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

Abstract

Aims: Iron deficiency (ID) is common in heart failure (HF) patients and negatively impacts symptoms and prognosis. The aetiology of ID in HF is largely unknown. We studied determinants and the biomarker profile of ID in a large international HF cohort.

Methods and results: We studied 2357 worsening HF patients from the BIOSTAT-CHF cohort. ID was defined as transferrin saturation <20%. Univariable and multivariable logistic regression models were constructed to identify determinants for ID. We measured 92 cardiovascular markers (Olink Cardiovascular III) to establish a biomarker profile of ID. The primary endpoint was the composite of all-cause mortality and first HF rehospitalization. Mean age (±standard deviation) of all patients was 69 ± 12.0 years, 26.1% were female and median N-terminal pro B-type natriuretic peptide levels (+interquartile range) were 4305 (2360-8329) ng/L. Iron deficiency was present in 1453 patients (61.6%), with highest prevalence in females (71.1% vs. 58.3%; P < 0.001). Independent determinants of ID were female sex, lower estimated protein intake, higher heart rate, presence of peripheral oedema and orthopnoea, chronic kidney disease, lower haemoglobin, higher C-reactive protein levels, lower serum albumin levels, and P2Y12 inhibitor use (all P < 0.05). None of these determinants were sex-specific. The biomarker profile of ID largely consisted of pro-inflammatory markers, including paraoxonase 3 (PON3) and tartrate-resistant acid phosphatase type 5. In multivariable Cox proportional hazard regression analyses, ID was associated to worse outcome, independently of predictors of ID (hazard ratio 1.25, 95% confidence interval 1.06-1.46; P = 0.007).

Conclusion: Our data suggest that the aetiology of ID in worsening HF is complex, multifactorial and seems to consist of a combination of reduced iron uptake (malnutrition, fluid overload), impaired iron storage (inflammation, chronic kidney disease), and iron loss (antiplatelets).

Keywords: Antiplatelets; Fluid retention; Heart failure; Inflammation; Iron deficiency; Protein intake.

Figure 1

(A) Restricted cubic spline of the association between estimated protein intake and the prevalence of iron deficiency. (B) Restricted cubic spline of the association between C-reactive protein and the prevalence of iron deficiency. (C) Restricted cubic spline of the association between serum albumin and the prevalence of iron deficiency. (D) Restricted cubic spline of the association between haemoglobin and the prevalence of iron deficiency. The solid lines indicate estimates of the prevalence of iron deficiency across continuous levels of estimated protein intake, C-reactive protein, serum albumin, and haemoglobin, fitted using logistic regression analysis. The dashed lines indicate 95% confidence intervals.

Figure 2

Biomarker expression profile (volcano plot) in iron-deficient heart failure patients compared to patients without iron deficiency. The volcano plot shows the difference in cardiovascular biomarker expression in patients with and without iron deficiency. Each dot represents one of the 92 biomarkers of the Olink Cardiovascular III panel. On the x-axis, the log₂-fold change in biomarker expression is depicted (positive log₂-fold change is higher biomarker expression in patients with iron deficiency; negative log₂-fold change is lower biomarker expression in patients with iron deficiency), while the y-axis shows the magnitude of the biomarker expression difference as −log₁₀ of the P-value. Red dots are biomarkers with a significant up- or down-regulation in patients with iron deficiency (corrected for a false discovery rate of 5%); green dots indicate biomarkers with an absolute log₂-fold change of >0.25. Most biomarkers were significantly up-regulated in patients with ID (n = 39, 42.4%), while 15 biomarkers had significantly lower expression (16.3%). FABP4, fatty acid binding protein 4; GDF15, growth differentiation factor 15; NT-proBNP, N-terminal prohormone brain natriuretic peptide; OPN, osteopontin; PON3, paraoxonase 3; ST2, ST2 protein; TNF-R1, tumour necrosis factor receptor 1; TR, transferrin receptor protein 1; TR-AP, tartrate-resistant acid phosphatase type 5.

Take home figure

Determinants of iron deficiency in heart failure. Several graphical elements in this figure are provided by Freepik and DinosoftLabs from www.flaticon.com.