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

AIMS: Neuregulin1-ß (NRG1-ß) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1-ß 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-ß 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-ß 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-ß 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-ß 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-ß with outcomes was modified by ischaemia (log-rank P = 0.020; Pinteraction = 0.553) such that only in ischaemic patients, higher NRG1-ß was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1-ß trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48-1.05, P = 0.085). CONCLUSIONS: Neuregulin1-ß was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1-ß with outcomes in non-ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1-ß 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).