Original Investigation
Identifying Pathophysiological Mechanisms in Heart Failure With Reduced Versus Preserved Ejection Fraction

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Abstract

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)

Key Words

biomarkers
HFpEF
HFrEF
network analysis
pathophysiology

Abbreviations and Acronyms

GDF
growth differentiation factor
HFmrEF
heart failure with a mid-range ejection fraction
HFpEF
heart failure with a preserved ejection fraction
HFrEF
heart failure with a reduced ejection fraction
IL1RL1
interleukin-1 receptor-like type 1
ITGB2
integrin subunit beta 2
NT-proBNP
N-terminal pro–B-type natriuretic peptide

Cited by (0)

BIOSTAT-CHF was funded by the European Commission (FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29). Support was also provided by the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON2014-11 RECONNECT. Dr. Westenbrink has received consulting and speaker fees from Boehringer Ingelheim and Bayer; and has received a travel grant from Novartis. Dr. van Veldhuisen has received board membership fees or travel expenses from Novartis, Johnson & Johnson, and Vifor. Dr. Metra has received consulting honoraria from Amgen, AstraZeneca, Bayer, Novartis, Relypsa, Servier, Stealth Therapeutics, and Trevena; and speaker fees from Abbott Vascular, Novartis, and Servier. Dr. Anker has received grants from Vifor and Abbott Vascular; and fees for consultancy or speaking from Vifor, V-Wave, Impulse Dynamics, Bayer, Boehringer Ingelheim, Brahms, Janssen, Novartis, Servier, Stealth Peptides, and ASTRA. Dr. Cleland has served on the advisory board for Amgen, Novartis, and Medtronic; and has received research grants from Amgen, Medtronic, Novartis, Philips, Stealth Biotherapeutics, and Bristol-Myers Squibb. Dr. Filippatos has received committee fees and/or research grants from Novartis, Bayer, Medtronic, Vifor, and Servier; has received a research grant from the European Union; and is a member of the steering committee of trials sponsored by Novartis and Servier. Dr. Lang has received consultancy fees and/or research grants from Amgen, AstraZeneca, Merck Sharp & Dohme, Novartis, and Servier. Dr. Voors has received consultancy fees and/or research grants from Alere, Amgen, Bayer, Boehringer Ingelheim, Cardio3Biosciences, Celladon, GlaxoSmithKline, Merck/Merck Sharp & Dohme, Novartis, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, Vifor, and ZS Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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