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

Camilla Hage (1) , Eva Wärdell (1) , Cecilia Linde (1) , Erwan Donal (2, 3) , Carolyn S. P. Lam (4, 5) , Claude Daubert (3) , Lars H. Lund (1) , Agneta Månsson-Broberg (1)

1 Karolinska Institutet [Stockholm]
2 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
3 CIC-IT Rennes
4 Duke-National University of Singapore Graduate Medical School
5 UMCG - University Medical Center Groningen [Groningen]

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; P = 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).

Mots clés: Neuregulin1-β; Prognosis; Coronary artery disease; HFrEF; HFpEF

Domaines: Cardiologie et système cardiovasculaire

Camilla Hage, Eva Wärdell, Cecilia Linde, Erwan Donal, Carolyn S. P. Lam, et al.. Circulating neuregulin1-beta in heart failure with preserved and reduced left ventricular ejection fraction. ESC Heart Failure, 2020, 7 (2), pp.445-455. ⟨10.1002/ehf2.12615⟩. ⟨hal-02469267⟩