Heart failure : role of metabolic biomarkers, ejection fraction, and sex

Background: Heart failure (HF) is common and associated with impaired quality of life (QoL) and poor prognosis. There is a ternary classification of HF based on ejection fraction (EF): HF with preserved(HFpEF), mid-range EF(HFmrEF), and reduced EF(HFrEF). How to treat the syndrome of HFpEF, and the extent to which HFpEF and HFrEF are similar, still remain elusive. Likewise, despite the fact that half of the patients with HF are women, the role of sex in HF is often overlooked.

Aims: (1) To investigate whether HFpEF and HFrEF share features of anabolic impairment regarding insulin-like growth factor 1 (IGF-1) and IGF binding protein-1 (IGFBP-1). (2) To assess levels of the obesity related peptides, leptin and adiponectin, and whether the obesity paradox exists in HFpEF. (3) To investigate potential sex-specific differences in QoL in HFpEF. (4) To assess the impact of sex on N-terminal B-type natriuretic peptide (NT-proBNP) in chronic HF across the EF spectrum.

Results: The IGF-1 axis in HFpEF and HFrEF Serum IGF-1and IGFBP-1 concentrations and their associations with other biomarkers and outcomes were analysed in patients with HFpEF and HFrEF. IGF-1 concentrations were lower and associated with poor prognosis in HFrEF only. However, IGFBP-1 was increased and associated with NTproBNP in both HF phenotypes. This suggests inhibition of the IGF-1-axis in both syndromes and a possible mechanistic link between IGFBP-1 and natriuretic peptides in HF. Leptin and adiponectin in HFpEF and HFrEF. Serum leptin and adiponectin concentrations and their associations with other biomarkers and outcomes in patients with HFpEF and HFrEF were analysed. Our findings indicate that the two HF phenotypes share elevated levels of leptin and adiponectin. The obesity paradox regarding leptin, with higher levels being associated with better outcome was nevertheless only demonstrated in HFrEF, pointing towards a more conventional metabolic profile in HFpEF. Sex and quality of life in HFpEF. We assessed QoL in HFpEF through generic and HF specific QoL instruments. Women with HFpEF express worse global QoL than men. Overall, QoL was only weakly associated with measures of HF severity and the associations were weaker in women. In men only, poor QoL was associated with worse outcome. Overall, this suggests, that in order to improve QoL in HFpEF patients, in particular in women, other factors than HF must be addressed. Impact of sex on NT-proBNP across HF phenotypes. We analysed concentrations of NT-proBNP, and associations with clinical characteristics and outcomes in the three HF phenotypes, by sex. Women with chronic HF across the entire EF spectrum have higher NT-proBNP concentrations than men. However, associations between NT-proBNP concentrations and clinical characteristics as well as outcomes are largely similar. This supports the current use of NT-proBNP for prognostic purposes across HF phenotypes but the impact of sex differences in the lower NT-proBNP range warrants further investigation.

Conclusion: HFpEF and HFrEF display important similarities and differences related to metabolic biomarkers, natriuretic peptides, and sex. The impact of these factors on the pathogenesis of and in manifest HF, and as potential therapeutic targets warrants further investigation.

List of scientific papers

I. HFpEF and HFrEF display different phenotypes as assessed by IGF-1 and IGFBP-1. Faxén UL, Hage C, Benson L, Zabarovskaja S, Andreasson A, Donal E, Daubert JC, Linde C, Brismar K, Lund LH. Journal of Cardiac Failure. 2017, Apr, 23(4):293-303.
https://doi.org/10.1016/j.cardfail.2016.06.008

II. HFpEF and HFrEF exhibit different phenotypes as assessed by leptin and adiponectin. Faxén UL, Hage C, Andreasson A, Donal E, Daubert JC, Linde C, Brismar K, Lund LH. International Journal of Cardiology. 2017 Feb 1; 228 709-716.
https://doi.org/10.1016/j.ijcard.2016.11.194

III. Patient reported outcome in HFpEF: Sex-specific differences in quality of life and association with outcome. Faxén UL, Hage C, Donal E, Daubert JC, Linde C, Lund LH. International Journal of Cardiology. 2018, 267 128-232.
https://doi.org/10.1016/j.ijcard.2018.04.102

IV. N-terminal pro-B-type natriuretic peptide in chronic heart failure: The impact of sex across the ejection fraction spectrum. Faxén UL, Strömberg A, Dahlström U, Andersson DC, Lund LH, Savarese G. [Manuscript]