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Iron Deficiency in Worsening Heart Failure Is Associated with Reduced Estimated Protein Intake, Fluid Retention, Inflammation, and Antiplatelet Use

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Iron Deficiency in Worsening Heart Failure Is Associated with Reduced Estimated Protein Intake, Fluid Retention, Inflammation, and Antiplatelet Use European Heart Journal (2019) 40, 3616–3625 CLINICAL RESEARCH doi:10.1093/eurheartj/ehz680 Heart failure/cardiomyopathy Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use Haye H. van der Wal1, Niels Grote Beverborg 1, Kenneth Dickstein2,3, Stefan D. Anker 4, Chim C. Lang5, Leong L. Ng 6,7, Dirk J. van Veldhuisen1, Adriaan A. Voors1, and Peter van der Meer1* 1Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, The Netherlands; 2University of Bergen, 5007 Bergen, Norway; 3Stavanger University Hospital, Gerd-Ragna Bloch Thorsens Gate 8, 4011 Stavanger, Norway; 4Division of Cardiology and Metabolism-Heart Failure, Cachexia & Sarcopenia; Department of Cardiology (CVK), Berlin-Brandenburg Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charite´ University Medicine, Charite´pl. 1, 10117 Berlin, Germany; 5Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, UK; 6Department of Cardiovascular Sciences, University of Leicester, Groby Road, Leicester, LE3 9QP, UK; and 7NIHR Leicester Biomedical Research Unit, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK Received 18 April 2019; revised 4 July 2019; editorial decision 2 September 2019; accepted 10 September 2019; online publish-ahead-of-print 26 September 2019 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 inter- national HF cohort. ................................................................................................................................................................................................... Methods We studied 2357 worsening HF patients from the BIOSTAT-CHF cohort. ID was defined as transferrin saturation and results <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 pri- mary endpoint was the composite of all-cause mortality and first HF rehospitalization. Mean age (±standard devi- ation) of all patients was 69 ± 12.0 years, 26.1% were female and median N-terminal pro B-type natriuretic peptide levels (þinterquartile 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 mul- tivariable Cox proportional hazard regression analyses, ID was associated to worse outcome, independently of pre- dictors 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 kid- ney disease), and iron loss (antiplatelets). ᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿ Keywords Heart failure • Iron deficiency • Inflammation • Protein intake • Fluid retention • Antiplatelets * Corresponding author. Tel: þ31 50 3612355, Fax: þ31 50 3614391, Email: [email protected] VC The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Iron deficiency in worsening heart failure 3617 . bioinformatics (e.g. Uniprot and DisGeNET) and by consulting experts in Introduction . the cardiovascular field. All biomarkers were measured by Olink Numerous studies showed the adverse clinical and prognostic conse- . Proteomics (Uppsala, Sweden) using the Proximity Extension Assay tech- . 11 quences of iron deficiency (ID) in patients with chronic heart failure . nology, as previously described. Results are reported as Normalized 1–4 . (HF). Despite the significant prevalence of ID in HF, its pathophysi- . Protein eXpression (NPX) on a log2 scale. ology and aetiology are not well-understood. Suggested mechanisms . Definitions and study endpoints for ID in HF are poor dietary iron intake, drug interactions, (occult) . gastrointestinal blood loss due to antiplatelet drugs and anticoagu- . Anaemia was defined as a haemoglobin level <12 g/dL in women and . <13 g/dL in men as per WHO standards.12 Iron deficiency was defined as lants, and hepcidin-induced iron entrapment due to chronic low- . a TSAT <20%, as proposed by Grote Beverborg et al.13 This definition grade inflammation.5 While ID is present in approximately half of all . has been validated against the gold standard test for ID (bone marrow 1,4 . HF patients, its prevalence seems highest in females. It is currently . 4,13 . iron staining) in HF patients and has previously been used. Daily pro- unclear which factors are driving this sex difference. In the present . tein intake of patients was estimated using spot urinary nitrogen and body study, we identified determinants of ID in a large international cohort . 14 . mass index. Median follow-up of the study was 21 months. The primary of worsening HF patients and sought to find sex-specific clinical and . endpoint of this study was the composite of all-cause mortality and first biochemical predictors of ID. Moreover, we established a cardiovas- . HF rehospitalization. Secondary endpoints included all-cause mortality . cular biomarker profile of patients with ID. and first HF rehospitalization. Statistical analyses Methods . Data are presented as mean ± standard deviation (SD) when normally . distributed, as median and interquartile range (IQR) when non-normally Study population . distributed or as percentage when categorical. Baseline characteristics . We included HF patients from the BIOSTAT-CHF study (A systems . were compared using the Student’s t-test (normally distributed variables), BIOlogy Study to TAilored Treatment in Chronic Heart Failure). This co- . the Mann–Whitney U test (non-normally distributed variables), and the 6–8 . 2 hort has been described in full detail elsewhere. In short, the . v test (categorical or binary variables). All baseline characteristics were BIOSTAT-CHF study included patients either hospitalized for HF or pre- . stratified by iron status and sex. After baseline analyses, skewed variables . senting with worsening HF in the outpatient setting. Patients were eligible . were natural log2-transformed to obtain normal distributions. To identify to participate with a left ventricular ejection fraction (LVEF) of <_40% or, . independent predictors of ID, univariable and multivariable logistic re- . alternatively, brain natriuretic peptide or N-terminal pro B-type natri- . gression models were constructed. Associates of ID with a univariable uretic peptide (NT-proBNP) levels of >400 ng/L or >2000 ng/L, respect- . P-value of <_0.1 were entered into the multivariable logistic regression ively. Additionally, patients had to receive suboptimal evidence-based HF . models. Final multivariable models were established using backward elim- . treatment (i.e. <_50% of target dose of angiotensin-converting enzyme . ination based on the significance of each variable. Bootstrap analyses with inhibitors, angiotensin receptor blockers, and/or beta-blockers). After . 1000 repeats (using the ‘swboot’ package in Stata) were performed to . study inclusion, treating physicians were encouraged to up-titrate these . evaluate the robustness of the final models. Variables selected >700 times drugs during a 3-month treatment optimization phase. The BIOSTAT- . were considered robust predictors. As a sensitivity analysis, a regulariza- CHF study was conducted in accordance with the Declaration of . tion approach was performed using multivariable lasso regression. The . Helsinki. All patients provided written informed consent prior to any . final model was checked for multicollinearity by calculating the variance study-related activities. inflation factor. Restricted cubic splines (three knots for all variables) . Of all 2516 patients enrolled in the BIOSTAT-CHF cohort, serum for . were constructed for better visualization of the predictive value
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