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- Faxén, Ulrika Ljung
(author)
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Heart failure : role of metabolic biomarkers, ejection fraction, and sex
- 2018
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Doctoral thesis (other academic/artistic)abstract
- 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 sexdifferences 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.
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| 2. |
- Ljung Faxén, Ulrika, et al.
(author)
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HFpEF and HFrEF Display Different Phenotypes as Assessed by IGF-1 and IGFBP-1
- 2017
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In: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 23:4, s. 293-303
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Journal article (peer-reviewed)abstract
- BackgroundAnabolic drive is impaired in heart failure with reduced ejection fraction (HFrEF) but insufficiently studied in heart failure with preserved ejection fraction (HFpEF). Insulin-like growth factor 1 (IGF-1) mediates growth hormone effects and IGF binding protein 1 (IGFBP-1) regulates IGF-1 activity. We tested the hypothesis that HFpEF and HFrEF are similar with regard to IGF-1 and IGFBP-1.Methods and ResultsIn patients with HFpEF (n = 79), HFrEF (n = 85), and controls (n = 136), we analyzed serum IGF-1 and IGFBP-1 concentrations, correlations, and associations with outcome. Age-standardized scores of IGF-1 were higher in HFpEF, median arbitrary units (interquartile range); 1.21 (0.57–1.96) vs HFrEF, 0.09 (-1.40–1.62), and controls, 0.22 (-0.47-0.96), P overall <.001. IGFBP-1 was increased in HFpEF, 48 (28–79), and HFrEF, 65 (29–101), vs controls, 27(14–35) µg/L, P overall <.001. These patterns persisted after adjusting for metabolic and HF severity confounders. IGF-1 was associated with outcomes in HFrEF, hazard ratio per natural logarithmic increase in IGF-1 SD score 0.51 (95% confidence interval 0.32–0.82, P = .005), but not significantly in HFpEF. IGFBP-1 was not associated with outcomes in either HFpEF nor HFrEF.ConclusionHFpEF and HFrEF phenotypes were similar with regard to increased IGFBP-1 concentrations but differed regarding IGF-1 levels and prognostic role. HFrEF and HFpEF may display different impairment in anabolic drive.
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| 3. |
- Ljung Faxen, Ulrika, et al.
(author)
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HFpEF and HFrEF exhibit different phenotypes as assessed by leptin and adiponectin
- 2017
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In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 228, s. 709-716
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Journal article (peer-reviewed)abstract
- Background: Heart failure with reduced ejection fraction (HFrEF) exhibits a reverse metabolic profile. Whether this profile exists in HF with preserved ejection fraction (HFpEF) is unknown. We tested the hypothesis that HFpEF and HFrEF are similar regarding concentrations of and prognostic impact of leptin and adiponectin.Methods: In patients with HFpEF(n = 79), HFrEF(n = 84), and controls(n = 71), we analyzed serum leptin and adiponectin concentrations, their correlations, and associations with outcome.Results: Leptin levels in HFpEF and HFrEF were increased (p < 0.05) compared to controls; with the highest levels in HFpEF, median (IQR), 23.1 (10.2-51.0), vs. HFrEF 15.0 (6.2-33.2), and vs. controls 10.8 (5.4-18.9) ng/mL. There was no difference between HFpEF and HFrEF p=0.125 (adjusted for gender, BMI and age). Leptin was inversely associated with NT-proBNP (r = -0.364 p = 0.001) and associated with better outcome in HFrEF (HR per ln increase of leptin 0.76, 95% CI 0.58-0.99, p = 0.044) but not in HFpEF.Crude levels of adiponectin were similar in HFpEF: 11.8 (7.9-20.1), HFrEF: 13.7 (7.0-21.1), and controls: 10.5 (7.4-15.1) mu g/L. In men, adjusted similarly as leptin, there was no difference between HFpEF and HFrEF, p = 0.310 but, compared to controls, higher levels in HFpEF (p - 0.044) and HFrEF (p - 0.001). Adiponectin correlated positively with NT-proBNP; r = 0.396 p < 0.001 and higher levels were associated with adverse outcome only in HFrEF (HR per ln increase 2.88 (95% CI 1.02-8.14, p = 0.045).Conclusion: HFpEF and HFrEF share elevated levels of leptin and adiponectin. However, the concept of reverse metabolic profile could not be confirmed in HFpEF, suggesting that HFpEF might have a conventional metabolic profile, rather than a distinct HF syndrome.
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| 4. |
- Ljung Faxen, Ulrika, et al.
(author)
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N-terminal pro-B-type natriuretic peptide in chronic heart failure: The impact of sex across the ejection fraction spectrum
- 2019
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In: International Journal of Cardiology. - : ELSEVIER IRELAND LTD. - 0167-5273 .- 1874-1754. ; 21, s. 225-225
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Journal article (peer-reviewed)abstract
- Objective: The aim was to assess sex-specific differences in N-terminal B-type natriuretic peptide (NT-proBNP) regarding concentrations, predictors of high concentrations, and prognostic role, in a large and unselected population with chronic heart failure (HF) with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF). Methods and results: In 9847 outpatients with HFpEF, HFmrEF, and HFrEF (49 vs. 35 vs. 25% females, respectively) from the Swedish HF Registry, median NT-proBNP concentrations were 1598 ng/L in females vs. 1310 ng/L in males in HFpEF, 1764 vs. 1464 ng/L in HFmrEF, and 2543 vs. 2226 ng/L in HFrEF (p amp;lt; 0.05 for all). The differences persisted after multiple adjustment. The largest sex-difference in NT-proBNP levels was observed in HFpEF with sinus rhythm, where median concentrations were 1.4 folds higher in females (923 vs. 647 ng/L). Independent predictors of NT-proBNP levels (defined as above the different medians according to sex and HF phenotype) were overall consistent across sexes and EF. NT-proBNP levels were similarly associated with risk of all-cause death/HF hospitalization in both sexes regardless of EF. Conclusion: Concentrations of NT-proBNPwere higher in females across the EF spectrum, with larger relative differences in HFpEF with sinus rhythm. However, similar predictors of high levels were observed in both sexes. There were no sex-differences in the prognostic role of NT-proBNP. These findings support the use of NT-proBNP for prognostic purposes in chronic HF, regardless of sex. (c) 2019 Elsevier B.V. All rights reserved.
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| 5. |
- Stolfo, Davide, et al.
(author)
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Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum Phenotyping, and Prognostic and Therapeutic Implications
- 2019
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In: JACC. Heart failure. - : ELSEVIER SCI LTD. - 2213-1779 .- 2213-1787. ; 21, s. 505-505
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Journal article (peer-reviewed)abstract
- OBJECTIVES This study assessed sex-related differences in a large cohort of unselected patients with heart failure (HF) across the ejection fraction (EF) spectrum. BACKGROUND Females are under-represented in randomized clinical trials. Potential sex-related differences in HF may question the generalizability of trials. METHODS In the Swedish Heart Failure Registry population multivariate Cox and logistic regression models were fitted to investigate differences in prognosis, prognostic predictors, and treatments across mates and females. RESULTS Of 42,987 patients, 37% were females (55% with HF with preserved EF [HFpEF], 39% with HF with mid-range EF [HFmrEF], and 29% with HF with reduced EF [HFrEF]). Females were older and more symptomatic and more likely to have hypertension and kidney disease but less likely to have diabetes and ischemic heart disease. After adjustments, females were more likely to use beta-blockers and digoxin but less likely to receive HF device therapy. Crude mortality/HF hospitalization rates for HFpEF (hazard ratio [HR]: 1.16) and HFmrEF (HR: 1.14) were significantly higher in females but lower in females with HFrEF (HR: 0.95). After adjustments, the risk was significantly tower in females regardless of EF (HR: 0.80 in HFrEF, HR: 0.91 in HFmrEF, and HR: 0.93 in HFpEF). The main sex-related differences in prognostic predictors concerned diabetes in HFrEF and anemia in HFmrEF. CONCLUSIONS Mates and females with HF showed different characteristics across the EF spectrum. Mates reported a lower crude risk of mortality/morbidity in HFpEF and HFmrEF but higher risk of HFrEF, although after adjustments, prognosis was better in females regardless of EF. The observed sex-related differences highlight the need for an adequate representation of females in HF randomized controlled trials to improve generatizabitity.
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