ESC HEART FAILURE ORIGINAL RESEARCH ARTICLE ESC Heart Failure 2020; 7: 4222–4230 Published online 11 October 2020 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13053 Short‐term changes in left and right systolic function following ferric carboxymaltose: a substudy of the Myocardial‐IRON trial Enrique Santas1,2††, Gema Miñana1,2††, Ingrid Cardells3, Patricia Palau1,2, Pau Llàcer4, Lorenzo Fácila5, Luis Almenar6, Maria P. López‐Lereu7, Jose V. Monmeneu7, Juan Sanchis1,2, Alicia M. Maceira7, Antoni Bayés‐ Genís2,8††, Julio Núñez1,2* and Myocardial‐IRON Investigators 1 Cardiology Department, Hospital Clínico Universitario de Valencia, Universidad de Valencia, INCLIVA, Valencia, Spain; 2CIBER Cardiovascular, Madrid, Spain; 3Cardiology Department, Hospital de Manises, Valencia, Spain; 4Internal Medicine Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; 5Cardiology Department, Hospital General Universitario de Valencia, Valencia, Spain; 6Cardiology Department, Hospital Universitario La Fe de Valencia, Valencia, Spain; 7Cardiovascular Imaging Unit, ERESA‐ Ascires Biomedical Group, Valencia, Spain; 8Cardiology Department and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Barcelona, Spain Abstract Aims The mechanisms underlying the beneficial effect of ferric carboxymaltose (FCM) in patients with heart failure (HF) and iron deficiency (ID) have not been completely characterized. The Myocardial‐IRON trial was a double‐blind, randomized trial that evaluated myocardial iron repletion following FCM vs. placebo in 53 patients with HF and ID. In this post hoc analysis, we evaluated whether treatment with FCM was associated with cardiac magnetic resonance changes in left and right ventric- ular function (LVEF and RVEF, respectively) at different points of systolic dysfunction. Methods and results We included patients from the Myocardial‐IRON trial with left and right ventricular systolic dysfunction (LVSD and RVSD, respectively) at enrolment. Linear mixed regression models were used to evaluate changes at 7 and 30 days on LVEF and RVEF at cardiac magnetic resonance. At enrolment, 27 (50.9%) and 38 (71.7%) patients had LVEF < 40% (LVSD1) or <45% (LVSD2), respectively, and 10 (18.9%) and 17 (32.1%) patients had RVEF < 45% (RVSD1) or <51% in women and <52% in men (RVSD2), respectively. Treatment with FCM was associated with a significant improvement in LVEF at 30 days (LVSD1: Δ2.3%, P < 0.001; LVSD2: Δ4.1, P = 0.014). FCM was also associated with a significant and early improvement in RVEF at 7 days (RVSD1: Δ6.9%, P = 0.003; RVSD2: Δ3.2%, P = 0.003) that persisted at 30 days (RVSD1: Δ8.1%, P < 0.001; RVSD2: Δ4.7%, P < 0.001). Conclusions In patients with HF and systolic dysfunction with ID, FCM was associated with short‐term improvement in LVEF and, especially, in RVEF. Keywords Iron deficiency; Heart failure; Ventricular systolic function; Ferric carboxymaltose Received: 15 June 2020; Revised: 22 August 2020; Accepted: 22 September 2020 *Correspondence to: Julio Núñez, Cardiology Department, Hospital Clínico Universitario de Valencia, Universidad de Valencia, INCLIVA, Valencia, Spain. Email: yulnunez@gmail.com † These authors contributed equally to this work. Introduction the mechanisms underlying such benefits remain controversial.7,8 Different in vitro studies showed detrimental Iron deficiency (ID) is a common condition in patients with effects of ID on mitochondrial function among myoblasts and heart failure (HF), and it is associated with reduced functional cardiomyocytes.9,10 Iron treatment has been associated with capacity and worse prognosis.1–3 Treatment with ferric improved muscular energetics in patients with HF.11 How- carboxymaltose (FCM) has consistently been shown to im- ever, evidence on the benefits of iron treatment on myocar- prove surrogates of functional capacity and quality of life in dial function is scarce. The Myocardial‐IRON trial of patients patients with HF and reduced ejection fraction.4–6 However, with chronic HF and ID showed that treatment with FCM © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any me- dium, provided the original work is properly cited and is not used for commercial purposes. Systolic function changes after iron administration 4223 causes short‐term changes in cardiac magnetic resonance obtained with electrocardiographic gating and breath hold- (CMR) sequences suggestive of myocardial iron repletion.12 ing. Contiguous short‐axis cines from the atrioventricular ring Promising data from small clinical studies suggest that iron to the apex were acquired at rest every 1 cm with therapy may improve left ventricular ejection fraction (LVEF) steady‐state free precession imaging sequences (time resolu- on echocardiography,13,14 but conflicting results have also tion: 37 ms; voxel size: 1.7 × 1.7 × 7 mm). been published.15 Also, little is known about changes in the LVEF and RVEF were calculated by semi‐automatic right ventricular ejection fraction (RVEF), especially on CMR, planimetry of endocardial and epicardial borders in the as a gold‐standard cardiac imaging technique. short‐axis view cine images. Further specifications of the In this subanalysis of the Myocardial‐IRON trial, we evalu- CMR sequences are available elsewhere.16 All measure- ated the association of treatment with FCM with short‐term ments were made on the Syngo MR C15 (Siemens) plat- changes in left and right ventricular systolic function in pa- form by the same operator. CMR studies were performed tients with established left and right ventricular systolic dys- at three time points: baseline and 7 and 30 days following function (LVSD and RVSD, respectively) at enrolment. treatment. CMR operators were blinded to treatment allocation. Methods Study sample and trial intervention Endpoints This is a post hoc analysis of an investigator‐initiated, The endpoints of this subanalysis were changes in LVEF and multicentre, randomized, double‐blind, placebo‐controlled RVEF at 7 and 30 days after treatment in patients with clinical trial designed to evaluate the effect of intravenous established LVSD and RVSD at baseline. LVSD and RVSD were FCM vs. placebo on myocardial iron repletion estimated by both defined at two cut‐offs: LVEF < 40% (LVSD1) or T2* and T1 mapping CMR sequences, in patients with stable LVEF < 45% (LVSD2), and RVEF < 45% (RVSD1) or RVEF < 51% chronic HF (New York Heart Association Classes II and III), in women and <52% in men (RVSD2), based on recent recom- with systolic dysfunction (LVEF < 50%), and with ID (serum mendations from the European Association of Cardiovascular ferritin <100 or 100–299 μg/L with transferrin saturation Imaging.17 <20%). Inclusion and exclusion criteria are listed in Secondary endpoints included the correlation between Supporting Information, Table S1. The trial (NCT03398681) proxies of systemic iron repletion (ΔFerritin and ΔTSAT) and was conducted in five academic centres in Spain. Patients myocardial iron repletion (ΔT2* and ΔT1 mapping) and were randomized 1:1 to receive either FCM or placebo. changes in LVEF and RVEF. FCM (Ferinject®, Vifor Pharma, Glattbrugg, Switzerland) was given intravenously as perfusion of 20 mL solution (equiva- lent to 1000 mg of iron) diluted in a sterile saline solution (0.9% NaCl) administered over at least 15 min. In the pla- Statistical analysis cebo group, an intravenous saline solution (0.9% weight/volume NaCl) was administered over the same time. All statistical comparisons were performed under the The materials used in drug administration were entirely cov- intention‐to‐treat principle using Stata 15.1 (Stata Statistical ered with aluminium foil, and the injection site shielded Software, College Station, TX, USA). Observed mean ΔLVEF from the patient’s view to ensure that patients were un- and ΔRVEF values across treatment allocation were reported aware of the treatment arm. Study personnel responsible and compared using the t‐test. Spearman correlation coeffi- for the study drug preparation and administration were cient was used to explore the association among maximum not involved in any study assessment. At 30 days, patients absolute changes in parameters indicative of iron repletion assigned to placebo received intravenous FCM if ID (ΔFerritin, ΔTSAT, ΔT2*, and ΔT1 mapping) and absolute persisted. The study design, protocol, and main results have changes in LVEF and RVEF. Linear mixed regression models been published and are available elsewhere.12,16 were used to evaluate the primary endpoints. All analyses were adjusted for age, gender, hospital (as a cluster variable), the interaction term treatment × visit (7 and 30 days), and Cardiac magnetic resonance the baseline value of the regressed outcome. As a prespecified analysis, no adjustment was made for multiple Cardiac magnetic resonance studies were performed by two comparisons. Results from the linear mixed regression experienced operators on a 1.5 T MR scanner (Essenza and models are presented as least square means with their re- Avanto, Siemens, Erlangen, Germany) using the spine and spective P‐values. A two‐sided P‐value of 0.05 was consid- phased array six‐channel surface coils. All images were ered significant for all analyses. ESC Heart Failure 2020; 7: 4222–4230 DOI: 10.1002/ehf2.13053 Table 1 Baseline characteristics by treatment arm according to different cut points of left and right ventricular ejection fraction at enrolment 4224 P‐ P‐ P‐ RVEF < 51% in women or P‐ Variables LVEF < 40% value LVEF < 45% value RVEF < 45% value <52% in men value n (%) 27 (50.9) 38 (71.7) 10 (18.9%) 17 (32.1%) Treatment arm Placebo Iron Placebo Iron Placebo Iron Placebo Iron n (%) 17 (63) 10 (37) 20 (53) 18 (47) 4 (40) 6 (60) 7 (41) 10 (59) Demographics and medical history Age (years) 71 (67–73) 70 (64–75) 0.651 71 (65–78) 73 (64–77) 0.861 73 (68–82) 67 (61–73) 0.861 73 (67–78) 65 (62–73) 0.051 Male, n (%) 14 (82) 10 (100) 0.232 17 (85) 14 (78) 0.437 3 (75) 4 (67) 0.667 6 (86) 7 (70) 0.441 Hypertension, n (%) 12 (71) 8 (80) 0.475 13 (65) 14 (78) 0.307 4 (100) 4 (67) 0.333 5 (71) 8 (80) 0.559 Diabetes mellitus, n (%) 9 (53) 9 (90) 0.057 10 (50) 12 (67) 0.239 3 (75) 3 (50) 0.452 6 (86) 6 (60) 0.278 Dyslipidaemia, n (%) 11 (65) 9 (90) 0.161 12 (60) 15 (83) 0.110 4 (100) 6 (100) 1.000 5 (71) 8 (80) 0.559 History of IHD, n (%) 7 (41) 6 (60) 0.293 8 (40) 8 (44) 0.520 0 (0) 1 (17) 0.600 1 (14) 3 (30) 0.441 Admission for AHF in last year, 11 (65) 5 (50) 0.363 13 (65) 10 (55) 0.396 1 (25) 4 (67) 0.262 4 (57) 5 (50) 0.581 n (%) History of atrial fibrillation, n 9 (53) 3 (30) 0.226 11 (55) 5 (28) 0.085 3 (75) 3 (50) 0.452 5 (71) 5 (50) 0.354 (%) Vital signs HR at baseline (b.p.m.) 68 (64–84) 73 (71–80) 0.763 68 (64–81) 73 (67–80) 0.753 92 (71–104) 77 (73–80) 0.588 84 (59–100) 79 (73–86) 0.845 Systolic blood pressure 123 (113–131) 111 (97–120) 0.138 124 (113–139) 118 (109–132) 0.306 122 (120–125) 105 (90–117) 0.306 122 (113–129) 111 (97–120) 0.187 (mmHg) Diastolic blood pressure 66 (63–73) 62 (58–68) 0.151 66 (62–74) 63 (58–70) 0.232 68 (59–75) 65 (59–70) 0.213 65 (61–75) 65 (59–70) 0.353 (mmHg) Laboratory 13.7 (13.1– 13.2 (13–13.3) 0.152 13.6 (12.9– 12.8 (11.9– 0.018 14.5 (13.6– 12.7 (11.9– 0.018 14.4 (12.8– 12.9 (11.9– 0.117 Haemoglobin (g/dL) 14.6) 14.6) 13.3) 14.7) 13.3) 14.8) 13.3) 44.0 (40.6–45) 41.5 (38.1–43) 0.258 43.7 (40.5–45) 39.6 (38–43) 0.025 46.1 (43.1– 40.0 (38–43) 0.025 45.3 (41–47.2) 41.5 (38–43) 0.129 Haematocrit (%) 47.5) 14.9 (9.0–20.5) 15.3 (12.0– 0.82114.5 (9.3–20.2) 14.1 (11.0– 0.81512.2 (9.6–18.4) 14.1 (12–16) 0.815 9.6 (9–14.9) 14.1 (12–16) 0.241 Transferrin saturation (%) 19.2) 19.2) Ferritin (ng/mL) 48 (30–85) 61 (56–81) 0.353 48 (26–88) 61 (48–99) 0.273 36 (23–45) 72 (56–271) 0.273 42.0 (25–48) 74 (59–101) 0.004 1.11 (0.95– 1.11 (0.94– 0.812 1.18 (0.95– 1.12 (0.97– 0.826 1.29 (1.06– 1.05 (0.94– 0.826 1.42 (1.11– 1.12 (0.94– 0.696 Creatinine (mg/dL) 1.46) 1.24) 1.51) 1.39) 1.44) 1.52) 1.48) 1.61) 2 eGFR (mL/min/1.73 m ) 67.6 (46.8– 69.6 (59.4– 0.379 58.4 (45.5– 59.7 (51.8– 0.826 49.5 (48–64.5) 62.0 (45–86.1) 0.803 49.3 (46.8– 58.4 0.922 79.3) 86.1) 79.2) 71.3) 70.6) (41.9.71.3) Serum sodium (mEq/L) 141 (140–142) 140 (138–142) 0.761 140 (139–142) 140 (138–142) 0.614 139 (136–141) 140 (138–141) 0.614 141 (137–144) 140 (138–142) 0.806 1760 (1026– 2628 (1728– 0.303 1503 (976– 2269 (1220– 0.511 2083 (1508– 3190 (2110– 0.502 2177 (1760– 2738 (2110– 0.588 NT‐proBNP (pg/mL) 2667) 2836) 2898) 2836) 2352) 4998) 3999) 3952) CMR parameters 2 LVEDVI (mL/m ) 119 (105–137) 128 (104–148) 0.900 122 (101–141) 111 (98–141) 0.334 115 (98–127) 110 (73–141) 0.334 105 (91–126) 110 (78–141) 0.922 2 LVESVI (mL/m ) 85 (68–99) 86 (72–101) 0.920 83 (67–95) 73 (54–87) 0.156 78 (62–94) 73 (46–87) 0.152 68 (55–89) 64 (46–87) 0.588 a LVEF (%) 31.7 ± 5.6 32.0 ± 5.3 0.919 33.6 ± 6.8 37.1 ± 7.2 0.912 31.7 ± 7.1 35.2 ± 7.3 0.139 34.4 ± 7.4 39 ± 6 0.238 LVEF (%) 33 (28–36) 32 (27–38) 0.919 34 (29–38) 38 (31–44) 0.139 33 (27–37) 38 (27–41) 0.280 36 (30–39) 39 (38–44) 0.238 a RVEF (%) 53.5 ± 10.5 51.3 ± 13.4 0.725 54.1 ± 10.1 52.9 ± 12.9 0.725 37.7 ± 2.6 38.3 ± 7.5 0.965 42.3 ± 6.4 42.8 ± 8.1 0.578 RVEF (%) 57 (48–59) 53 (43–53) 0.725 57 (47–61) 53 (43–63) 0.965 37 (35–39) 40 (37–43) 0.286 41 (36–48) 44 (39–49) 0.558 T2* (ms) 36 (32–42) 41 (34–46) 0.279 37 (32–42) 39 (34–46) 0.292 52 (40–68) 39 (34–45) 0.292 42.3 (33–59) 42.8 (37–46) 0.695 1082 (1064– 1078 (1067– 0.651 1073 (1031– 1082 (1067– 0.293 1116 (1087– 1079 (1050– 0.292 1101 (1064– 1081 (1050– 0.435 T1 mapping (ms) 1132) 1096) 1130) 1122) 1142) 1096) 1138) 1096) Medical treatment Diuretics, n (%) 16 (94) 9 (90) 0.631 18 (90) 16 (89) 0.656 4 (100) 5 (83) 0.600 7 (100) 9 (90) 0.588 (Continues) ESC Heart Failure 2020; 7: 4222–4230 E. Santas et al. DOI: 10.1002/ehf2.13053 Systolic function changes after iron administration 4225 rate; HR, heart rate; IHD, ischaemic heart disease; LVEDVI, left ventricular end‐diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end‐systolic volume ACEI, angiotensin‐converting enzyme inhibitor; AHF, acute heart failure; ARB, angiotensin II receptor blocker; CMR, cardiac magnetic resonance; eGFR, estimated glomerular filtration Results 0.268 0.162 0.268 0.360 value P‐ From May 2017 to June 2018, 53 patients were randomized RVEF < 51% in women or to receive FCM (n = 27) or placebo (n = 26). All patients had 3 (30) 9 (90) 7 (70) 1 (10) ID at baseline. The mean age was 71.0 ± 9.8, and 13 <52% in men (24.5%) patients were women. Ischaemic aetiology was pres- ent in 26 (49%) patients, and 50 (94.3%) were in NYHA Class II. Mean ± standard deviation LVEF and RVEF were 4 (57) 4 (70) 3 (43) 2 (28) 40.3 ± 10.4% and 56.3 ± 11.4%, and median (inter‐quartile range) were 39% (33–47) and 58% (49–63), respectively. De- tailed baseline characteristics of the patients in the two study index; MRA, mineralocorticoid receptor antagonist; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; RVEF, right ventricular ejection fraction. groups have been reported elsewhere.12,16 At enrolment, 0.024 0.333 0.262 0.333 value P‐ LVSD1 and LVSD2 were found in 27 (50.9%) and 38 (71.7%) patients, respectively. The number of patients with RVSD1 and RVSD2 was 10 (18.9%) and 17 (32.1%), respectively. Base- 1 (17) 5 (83) 4 (67) 1 (17) line characteristics across treatment interventions at differ- RVEF < 45% ent cut‐offs of LVEF and RVEF are shown in Table 1. Iron treatment and left ventricular systolic 4 (100) 2 (50) 1 (25) 2 (50) function In the whole sample, baseline LVEF was not different accord- ing to treatment allocation (P = 0.128). LVEF also did not sig- 0.115 0.272 0.284 0.135 value Values are expressed as median (inter‐quartile range); categorical variables are presented as percentages. P‐ nificantly differ between FCM and placebo at 7 days (Figure 1A). Among patients with LVSD1 and LVSD2, we did not find 17 (94) significant differences in baseline characteristics across treat- 9 (50) 7 (39) 7 (39) ment interventions (Table 1). In the prespecified subgroups, LVEF < 45% observed means of LVEF across treatment allocation are pre- sented in Supporting Information, Figure S1. Overall, LVEF was higher in the active group at 30 days. 15 (75) 12 (60) 7 (35) 5 (20) The inferential analysis showed that treatment with FCM was associated with a significant improvement in LVEF at 30 days (LVSD1: Δ2.3%, P < 0.001; LVSD2: Δ4.1, P = 0.014), but not at 7 days (Figure 1B and 1C). Individual predicted 0.136 0.402 0.481 0.316 value P‐ values are shown in Supporting Information, Figure S2. The im- provement in LVEF was mainly at the expense of a reduction of 10 (100) the left ventricular end‐systolic volumes (Supporting Informa- 4 (40) 5 (50) 4 (40) tion, Figure S3). In patients with systolic dysfunction at base- LVEF < 40% Values are expressed as mean ± standard deviation. line, we could not find any significant correlations among changes in proxies of iron repletion and changes in ventricular systolic function (Supporting Information, Table S2). 11 (65) 13 (76) 7 (41) 4 (23) Iron treatment and right ventricular systolic function In the entire sample, RVEF was not different across treatment Sacubitril/valsartan, n (%) arms (P = 0.908), and we did not find significant differences in RVEF changes across treatment arms at Day 7 or Day 30 Beta‐blockers, n (%) ACEI or ARB, n (%) Table 1 (continued) (Figure 2A). Among patients with RVSD1 or RVSD2, we did not identify significant differences in RVEF or other important MRA, n (%) baseline characteristics across both treatment arms (Table 1). Variables In both RVEF subgroups, the observed means of RVEF along the visits after the intervention were mainly higher in the ac- tive arm (Supporting Information, Figure S1). In multivariate a ESC Heart Failure 2020; 7: 4222–4230 DOI: 10.1002/ehf2.13053 4226 E. Santas et al. FIGURE 1 Differences in left ventricular ejection fraction (LVEF) on cardiac magnetic resonance (CMR) at 7 and 30 days following the administration of ferric carboxymaltose in patients included in the Myocardial‐IRON trial. Values are presented as the least square means from each mixed linear regres- sion model. All models were adjusted by hospital (as a cluster variable), the interaction term treatment × visit (7 and 30 days), age, gender, and the baseline (pretreatment) value of the regressed outcome. (A) LVEF differences in all patients. (B) LVEF differences in patients with baseline LVEF < 40%. (C) LVEF differences in patients with baseline LVEF < 45%. FIGURE 2 Differences in right ventricular ejection fraction (RVEF) on cardiac magnetic resonance (CMR) at 7 and 30 days following the administration of ferric carboxymaltose in patients included in the Myocardial‐IRON trial. Values are presented as the least square means from each mixed linear re- gression model. All models were adjusted by hospital (as a cluster variable), the interaction term treatment × visit (7 and 30 days), age, gender, and the baseline (pretreatment) value of the regressed outcome. (A) RVEF differences in all patients. (B) RVEF differences in patients with baseline RVEF < 45%. * (C) RVEF differences in patients with RVEF < 51% in women and <52% in men . setting, FCM was associated with a significant improvement baseline, FCM was associated with a significant short‐term in RVEF at 7 days (RVSD1: Δ6.9%, P = 0.003; RVSD2: Δ3.2%, improvement in both LVEF and RVEF vs. placebo. The in- P = 0.003) and 30 days (RVSD1: Δ8.1%, P < 0.001; RVSD2, crease in RVEF was larger in magnitude and already present Δ4.7%, P < 0.001; Figure 2B and 2C). Individual predicted at 7 days following iron therapy. To the best of our knowl- values are shown in Supporting Information, Figure S2. We edge, this is the first report of iron repletion resulting in a sig- could not find a significant statistical association between nificant short‐term improvement of RVEF evaluated by CMR proxies of iron repletion and changes in RVEF (Supporting In- in patients with baseline RVSD. formation, Table S2). In a sensitivity analysis including only patients with RVSD at Ferric carboxymaltose treatment and changes in baseline, the improvement in LVEF was highly significant at left ventricular ejection fraction 30 days, and changes in LVEF were, at least, similar in magni- tude than those found for RVEF (ΔLVEF when RVSD1:10.5%, Iron is an essential micronutrient in the mitochondrial func- P = 0.003; ΔLVEF when RVSD2: 6.4%, P = 0.003) as it is shown tion and energy production. Accumulating data from in vitro in Figure 3. and basic research indicate that ID has deleterious effects on the contractile function of cardiomyocytes that can be re- Discussion versed following iron repletion.9,18 In a recent study on hu- man embryonic cardiomyocytes derived from stem cells, ID In this post hoc analysis of the Myocardial‐IRON trial con- resulted in impaired energy production with a profound de- ducted in patients with ID and systolic dysfunction at crease in the amount of phosphocreatine and ATP. 10 This ESC Heart Failure 2020; 7: 4222–4230 DOI: 10.1002/ehf2.13053 Systolic function changes after iron administration 4227 FIGURE 3 Differences in left ventricular ejection fraction (LVEF) on cardiac magnetic resonance (CMR) following the administration of ferric carboxymaltose in patients with right ventricular systolic dysfunction at enrolment. All models were adjusted by hospital (as a cluster variable), the interaction term treatment × visit (7 and 30 days), age, gender, and the baseline (pretreatment) value of the regressed outcome. RVEF, right ventricular ejection fraction. mitochondrial dysfunction severely hampered mechanical LVSD1 and LVSD2 were 31.8% and 35.3%, respectively), differ- function. The restitution of intracellular iron reversed the ences were more evident and became significant. Our results negative effects of ID on the cardiomyocytes.10 In an animal are hypothesis generating but are in line with prior data, model of ID, iron sucrose treatment prevented myocardial fi- showing an improvement in LVEF at 30 days in patients with brosis and improved cardiac function.13 Surprisingly, despite baseline LVSD after treatment with FCM. the growing evidence and research on the benefits of intrave- In our study, we observed a reduction of left ventricular vol- nous iron treatment in HF,2,5,6,19,20 there are limited data on umes following FCM treatment, but they were more marked the effect of iron repletion on LVEF, especially in clinical stud- and evident on left ventricular end‐systolic volume. This might ies on real‐world patients with HF. Some observational and reflect that FCM, at least at the short term, had a predominant interventional studies have suggested that iron therapy may effect on cardiac contractility instead of true remodelling (left be related to reverse cardiac remodelling and LVEF improve- ventricular end‐diastolic being less dependent on the contrac- ment on echocardiography.13,15,21,22 Gaber et al. evaluated tility). However, further research will be necessary to provide the effects of ID correction with iron dextran in 40 patients definite answers. For instance, the IRON‐CRT trial is currently with LVEF < 40% and ID without anaemia. In this study, LVEF evaluating whether FCM is capable of improving LVEF and car- did not change significantly following the correction of ID diac remodelling in patients with HF and reduced ejection frac- (32 ± 8% vs. 34 ± 9%). However, there was an increase in tion with an incomplete response to cardiac resynchronization the S′‐wave velocity and an improvement in peak systolic therapy.23 A planned echocardiographic substudy of the strain.15 Usmanov et al. evaluated the effects of 26 weeks’ EFFECT‐HF study will also provide valuable information on this treatment with intravenous iron sucrose (no control group) topic.24 Future studies focusing on advance cardiac imaging in 32 advanced HF who had anaemia and renal dysfunction, techniques able to detect subtle changes in contractility, such showing an improvement in LVEF and reduction in left ven- as myocardial deformation analyses, and larger randomized tricular volumes. However, this study does not allow us to controlled trials will help to better elucidate the potential ben- separate the effect of correcting anaemia vs. iron treatment efits of iron treatment in the heart. per se.14 In the Myocardial‐IRON trial, albeit changes consis- tent with myocardial iron repletion on CMR sequences, we did not find an improvement in LVEF with FCM treatment. Ferric carboxymaltose treatment and changes in However, there was a trend towards increasing in LVEF at right ventricular ejection fraction 30 days (44.8% vs. 40.9%, respectively; P = 0.056). Of note, the mean LVEF value on patients included in the trial was There are very limited data on the effect of iron therapy on 40.3%. In the present subanalysis, when we restricted the the right heart. The myocardial iron load is reduced in the analysis on patients with LVSD at enrolment (mean LVEF in right ventricle in advanced HF.25 Alioglu et al. showed that ESC Heart Failure 2020; 7: 4222–4230 DOI: 10.1002/ehf2.13053 4228 E. Santas et al. ID anaemia was negatively associated with right ventricular randomized clinical trial, assuming a power of 0.9 and differ- myocardial function indexes in a small study performed in ence of 2 ± 4% in LVEF and 4 ± 5% in RVEF at 30 days children.26 There is evidence from basic research that ID favouring the active treatment, should at least include 80 may be involved in the pathogenesis of pulmonary hyperten- and 52 patients, respectively. Second, more than half of the sion. In an animal model, ID rapidly promoted pulmonary vas- patients were non‐ischaemic, and the proportion of those cular remodelling, pulmonary hypertension, and right with very severely reduced LVEF was low. Left gadolinium en- ventricular hypertrophy.27 Pulmonary vascular remodelling hancement imaging was not performed systematically per and haemodynamic changes induced by ID in rats were re- study protocol. Thus, extrapolation of these findings to less versed by iron replacement.27 The potential benefit of iron selected samples, patients with advanced ischaemic heart replacement therapy in the right ventricle and pulmonary cir- disease with extensive scars, and more severe forms of sys- culation is an area of utmost interest. However, the potential tolic dysfunction remains to be confirmed. Third, due to the benefit of iron on the right heart in HF has not been de- small sample size and study design, we could not evaluate scribed yet. Darbepoetin α improved left and right ventricular the effect of FMC on pulmonary artery pressures or other function by echocardiography in a small randomized study on pulmonary circulation parameters, which could help to ex- patients with anaemia and chronic HF, but this was not a plain the benefit of FCM on the right heart. Fourth, the lack study of iron repletion treatment.28 Our research shows for of advanced imaging methods for evaluating systolic dysfunc- the first time that treatment with FCM is associated with an tion should be also be remarked. Albeit the sample size is early improvement in RVEF, which is maintained at 30 days. small, the placebo‐controlled nature of the trial, with investi- In addition, the magnitude of the changes appears to be gators and operators blinded to treatment intervention, and higher than those found for the left ventricle (7–8% absolute the use of CMR as a standard gold technique in LVEF and increase in patients with RVEF < 45% at enrolment). Interest- RVEF assessment are the major strengths of the study.30,31 ingly, changes in LVEF were bigger in magnitude (6–10%) when the analyses were limited to patients with baseline RVSD. The latter suggests that the improvement in RVEF Conclusions may be, to a large extent, secondary to an increase in LVEF as a result of interventricular dependence in patients with In this post hoc analysis from the Myocardial‐IRON trial on biventricular dysfunction. However, the mechanisms underly- patients with stable HF and ID with systolic dysfunction at ing the improvement in RVEF following FCM treatment re- baseline, treatment with FCM was associated with main elusive. Other possibilities deserve to be mentioned. short‐term improvements in LVEF on CRM but especially in FCM may also directly exert positive effects on right myocar- RVEF. Further trials should confirm these findings and explore dial contractility, induce positive changes in the pulmonary the potential benefit of FCM on the right heart. circulation, and therefore improve right ventricular to pulmo- nary artery coupling. In this work, we did not find a significant correlation among parameters of iron repletion and changes in ventricular systolic function. However, it may be due to a Conflict of interest type II error given the limited sample size. The improvement of RVEF following FCM treatment should J.N. received board speaker fees and travel expenses from be considered hypothesis generating. Still, it may help disen- Novartis, Roche Diagnostics, Abbott, Rovi, Vifor Pharma, tangle part of the mechanisms underlying the clinical benefits Daiichi Sankyo, Novonordisk, Boehringer Ingelheim, and related to iron repletion therapy in HF. For instance, FCM can AstraZeneca (modest). L.F. received speaker fees and travel improve decongestion in the short term, as it has been re- expenses from Novartis (modest). J.S. received speaker fees ported in a recent substudy from the FAIR‐HF trial.29 The from AstraZeneca, Abbott, and Edwards Lifesciences (mod- early improvement in right ventricular performance in our est). A.B.‐G. received board membership fees and travel ex- study may partly help to explain this symptomatic benefit. penses from Novartis, Roche Diagnostics, Vifor Pharma, and The potential association of iron status and right HF should Critical Diagnostics (modest). All other authors declare no be confirmed and explored in upcoming studies. competing interests. Limitations Funding The present study has several limitations. First, this is a small This work was supported in part by an unrestricted grant post hoc analysis in which residual confounding may play an from Vifor Pharma and Proyectos de Investigación de la unmeasurable critical role. To confirm the beneficial effect Sección de Insuficiencia Cardiaca 2017 from Sociedad of FCM on left and right ventricular function, a further Española de Cardiología. ESC Heart Failure 2020; 7: 4222–4230 DOI: 10.1002/ehf2.13053 Systolic function changes after iron administration 4229 Supporting information Figure S2. Individual predicted values of left and right ventric- ular ejection fraction at 7 and 30 days across treatment allo- Additional supporting information may be found online in the cation in patients included in the Myocardial‐IRON trial. All Supporting Information section at the end of the article. models were adjusted by hospital (as a cluster variable), the interaction term treatment*visit (7 and 30‐d), age, gender, Table S1. Inclusion and exclusion criteria in the and the baseline (pre‐treatment) value of the regressed out- Myocardial‐IRON trial. come CMR: cardiac magnetic resonance; LVEF: left ventricular Table S2. Spearman correlations among changes in parame- ejection fraction; RVEF: right ventricular ejection fraction. ters of iron repletion and changes in left and right ventricular Figure S3. Absolute changes in indexed left ventricular vol- systolic function umes at 7 and 30 days following the administration of ferric Figure S1. Observed means of left and right ventricular ejec- carboxymaltose in patients included in the Myocardial‐IRON tion fraction on cardiac magnetic resonance at baseline, 7 trial. LVEF: left ventricular ejection fraction; LVEDV: left ven- and 30 days across treatment allocation in patients included tricular end‐diastolic volume; LVEF: left ventricular ejection in the Myocardial‐IRON trial. CMR: cardiac magnetic reso- fraction; LVESD: left ventricular end‐systolic volume; MRI: nance; LVEF: left ventricular ejection fraction; NS: non‐signif- magnetic resonance imaging. icant; RVEF: right ventricular ejection fraction. References 1. 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