Abstract
Aims
Iron deficiency (ID) is associated with an impaired cardiac function and remodelling in heart failure (HF). Treatment with ferric carboxymaltose (FCM) has been showed recently to improve biventricular systolic function and ventricular strain parameters in patients with HF with reduced ejection fraction and ID, but there is no evidence on the benefit of FCM on the left atrium (LA). In this study, we aimed to evaluate the effect of FCM on LA longitudinal strain (LA‐LS).
Methods and results
This is a post hoc subanalysis of a double‐blind, placebo‐controlled, randomized clinical trial that enrolled 53 ambulatory patients with HF, left ventricular ejection fraction (LVEF) < 50%, and ID [Myocardial‐IRON trial (NCT03398681)], treated with FCM or placebo. Cardiac magnetic resonance‐featured tracking (CMR‐FT) strain changes were evaluated before and 7 and 30 days after randomization using linear mixed regression analysis. The median age of the sample was 68 years (interquartile range: 64–76), and 20 (69%) were men. Mean ± standard deviation of LVEF was 39 ± 11%, and most (97%) were in stable New York Heart Association class II. At baseline, mean LA‐LS was −8.9 ± 3.5%. At 30 days, and compared with placebo, LA‐LS significantly improved in those allocated to FCM treatment arm (LA‐LS = −12.0 ± 0.5 and −8.5 ± 0.6, respectively; − 3.55%, P < 0.001).
Conclusions
In patients with stable HF, LVEF < 50%, and ID, treatment with FCM was associated with short‐term improvements in LA‐LS assessed by CMR‐FT. Future works should assess the potential benefit of iron repletion on LA function.
Keywords: Heart failure, Iron deficiency, Ferric carboxymaltose, Cardiovascular magnetic resonance, Feature tracking, Left atrial
Background
Iron deficiency (ID) is a common condition in patients with heart failure (HF), linked to a reduced exercise capacity, worse functional status, and an increased risk of adverse events. 1 , 2 , 3 , 4 Treatment with ferric carboxymaltose (FCM) has been shown to improve symptoms and quality of life and to reduce the risk of hospital readmissions in patients with HF with reduced ejection fraction. 5 , 6 In this line, there is growing interest in the pathophysiological mechanisms underneath the clinical benefit of FCM in HF. ID directly impairs mitochondrial function, affecting cardiomyocyte's contractility and relaxation. 7 FCM may have direct benefits on the structure and function of the heart, but the evidence is still scarce. The Myocardial‐IRON trial showed that treatment with FCM was associated with short‐term changes in cardiac magnetic resonance (CMR) sequences (decrease in T2* and T1‐mapping) indicative of myocardial iron repletion. 8 In this study, FCM was associated with a short‐term improvement in biventricular CMR‐featured tracking (FT) strain parameters. 9 In the IRON‐CRT trial, FCM resulted in an improvement in biventricular systolic function. 10 , 11 However, there is still no evidence of the possible benefits of FCM on the left atrium (LA) function.
Aims
In the present study we aimed to assess the effect of FCM treatment on the LA longitudinal strain (LA‐LS) in patients with HF included in the Myocardial‐IRON trial.
Methods
This is a post hoc subanalysis of the Myocardial‐IRON trial, a double‐blind, placebo‐controlled, multicentre, randomized clinical trial that enrolled 53 patients with chronic HF, left ventricular ejection fraction (LVEF) < 50%, and ID (NCT03398681). 8 The study protocol and main results have been published elsewhere. 8 , 12 Briefly, patients were randomized 1:1 to receive FCM (Ferinject, Vifor Pharma, Glattbrugg, Switzerland) or placebo given intravenously as perfusion of 20 mL solution (equivalent to 1000 mg of iron) diluted in a saline solution (0.9% NaCl) administered over at least 15 min. In the placebo group, an intravenous saline solution (0.9% weight/volume NaCl) was administered over the same time. A CMR study on a 1.5 Tesla MR scanner (Essenza and Avanto, Siemens, Erlangen, Germany) was performed at baseline and at 7 and 30 days. Details on the CMR sequences and study protocol can be found elsewhere. 8 , 12 For strain analysis, FT analyses were performed by the same operator masked to treatment. The cine steady‐state free precession images were processed and analysed using a dedicated CMR‐FT software package (CVI42, Circle Cardiovascular Imaging, Canada). LA endocardial borders were manually traced in long‐axis views of the cine images when the atrium was at its minimum volume, and the fully automated tracking algorithm was applied, performing an automatic strain analysis (automatically computed in all slices that contain endocardial and epicardial contours). LA‐LS was measured as the peak systolic reservoir strain curve. The endpoint of this subanalysis was the change in LA‐LS assessed by CMR‐FT at 7 and 30 days. For this analysis, we excluded patients with atrial fibrillation (n = 24), leaving the final sample size in 29 patients. All statistical comparisons were performed under the intention‐to‐treat principle using Stata 15.1 (Stata Statistical Software, College Station, TX, USA). Observed mean values across treatment allocation were reported and compared using the paired t‐test. Linear mixed regression models (LMRMs) were used to evaluate the study endpoint. All analyses were adjusted for age, gender, hospital (as a cluster variable), the interaction term treatment * visit, and the baseline value of the regressed outcome. Results from the LMRMs are presented as least square means with their respective 95% confidence intervals and P‐values. A two‐sided P‐value of 0.05 was considered significant for all the analyses.
Results
The study population's median age was 68 years [interquartile range (IQR): 64–76], and 20 (69%) were men. Ischaemic aetiology was present in 13 patients (45%), and most (97%) were in stable New York Heart Association class II. At baseline, all patients exhibited ID, with median ferritin and transferrin saturation of 77 μg/L (IQR: 48–131) and 16% (IQR: 12–20), respectively. The mean LVEF was 39 ± 11%. Mean ± standard deviations of LA‐LS parameters in the whole cohort was −8.9 ± 3.5%. Baseline characteristics in the two study groups are presented in Table 1 . No significant differences across treatment arms were found, except in the haemoglobin value, which was lower in the FCM group, and in LA‐LS, which was also initially worse in the FCM group.
Table 1.
Baseline characteristics of the patients according to treatment arm
| Placebo (n = 12) | FCM (n = 17) | Total (N = 29) | P‐value | |
|---|---|---|---|---|
| Age, years, mean (SD) | 65.8 (13.5) | 70.2 (8.3) | 68.4 (10.8) | 0.286 |
| Women | 5 (41.7%) | 4 (23.5%) | 9 (31.0%) | 0.298 |
| NYHA class at baseline | 0.393 | |||
| NYHA class II | 12 (100.0%) | 16 (94.1%) | 28 (96.6%) | |
| NYHA class III | 0 (0.0%) | 1 (5.9%) | 1 (3.4%) | |
| Hypertension | 8 (66.7%) | 12 (70.6%) | 20 (69.0%) | 0.822 |
| Diabetes mellitus | 5 (41.7%) | 11 (64.7%) | 16 (55.2%) | 0.219 |
| Dyslipidaemia | 6 (50.0%) | 12 (70.6%) | 18 (62.1%) | 0.260 |
| Current smoker | 2 (16.7%) | 3 (17.6%) | 5 (17.2%) | 0.945 |
| Ischaemic heart disease | 4 (33.3%) | 9 (52.9%) | 13 (44.8%) | 0.296 |
| COPD | 2 (16.7%) | 6 (35.3%) | 8 (27.6%) | 0.269 |
| Prior stroke | 3 (25.0%) | 1 (5.9%) | 4 (13.8%) | 0.141 |
| Peripheral artery disease | 2 (16.7%) | 1 (5.9%) | 3 (10.3%) | 0.438 |
| LBBB | 3 (25.0%) | 5 (29.4%) | 8 (27.6%) | 0.793 |
| SBP, mmHg, mean (SD) | 126.8 (26.2) | 124.2 (21.9) | 125.3 (23.3) | 0.781 |
| DBP, mmHg, mean (SD) | 69.3 (10.6) | 63.4 (7.9) | 65.8 (9.4) | 0.100 |
| Heart rate, b.p.m., mean (SD) | 72.3 (9.6) | 66.1 (8.1) | 68.8 (9.2) | 0.073 |
| KCCQ, mean (SD) | 74.0 (22.4) | 73.3 (20.6) | 73.6 (21.0) | 0.930 |
| 6MWT, mean (SD) | 273.0 (92.5) | 290.1 (89.6) | 283.1 (89.5) | 0.621 |
| Haemoglobin, g/dL, mean (SD) | 13.7 (1.3) | 12.7 (1.2) | 13.1 (1.3) | 0.044 |
| Ferritin, ng/mL, mean (SD) | 99.8 (74.0) | 94.9 (79.4) | 96.9 (75.9) | 0.869 |
| Transferrin saturation, %, mean (SD) | 16.8 (6.8) | 16.7 (7.6) | 16.7 (7.2) | 0.957 |
| Sodium, mEq/L, mean (SD) | 141.5 (3.1) | 140.6 (2.6) | 141.0 (2.8) | 0.395 |
| NT‐proBNP, pg/mL, mean (SD) | 1522.6 (1468.8) | 2011.6 (1445.2) | 1809.3 (1449.5) | 0.380 |
| BUN, mg/dL, mean (SD) | 56.8 (18.1) | 54.6 (17.3) | 55.5 (17.3) | 0.751 |
| eGFR, mL/min/1.73 m2, mean (SD) | 76.0 (17.8) | 65.4 (20.1) | 69.8 (19.6) | 0.157 |
| LVEF, %, mean (SD) | 36.8 (13.0) | 40.8 (9.9) | 39.1 (11.2) | 0.362 |
| LVEDV, mL, mean (SD) | 259.0 (93.1) | 214.2 (55.3) | 232.8 (75.2) | 0.116 |
| LVESV, mL, mean (SD) | 167.4 (84.8) | 129.5 (48.8) | 145.2 (67.4) | 0.138 |
| LV‐GLS, %, mean (SD) | −4.8 (4.6) | −4.9 (5.1) | −4.8 (4.8) | 0.968 |
| LA‐LS, %, mean (SD) | −10.5 (3.7) | −7.6 (2.9) | −8.9 (3.5) | 0.029 |
| Diuretics | 12 (100.0%) | 16 (94.1%) | 28 (96.6%) | 0.393 |
| Beta‐blockers | 10 (83.3%) | 16 (94.1%) | 26 (89.7%) | 0.348 |
| MRAs | 8 (66.7%) | 9 (52.9%) | 17 (58.6%) | 0.460 |
| RAAS inhibitors | 9 (75.0%) | 14 (82.4%) | 23 (79.3%) | 0.630 |
6MWT, 6 min walking test; BUN, blood urea nitrogen; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FCM, ferric carboxymaltose; KCCQ, Kansas City Cardiomyopathy Questionnaire; LA‐LS, left atrium longitudinal strain; LBBB, left bundle branch block; LVEDV, left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end‐systolic volume; LV‐GLS, left ventricular global longitudinal strain; MRAs, mineralocorticoid receptor antagonists; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; NYHA, New York Heart Association; RAAS, renin‐angiotensin‐aldosterone system; SBP, systolic blood pressure; SD, standard deviation.
Observed mean values across treatment allocation were compared using the paired t‐test or χ 2 test when appropriate.
The inferential analysis, adjusting for the baseline value of LA‐LS, showed that LA‐LS did not significantly differ between FCM and placebo at 7 days (LA‐LS = −10.2 ± 0.3 and −9.6 ± 0.2, respectively; − 0.69%, P = 0.112), but at 30 days, LA‐LS significantly improved in the FCM arm compared with placebo (LA‐LS = −12.0 ± 0.5 and −8.5 ± 0.6, respectively; − 3.55%, P < 0.001), as it is shown in Figure 1 .
Figure 1.
Differences in left atrium longitudinal strain (LA‐LS) on cardiac magnetic resonance‐featured tracking sequences at 7 and 30 days, following the administration of ferric carboxymaltose (FCM) vs. placebo in patients in sinus rhythm included in the Myocardial‐IRON trial. Values are presented as the least square means from each linear mixed model. All models were adjusted by the participant centre (as a cluster variable), the interaction term treatment * visit (7 and 30 days), age, sex, and the baseline (pre‐treatment) value of the regressed outcome.
Discussion
In the present study, we show an improvement in LA‐LS by CMR‐FT analysis following the administration of FCM in patients with chronic HF with LVEF < 50% and ID. To the best of our knowledge, this is the first report of a short‐term improvement in an LA function parameter following iron repletion in patients with HF.
ID is an important comorbidity in HF, linked to an impaired mitochondrial respiration morphology, ATP production, and contractility, affecting cardiac remodelling. 1 , 2 , 7 Recently, iron repletion has been shown to improve biventricular systolic function in patients with HF with reduced ejection fraction at 3 months, 10 , 11 and treatment with FCM was associated to an even earlier improvement in biventricular strain parameters in the Myocardial‐IRON trial. 9 However, there is no evidence of the potential benefit of iron repletion in the LA. LA dysfunction and remodelling are increasingly important mechanisms in HF and critical contributors to HF progression. 13 Bo et al. reported that LA‐LS impairment by CMR‐FT has a significant prognostic impact in patients with HF with reduced ejection fraction in sinus rhythm. 14 Some therapies have been shown to potentially improve LA function or mechanics in HF, making LA a promising therapeutical target. 13 We report for the first time that treatment with FCM improved LA reservoir function in the short term in patients with chronic HF with systolic dysfunction and ID in sinus rhythm. Improvement in LA reverse remodelling may be one of the multiple factors leading to the clinical benefit of FCM in HF. Future works should confirm our findings and evaluate the potential benefits of iron repletion on LA function or remodelling in HF. Currently, an ongoing trial is assessing the potential clinical benefit of FCM in patients with atrial fibrillation and ID. 15
As limitations, first, we need to remark that this is a post hoc subgroup analysis that only included patients with sinus rhythm. Second, we cannot extrapolate these findings to a longer follow‐up or patients with preserved ejection fraction. Finally, we did not evaluate other atrial deformation parameters beyond LA‐LS. As strengths, we would like to highlight the randomized design of the data and the use of CRM‐FT as a highly reproducible imaging technique with high spatial resolution for the evaluation of LA function. 16
Conclusions
In this post hoc analysis of the Myocardial‐IRON trial on patients with chronic HF and ID, treatment with FCM was associated with an improvement in LA‐LS by CMR‐FT analysis at 30 days.
Funding
This work was supported in part by an unrestricted grant from Vifor Pharma, CIBER Cardiovascular (grant numbers 16/11/00420, 16/11/00403), Unidad de Investigacion Clinica y Ensayos Clinicos INCLIVA Health Research Institute, Spanish Clinical Research Network (SCReN; PT13/0002/0031, PT17/0017/0003), cofounded by Fondo Europeo de Desarrollo Regional—Instituto de Salud Carlos III, and Proyectos de Investigacion de la Seccion de Insuficiencia Cardiaca 2017 from Sociedad Espanola de Cardiologia.
Conflict of interest
J.N. has received board speaker fees and travel expenses from Novartis, Roche Diagnostics, Abbott, Rovi, Vifor Pharma, Daiichi Sankyo, Novo Nordisk, Boehringer Ingelheim, and AstraZeneca (modest). L.F. has received speaker fees and travel expenses from Novartis (modest). J.S. has received speaker fees from AstraZeneca, Abbott, and Edwards Lifesciences (modest). The remaining authors have no conflicts of interest to report.
Appendix A.
The Myocardial‐IRON study group investigators are as follows:
Department of Cardiology, Hospital Clínico Universitario de Valencia, Universitat de Valencia, INCLIVA, Valencia, Spain: Julio Nunez, MD, PhD; Enrique Santas, MD, PhD; Gema Minana, MD, PhD; Patricia Palau, MD, PhD; Jessika Gonzalez, MD; Ernesto Valero, MD; Sergio Garcia‐Blas, MD, PhD; Vicent Bodi, MD, PhD; Rafael de la Espriella‐Juan, MD; Jorge Navarro, MD, PhD; Juan Sanchis, MD, PhD; Francisco JChorro, MD, PhD; Meritxell Soler, MD; Amparo Villaescusa; Jose Civera; and Anna Mollar, PhD.
Department of Cardiology, Hospital General de Castellon, Universitat Jaume I, Castellon, Spain: Martina Amiguet, MD.
Department of Internal Medicine, Hospital Ramon y Cajal, Madrid, Spain: Pau Llacer, MD, PhD.
Department of Internal Medicine, Hospital de Manises, Manises, Spain: Maria del Carmen Moreno, MD.
Department of Cardiology, Hospital de Manises, Manises, Spain: Ingrid Cardells, MD, PhD.
Department of Cardiology, Hospital General Universitario de Valencia, Valencia, Spain: Lorenzo Facila, MD, PhD; Vicente Montagud, MD; and Veronica Vidal, MD.
Department of Cardiology, Hospital Universitario La Fe de Valencia, Valencia, Spain: Luis Almenar, MD, PhD; Raquel Lopez‐Vilella, MD; and Alicia Serrano, MD.
Santas, E. , del Canto, I. , Cardells, I. , Miñana, G. , Llàcer, P. , Almenar, L. , Fácila, L. , Maceira, A. M. , Sanchis, J. , Núñez, J. , and Myocardial‐IRON Investigators (2024) Improvement in left atrial strain following ferric carboxymaltose in heart failure: an analysis of the Myocardial‐IRON trial. ESC Heart Failure, 11: 1258–1262. 10.1002/ehf2.14630.
A complete list of the Myocardial‐IRON Investigators can be found in Appendix A.
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