Circulating neuregulin1-β in heart failure with preserved and reduced left ventricular ejection fraction

Camilla Hage, Eva Wärdell, Cecilia Linde, Erwan Donal, Carolyn S P Lam, Claude Daubert, Lars H Lund, Agneta Månsson-Broberg, Camilla Hage, Eva Wärdell, Cecilia Linde, Erwan Donal, Carolyn S P Lam, Claude Daubert, Lars H Lund, Agneta Månsson-Broberg

Abstract

Aims: Neuregulin1-β (NRG1-β) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1-β is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF).

Methods and results: Circulating NRG1-β was quantified in 86 stable patients with HFpEF (EF ≥45% and N-terminal pro-brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1-β and the composite outcome of all-cause mortality/HF hospitalization in HFpEF and all-cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th-75th percentile) NRG1-β was 6.5 (2.1-11.3) ng/mL; in HFrEF, 3.6 (2.1-7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9-3.6) ng/mL; after HTx 2.1 (1.4-3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1-34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1-β was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04-2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1-β with outcomes was modified by ischaemia (log-rank P = 0.020; Pinteraction = 0.553) such that only in ischaemic patients, higher NRG1-β was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1-β trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48-1.05, P = 0.085).

Conclusions: Neuregulin1-β was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1-β with outcomes in non-ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1-β from microvascular endothelial dysfunction in the former (non-ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).

Trial registration: ClinicalTrials.gov NCT00774709.

Keywords: Coronary artery disease; HFpEF; HFrEF; Neuregulin1-β; Prognosis.

Conflict of interest statement

There are no conflicts of interest related to this study. However, to the extent that findings in KaRen and MetAnEnd may affect the use of heart failure drugs or devices, we disclose the following. C.H. received consulting fees from Novartis and Roche and speaker honoraria from MSD; L.H.L. received research grants from AstraZeneca, Relypsa, Novartis, Boerhinger Ingelheim, and Boston Scientific and consulting or speaker honoraria from Novartis, Vifor, Bayer, Sanofi, Fresenius, and Merck; C.L. received research grants, speaker honoraria, and consulting fees from Medtronic and speaker honoraria and consulting fees from St. Jude Medical; E.D. received speaker honoraria and consulting fees from Novartis and AstraZeneca; J.C.D. received research grants, speaker honoraria, and consulting fees from Medtronic and St. Jude Medical; C.S.P.L. was supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, WebMD Global LLC, and Radcliffe Group Ltd.

© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
Concentrations of log NRG1‐β in HFpEF, HFrEF, 1 year after left ventricular assist device implantation (LVAD), 1 year after heart transplantation (HTx), and healthy controls. All groups individually and overall versus control P < 0.001.
Figure 2
Figure 2
Association between log NRG1‐β concentrations and log NT‐proBNP and interaction of ischaemia (A) in HFpEF and (B) in HFrEF. Curves depict, with 95% confidence interval, presence of ischaemia in red and no ischaemia present in blue.
Figure 3
Figure 3
(A–D) Kaplan–Meier analyses displaying increased survival free of HF hospitalization by median NRG1‐β (A) in HFpEF displaying improved prognosis above median NRG1‐β; (B) in HFrEF displaying worse prognosis above median NRG1‐β; (C) in HFpEF displaying worse prognosis in the presence of ischaemia above median NRG1‐β but still improved prognosis in the absence of ischaemia; and (D) in HFrEF displaying worse prognosis above median NRG1‐β regardless of the presence of ischaemia.

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