Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial

Christiane E Angermann; Susanne Sehner; Louisa M S Gerhardt; Carlos G Santos-Gallego; Juan Antonio Requena-Ibanez; Tanja Zeller; Christoph Maack; Javier Sanz; Stefan Frantz; Georg Ertl; Juan J Badimon

doi:10.1093/eurheartj/ehae917

Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial

Christiane E Angermann, Susanne Sehner, Louisa M S Gerhardt, Carlos G Santos-Gallego, Juan Antonio Requena-Ibanez, Tanja Zeller, Christoph Maack, Javier Sanz, Stefan Frantz, Georg Ertl, Juan J Badimon

Institute of Cardiogenetics

17 Citations (Scopus)

Abstract

BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) impact iron metabolism in patients with heart failure but mechanisms are incompletely understood. This post hoc analysis explored interrelations between iron homeostasis, cardiac structure/function, exercise capacity, haematopoiesis, and sympathetic activity at baseline, and the effects of 6-month treatment with empagliflozin vs. placebo by anaemia status in EMPATROPISM-FE study participants.

METHODS: Myocardial iron content (MIC, estimated by cardiac magnetic resonance T2* imaging), left ventricular (LV) volumes and LV ejection fraction (LVEF), exercise capacity, laboratory iron markers (LIM), haemoglobin/haematocrit, erythropoietin, and plasma norepinephrine were determined at baseline and 6 months.

RESULTS: At baseline, 24/80 participants (30%) had anaemia (haemoglobin < 13/<12 mg/dL in men/women). Patients with vs. without anaemia had higher T2* (indicating lower MIC, P < .001), lower peak oxygen consumption (VO2max, P = .024) and hepcidin (P = .017), and higher erythropoietin (P = .040) and norepinephrine (P = .016). Across subgroups, lower MIC correlated with higher LV volumes (P < .01) and norepinephrine (P < .001), and lower LVEF (P < .01), VO2max (P < .001) and haemoglobin/haematocrit (P < .001). Associations with LIM were poor (all P > .10). Empagliflozin increased MIC (P < .012), improved exercise capacity, and activated haematopoiesis. Changes in LIM and norepinephrine suggested progressive systemic iron depletion and sympatholysis. LV reverse remodelling was greater in individuals with anaemia.

CONCLUSIONS: Dysregulated cellular iron uptake/availability may be a shared mechanism in myocardial structural/functional impairment, reduced exercise capacity, and restricted haematopoiesis in heart failure, which are worse in patients with anaemia, and improve with empagliflozin. Empagliflozin increases MIC and decreases norepinephrine. Given this inverse association, sympatholysis may help explain the diverse cardiac and systemic benefits from SGLT2i therapy.

CLINICAL TRIAL REGISTRATION: NCT03485222 (www.clinicaltrials.gov).

Original language	English
Journal	European Heart Journal
Volume	46
Issue number	16
Pages (from-to)	1507-1523
Number of pages	17
ISSN	0195-668X
DOIs	https://doi.org/10.1093/eurheartj/ehae917
Publication status	Published - 22.04.2025

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10.1093/eurheartj/ehae917

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Angermann, C. E., Sehner, S., Gerhardt, L. M. S., Santos-Gallego, C. G., Requena-Ibanez, J. A., Zeller, T., Maack, C., Sanz, J., Frantz, S., Ertl, G., & Badimon, J. J. (2025). Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial. European Heart Journal, 46(16), 1507-1523. https://doi.org/10.1093/eurheartj/ehae917

@article{38f885389ef14d389fe5eb6fdcf3ae75,

title = "Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial",

abstract = "BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) impact iron metabolism in patients with heart failure but mechanisms are incompletely understood. This post hoc analysis explored interrelations between iron homeostasis, cardiac structure/function, exercise capacity, haematopoiesis, and sympathetic activity at baseline, and the effects of 6-month treatment with empagliflozin vs. placebo by anaemia status in EMPATROPISM-FE study participants.METHODS: Myocardial iron content (MIC, estimated by cardiac magnetic resonance T2* imaging), left ventricular (LV) volumes and LV ejection fraction (LVEF), exercise capacity, laboratory iron markers (LIM), haemoglobin/haematocrit, erythropoietin, and plasma norepinephrine were determined at baseline and 6 months.RESULTS: At baseline, 24/80 participants (30\%) had anaemia (haemoglobin < 13/<12 mg/dL in men/women). Patients with vs. without anaemia had higher T2* (indicating lower MIC, P < .001), lower peak oxygen consumption (VO2max, P = .024) and hepcidin (P = .017), and higher erythropoietin (P = .040) and norepinephrine (P = .016). Across subgroups, lower MIC correlated with higher LV volumes (P < .01) and norepinephrine (P < .001), and lower LVEF (P < .01), VO2max (P < .001) and haemoglobin/haematocrit (P < .001). Associations with LIM were poor (all P > .10). Empagliflozin increased MIC (P < .012), improved exercise capacity, and activated haematopoiesis. Changes in LIM and norepinephrine suggested progressive systemic iron depletion and sympatholysis. LV reverse remodelling was greater in individuals with anaemia.CONCLUSIONS: Dysregulated cellular iron uptake/availability may be a shared mechanism in myocardial structural/functional impairment, reduced exercise capacity, and restricted haematopoiesis in heart failure, which are worse in patients with anaemia, and improve with empagliflozin. Empagliflozin increases MIC and decreases norepinephrine. Given this inverse association, sympatholysis may help explain the diverse cardiac and systemic benefits from SGLT2i therapy.CLINICAL TRIAL REGISTRATION: NCT03485222 (www.clinicaltrials.gov).",

author = "Angermann, \{Christiane E\} and Susanne Sehner and Gerhardt, \{Louisa M S\} and Santos-Gallego, \{Carlos G\} and Requena-Ibanez, \{Juan Antonio\} and Tanja Zeller and Christoph Maack and Javier Sanz and Stefan Frantz and Georg Ertl and Badimon, \{Juan J\}",

note = "{\textcopyright} The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2025",

month = apr,

day = "22",

doi = "10.1093/eurheartj/ehae917",

language = "English",

volume = "46",

pages = "1507--1523",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "16",

}

Angermann, CE, Sehner, S, Gerhardt, LMS, Santos-Gallego, CG, Requena-Ibanez, JA, Zeller, T, Maack, C, Sanz, J, Frantz, S, Ertl, G & Badimon, JJ 2025, 'Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial', European Heart Journal, vol. 46, no. 16, pp. 1507-1523. https://doi.org/10.1093/eurheartj/ehae917

Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial. / Angermann, Christiane E; Sehner, Susanne; Gerhardt, Louisa M S et al.
In: European Heart Journal, Vol. 46, No. 16, 22.04.2025, p. 1507-1523.

Research output: Journal Articles › Journal articles › Research › peer-review

TY - JOUR

T1 - Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction

T2 - the EMPATROPISM-FE trial

AU - Angermann, Christiane E

AU - Sehner, Susanne

AU - Gerhardt, Louisa M S

AU - Santos-Gallego, Carlos G

AU - Requena-Ibanez, Juan Antonio

AU - Zeller, Tanja

AU - Maack, Christoph

AU - Sanz, Javier

AU - Frantz, Stefan

AU - Ertl, Georg

AU - Badimon, Juan J

PY - 2025/4/22

Y1 - 2025/4/22

N2 - BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) impact iron metabolism in patients with heart failure but mechanisms are incompletely understood. This post hoc analysis explored interrelations between iron homeostasis, cardiac structure/function, exercise capacity, haematopoiesis, and sympathetic activity at baseline, and the effects of 6-month treatment with empagliflozin vs. placebo by anaemia status in EMPATROPISM-FE study participants.METHODS: Myocardial iron content (MIC, estimated by cardiac magnetic resonance T2* imaging), left ventricular (LV) volumes and LV ejection fraction (LVEF), exercise capacity, laboratory iron markers (LIM), haemoglobin/haematocrit, erythropoietin, and plasma norepinephrine were determined at baseline and 6 months.RESULTS: At baseline, 24/80 participants (30%) had anaemia (haemoglobin < 13/<12 mg/dL in men/women). Patients with vs. without anaemia had higher T2* (indicating lower MIC, P < .001), lower peak oxygen consumption (VO2max, P = .024) and hepcidin (P = .017), and higher erythropoietin (P = .040) and norepinephrine (P = .016). Across subgroups, lower MIC correlated with higher LV volumes (P < .01) and norepinephrine (P < .001), and lower LVEF (P < .01), VO2max (P < .001) and haemoglobin/haematocrit (P < .001). Associations with LIM were poor (all P > .10). Empagliflozin increased MIC (P < .012), improved exercise capacity, and activated haematopoiesis. Changes in LIM and norepinephrine suggested progressive systemic iron depletion and sympatholysis. LV reverse remodelling was greater in individuals with anaemia.CONCLUSIONS: Dysregulated cellular iron uptake/availability may be a shared mechanism in myocardial structural/functional impairment, reduced exercise capacity, and restricted haematopoiesis in heart failure, which are worse in patients with anaemia, and improve with empagliflozin. Empagliflozin increases MIC and decreases norepinephrine. Given this inverse association, sympatholysis may help explain the diverse cardiac and systemic benefits from SGLT2i therapy.CLINICAL TRIAL REGISTRATION: NCT03485222 (www.clinicaltrials.gov).

AB - BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) impact iron metabolism in patients with heart failure but mechanisms are incompletely understood. This post hoc analysis explored interrelations between iron homeostasis, cardiac structure/function, exercise capacity, haematopoiesis, and sympathetic activity at baseline, and the effects of 6-month treatment with empagliflozin vs. placebo by anaemia status in EMPATROPISM-FE study participants.METHODS: Myocardial iron content (MIC, estimated by cardiac magnetic resonance T2* imaging), left ventricular (LV) volumes and LV ejection fraction (LVEF), exercise capacity, laboratory iron markers (LIM), haemoglobin/haematocrit, erythropoietin, and plasma norepinephrine were determined at baseline and 6 months.RESULTS: At baseline, 24/80 participants (30%) had anaemia (haemoglobin < 13/<12 mg/dL in men/women). Patients with vs. without anaemia had higher T2* (indicating lower MIC, P < .001), lower peak oxygen consumption (VO2max, P = .024) and hepcidin (P = .017), and higher erythropoietin (P = .040) and norepinephrine (P = .016). Across subgroups, lower MIC correlated with higher LV volumes (P < .01) and norepinephrine (P < .001), and lower LVEF (P < .01), VO2max (P < .001) and haemoglobin/haematocrit (P < .001). Associations with LIM were poor (all P > .10). Empagliflozin increased MIC (P < .012), improved exercise capacity, and activated haematopoiesis. Changes in LIM and norepinephrine suggested progressive systemic iron depletion and sympatholysis. LV reverse remodelling was greater in individuals with anaemia.CONCLUSIONS: Dysregulated cellular iron uptake/availability may be a shared mechanism in myocardial structural/functional impairment, reduced exercise capacity, and restricted haematopoiesis in heart failure, which are worse in patients with anaemia, and improve with empagliflozin. Empagliflozin increases MIC and decreases norepinephrine. Given this inverse association, sympatholysis may help explain the diverse cardiac and systemic benefits from SGLT2i therapy.CLINICAL TRIAL REGISTRATION: NCT03485222 (www.clinicaltrials.gov).

U2 - 10.1093/eurheartj/ehae917

DO - 10.1093/eurheartj/ehae917

M3 - Journal articles

C2 - 39907687

SN - 0195-668X

VL - 46

SP - 1507

EP - 1523

JO - European Heart Journal

JF - European Heart Journal

IS - 16

ER -

Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial

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