiological differences between heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF) is needed OBJECTIVES: The purpose of this study was to establish biological pathways specifically related to HFrEF and HFpEF. METHODS The authors performed a network analysis to identify unique biomarker correlations in HFrEF and HFpEF using 92 biomarkers from different pathophysiological domains in a cohort of 1,544 heart failure (HF) patients. Data were independently validated in 804 patients with HF. Networks were enriched with existing knowledge on protein-protein interactions and translated into biological pathways uniquely related to HFrEF, HF with a midrange ejection fraction, and HFpEF. RESULTS In the index cohort (mean age 74 years; 34% female), 718 (47%) patients had HFrEF (left ventricular ejection fraction [LVEF] <40%) and 431 (27%) patients had HFpEF (LVEF ≥50%). A total of 8 (12%) correlations were unique for HFrEF and 6 (9%) were unique to HFpEF. Central proteins in HFrEF were N-terminal B-type natriuretic peptide, growth differentiation factor-15, interleukin-1 receptor type 1, and activating transcription factor 2, while central proteins in HFpEF were integrin subunit beta-2 and catenin beta-1. Biological pathways in HFrEF were related to DNA binding transcription factor activity, cellular protein metabolism, and regulation of nitric oxide biosynthesis. Unique pathways in patients with HFpEF were related to cytokine response, extracellular matrix organization, and inflammation. Biological pathways of patients with HF with a midrange ejection fraction were in between HFrEF and HFpEF. CONCLUSIONS Network analysis showed that biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas biomarker profiles specific for HFpEF are related to inflammation and extracellular matrix reorganization. (The BIOlogy Study to TAilored Treatment in Chronic Heart Failure [BIOSTAT-CHF]; EudraCT 2010-020808-29).
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Tromp et al. (2018) conducted an observational in Heart failure (n=2,348). Heart failure with reduced ejection fraction (HFrEF) vs. Heart failure with preserved ejection fraction (HFpEF) was evaluated on Unique biomarker correlations and biological pathways. Biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas profiles specific for HFpEF are related to inflammation and extracellular matrix reorganization.
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