Iron deficiency (ID) has been increasingly recognizedas an important co-morbidity associated with heart failure (HF). Irrespectiveof anemic status, ID significantly impairs exercise tolerance and is anindependent predictor of poor outcomes in patients with HF. Routine screeningof ID is necessary in HF patients, and intravenous iron repletion has beenrecommended by the American Heart Association HF treatment guidelines toimprove patient symptoms. Patients treated with intravenous iron showimprovement in quality of life, N-terminal pro-B-type natriuretic peptide levels,6-minute walk test and New York Heart Association functional class. The effectof iron therapy on HF re-hospitalization and mortality rate remains unclear.

Largedose oral iron treatment is found to be ineffective in improving HF patientsymptoms. This review summarizes the current knowledge on prevalence, clinical relevance,and molecular mechanism of ID in patients with chronic HF and availableevidence for parenteral iron therapy. KEY WORDSHeart failureIron deficiencyAnemiaPrognosisIron therapy   Heart failure (HF) is a global epidemic with approximately 6million adults being affected in United States alone (at a cost of about $20billion per year). Despite the availability of new treatment strategies, theincidence, hospitalizations and mortality associated with HF remains a bighealth burden.1 In addition to increasing age,the factors that contribute to poor prognosis in HF are the co-morbiditiesassociated with the disease.

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Iron deficiency (ID) has been increasinglyrecognized as the important co-morbidity that contributes to increasedincidence, re-hospitalization and poor survival in patients with HF.2 Anemia is the ultimateconsequence of ID, but both these diseases represent distinct clinicalscenarios. Identification of ID in chronic diseases such as HF is of importanceas iron repletion has shown to improve patient symptoms irrespective of anemicstatus. MECHANISMOF IRON DEFICIENCY IN HEART FAILURE Iron is an essential micronutrient in all types ofcells, more importantly, in energy demanding cells such as cardiomyocytes.3Iron acts as a co-factor for several enzymes involved in oxidativephosphorylation and plays a key role in oxygen transport througherythropoiesis. The etiology of ID in HF is not clearly understood – it couldpossibly be due to multiple factors including poor iron absorption due toedematous gastrointestinal tract, low bioavailability of iron, and chronicinflammatory state present in HF.

4  At the molecular level, one possiblemechanism of ID is related to hepcidin, an iron regulatory hormone, whosesynthesis is stimulated when iron stores or the cytokine, interlukin-6 (IL-6) levelsare elevated. In chronic inflammatory conditions, hepcidin levels are increasedowing to increased IL-6 and/or fluctuating iron levels. Elevated hepcidin resultsin removal of ferroportin from the duodenal surfaces, a protein that increases ironefflux into the bloodstream.5However, in HF, a reverse mechanism exists: initially hepcidin level increases,however, as HF progresses, hepcidin is downregulated maintaining ferroportinlevels thereby increasing iron efflux.6The reason for this is still not clearly understood. Importantly, lowerhepcidin was associated with poor outcomes in HF patients.

Another mechanism ofID in HF is thought to be due to liver congestion7that leads to increased hemosiderin laden macrophages. This results ininappropriate stimulation of hepcidin which then increases iron storessystematically. Importantly, cardiomyocytes have a high-energy demand and henceare susceptible to ID. In patients referred to cardiac transplantation,myocardial iron stores were lower compared to non-HF heart.8HF patients also showed reduced myocardial oxygen respiration and reduction inmitochondrial respiratory enzymes.9In experimental models, the left ventricular cardiomyocytes with IRP (iron-regulatoryprotein that maintains intracellular iron availability) depletion showedreduced mitochondrial complex I activity and the mice were unable to increase ventricularsystolic function in response to dobutamine stress.10Despite different possibilities for the mechanism underlying ID in HF disease,it is quite not clear what is the exact underlying pathophysiology.  PREVALENCEOF IRON DEFICIENCY IN HEART FAILUREThe prevalence of ID has been widely studied inpatients with chronic HF with reduced ejection fraction (HFrEF) and rangesbetween 36 to 69% among different races.

18There were no differences between the percentages of anemic and non-anemicsubjects highlighting the fact that ID is prevalent independent of anemicstatus. In patients presenting with acute decompensated HF (ADHF), theprevalence of ID was much higher than chronic HF.15A gender difference in the prevalence of ID in ADHF was shown by a study inFrance:19about 66% of men and 75% of women had ID. Independent correlates of ID in HFinclude increased age, higher New York Heart Association (NYHA) functionalclass, female gender, elevated N-terminal pro-B-type natriuretic peptide(NT-proBNP), and high sensitivity C-reactive protein.

2The prevalence of ID in HFpEF is still unknown. CONSEQUENCESOF IRON DEFICIENCY Heart failure with reduced ejectionfraction (HFrEF) In patients with HFrEF, ID greatly decreases thequality of life irrespective of the presence of anemia. Patients withconcurrent ID and HFrEF had lower peak oxygen consumption (peak VO2)and increased ventilator response to exercise (VE-VCO2 slope) comparedto those without concurrent ID, both reflecting poor exercise capacity.11Quality of life was significantly affected in HF patients irrespective ofdiagnostic criteria: European Quality of Life-5D, Kansas City Cardiomyopathy orthe Minnesota Living with Heart Failure questionnaires.

12Short-term 6-month follow-up showed higher odds of death in patients with HFand ID compared to patients with HF and no ID (8.7 vs 3.6% respectively, P<0.001).13Similarly, in long-term follow-up of about 2.

5 years, HF patients with ID hadhigher hazards of dying than without ID.13The association to mortality was independent of anemic status. Also, HFpatients with non-anemic ID had twice the risk of death than anemic patients oniron therapy.14In a study that used serum-soluble transferrin receptor (sTfR) and hepcidinlevels to define ID in ADHF patients, there was a 5% in-hospital mortality anda strikingly higher hazard of 6.59 (95% confidence interval CI, 2.97-14.

62, P<0.001) for death within 12 monthsof discharge.15Heart failure with preservedejection fraction (HFpEF)The definitive role of ID in patients with HFpEF ispoorly understood. In a small study16involving 26 HFpEF subjects, neither cardiac function (both systolic anddiastolic) nor reduced exercise capacity was dependent on ID. Another recentstudy17involving 40 HFpEF patients, ID was a predictor of decreased exercise toleranceindependent of ventricular diastolic function, renal function, hemoglobin andNT-proBNP. There was a significant correlation of both transferrin and ferritinlevels with peak VO2 in these subjects.

The difference in resultsbetween the two studies might be because the latter study involved subjectswith more advanced disease (higher NT-proBNP, higher NYHA class, previoushistory of ADHF and relatively lower peak VO2). More studies arerequired to identify the significance of ID in HFpEF patients. DIAGNOSISOF IRON DEFICIENCY IN HEART FAILUREDiagnosis of ID in HF is complicated by the fact thatthe symptom of fatigue and exercise intolerance associated with ID highlyoverlap with the symptoms of HF. ID is characterized as absolute and functionaldepending on the serum ferritin concentration (marker of iron stores) andtransferrin (iron transport protein) saturation level. In general population, aserum ferritin cut-off value of 30µg/L is used for the diagnosis of ID.Ferritin is an acute phase reactant, hence, in chronic inflammatory state suchas HF, a higher cut-off serum level is used for diagnosis of ID.

 Absolute ID is defined as reduced iron storesdespite normal iron homeostasis diagnosed as serum ferritin level of <100µg/L.(Table 1) Functional ID is definedas an inability to meet bodies iron demand despite having normal iron storesand measured as combination of serum ferritin (100-300µg/L) and transferrinsaturation (<20%) levels.3The gold standard assay to diagnose ID is the bone marrow Prussian blue stainto identify absence of iron granules. It is an invasive procedure and is notroutinely performed. IRONTHERAPY IN HEART FAILUREPARENTERAL IRONHaving proven the significant correlation of ID in HFpatients, several clinical trials of iron therapy have been conducted. Thecurrent treatment guidelines for HF with ID is displayed in Table 2 and is based on two largetrails: FAIR-HF20and CONFIRM-HF.21Both trials tested intravenous ferric carboxymaltose (FCM) in ambulatorychronic systolic HF patients with ID in NYHA classes II and III.

In FAIR-HFtrial including 459 HFrEF patients (EF<45%), self-reported Patient GlobalAssessment was used which improved in 50% of patients in the FCM group(compared to 28% of the placebo group), along with improvement in NYHAfunctional class, 6-minute walk test and quality-of-life assessments. Thepositive changes were present in patients with ID both with and without anemia.CONFIRM-HF included 304 HFrEF patients and after 6 months of iron treatment,the primary end-point of 6-minute walk test significantly improved in FCM groupcompared to placebo group. All secondary end-points including NYHA class,quality-of-life, fatigue score and time for first re-hospitalization improvedsignificantly in the FCM group. Both trials did not show any adverse side effectswith intravenous iron therapy. Although individual clinical trials were nottested for major clinical events, a meta-analysis22including FAIR-HF, CONFIRM-HF, EFFICACY-HF and FER-CARS-01 assessed the effectof iron therapy in cardiovascular hospitalization, and mortality in patientswith HF and ID.

Treatment with intravenous FCM had lower rates of combined HFhospitalizations and cardiovascular mortality (rate ratio 0.53, 95% CI0.33-0.86, P=0.

011). These findingsfrom the meta-analysis has to be validated in randomized clinical trials. ORAL  IRONIRONOUT HF23is a recent large-scale randomized clinical trial that tested the role of highdose oral iron therapy in 225 patients with HFrEF and ID. The primary end-pointwas change in peak VO2 at 16 weeks and secondary end points includedchange in NT-proBNP, 6-minute walk test and quality-of-life. In contrast toresults from trials that used intravenous iron, IRONOUT HF trial failed to showimprovements in both primary and secondary end-points.

 CONCLUSIONID is more common in patientswith HF and is often overlooked by physicians because of overlapping clinicalsymptoms. ID is associated with reduced exercise tolerance, poor quality-of-lifeand increased re-hospitalizations and mortality in HF. Routine screening for IDin patients with HF and treatment with iron is recommended by the HF treatment guidelines.Parenteral iron improves patient symptoms, quality-of-life and exercisecapacity as early as four weeks after iron therapy. Despite improvements in HFsymptoms, major clinical outcomes were not tested in clinical trials. Further,all trials included only patients with HFrEF and the role of ID in patientswith HFpEF is not clearly understood. More randomized clinical trials are currentlyunderway that might answer the open questions on the effect of iron repletionon long term symptom improvement, effects on re-hospitalization and survival inpatients with concurrent ID and HF