Identification of determinants of iron deficiency in worsening HF

Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use

Literature - Van der Wal H, Grote Beverborg N, Dickstein K et al., - Eur Heart J 2019 ehz680,

Introduction and methods

Iron deficiency (ID) has adverse clinical and prognostic consequences in patients with chronic heart failure (HF)[1-4]. Little is known about the pathophysiology and etiology of ID in HF, but suggested mechanisms include poor dietary iron intake, drug interactions, (occult) gastrointestinal blood loss due to antiplatelet drugs and anticoagulants, and hepcidin-induced iron entrapment due to chronic low-grade inflammation [5]. ID seems to be more prevalent in female than in male HF patients, but the factors driving this sex difference are unknown.

This study identified determinants of ID in a large international cohort of patients with worsening HF, in an attempt to find sex-specific clinical and biochemical predictors of ID. Furthermore, a CV biomarker profile of patients with ID was established. Data were used of the BIOSTAT-CHF study [6-8]. Patients hospitalized for HF or presenting with worsening HF in an outpatient setting were eligible if they had LVEF ≤40% or BNP >400 ng/L or NT-proBNP >2000 ng/L. Eligible patients had to receive suboptimal evidence-based HF treatment. Physicians were encouraged to uptitrate ACEi, ARB and/or beta-blockers in the 3 months following inclusion. Serum for iron status analysis was available in 2357 of BIOSTAT-CHF patients. Median follow-up was 21 months. ID was defined as transferrin saturation (TSAT) <20%, with TSAT calculated as follows: [72.17 * iron (mg/dL)]/transferrin (mg/dL).

Main results

  • 1453 Patients (61.6%) had ID, with the highest prevalence in females (71.1% vs. 58.3%, P<0.001).
  • Independent determinants of ID were lower estimated protein intake, higher heart rate, presence of peripheral edema and orthopnea, history of renal disease, lower hemoglobin, higher CRP, lower serum albumin and use of P2Y12 inhibitors (z-statistics ranging from 2.46 to 10.14, all P<0.005). The c-statistic of this model was 0.76.
  • No significant interaction was seen for sex with any of the determinants of ID.
  • Patients with ID showed significantly altered levels of several biomarkers. After correcting for the determinants for ID, only paraoxonase 3 (PON3) and tartrate-resistant acid phosphatase

type 5 (TR-AP, both downregulated) and ST2 protein (ST2), NT-proBNP and transferrin receptor protein 1 (TR, all three upregulated) were significantly associated with ID.

  • ID was independently associated with all-cause mortality and first HF rehospitalization, after correction for the BIOSTAT prediction model (HR: 1.30, 95%CI: 1.12-1.50, P=0.0005) and the logistic regression prediction (HR: 1.25, 95%CI: 1.06-1.46, P=0.007).


In a large cohort of patients with worsening HF, female sex, lower estimated protein intake, higher

heart rate, presence of peripheral edema and orthopnea, history of renal disease, lower hemoglobin, higher CRP, lower serum albumin and antiplatelet use were identified as independent determinants of ID, in a similar way for both sexes. The data suggest that the etiology of ID in worsening HF is multifactorial and may involve a combination of reduced iron uptake, impaired iron storage and iron loss. The adverse prognostic consequences of ID are independent of these predictors. A biomarker profile in which pro-inflammatory markers seem upregulated was found in patients with ID.


1. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165:575–582.e3.

2. van Veldhuisen DJ, Anker SD, Ponikowski P, Macdougall IC. Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches. Nat Rev Cardiol 2011;8:485–493.

3. Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010;31:1872–1880.

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5. Jankowska EA, von Haehling S, Anker SD, et al. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J 2013;34:816–829.

6. Voors AA, Anker SD, Cleland JG, et al. A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF. Eur J Heart Fail 2016;18:716–726.

7. Ouwerkerk W, Voors AA, Anker SD, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study. Eur Heart J 2017;38:1883–1890.

8. Voors AA, Ouwerkerk W, Zannad F, et al. Development and validation of multivariable models to predict mortality and hospitalization in patients with heart failure. Eur J Heart Fail 2017;19:627–634

Find this article online at Eur Heart J

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