Changes in myocardial iron content following administration of intravenous iron (Myocardial‐IRON): Study design

Abstract

Treatment with intravenous ferric carboxymaltose (FCM) has been shown to improve symptoms, functional capacity, and quality of life in patients with heart failure and iron deficiency. However, the underlying mechanisms for these beneficial effects remain undetermined. The aim of this study is to quantify cardiac magnetic resonance changes in myocardial iron content after administration of intravenous FCM in patients with heart failure and iron deficiency and contrast them with parameters of heart failure severity. This is a multicenter, double‐blind, randomized study. Fifty patients with stable symptomatic heart failure, left ventricular ejection fraction <50%, and iron deficiency will be randomly assigned 1:1 to receive intravenous FCM or placebo. Intramyocardial iron will be evaluated by T2* and T1 mapping cardiac magnetic resonance sequences before and at 7 and 30 days after FCM. After 30 days, patients assigned to placebo will receive intravenous FCM in case of persistent iron deficiency. The main endpoint will be changes from baseline in myocardial iron content at 7 and 30 days. Secondary endpoints will include the correlation of these changes with left ventricular ejection fraction, functional capacity, quality of life, and cardiac biomarkers. The results of this study will add important knowledge about the effects of intravenous FCM on myocardial tissue and cardiac function. We hypothesize that short‐term (7 and 30 days) myocardial iron content changes after intravenous FCM, evaluated by cardiac magnetic resonance, will correlate with simultaneous changes in parameters of heart failure severity. The study is registered at http://www.clinicaltrials.gov (NCT03398681).

1. INTRODUCTION

Iron deficiency (ID) is a common finding in patients with heart failure (HF). It is usually associated, even in the absence of anemia, with decrease in functional capacity, quality of life, and with increased risk of mortality and readmission.1, 2, 3, 4, 5, 6, 7 Treatment with intravenous (IV) ferric carboxymaltose (FCM) in patients with HF and ID has shown to improve symptoms, functional capacity, and quality of life, and to decrease hospitalizations under an acceptable safety profile.8, 9 Such benefit has been consistent in patients with and without anemia,10, 11 suggesting additional pathophysiological pathways besides anemia resolution. In addition, recent studies suggested that myocardial ID could play a direct role in the pathogenesis and progression of HF.12, 13, 14

Despite the fact that T2‐star (T2*) cardiac magnetic resonance (CMR) sequencing has been shown to provide a reliable assessment of myocardial iron content,15, 16, 17, 18 newer techniques, such as T1 mapping, have emerged as an alternative tool for myocardial iron assessment.19 Changes in myocardial T1 mapping are more linear and have fewer artifacts than with the T2* sequence, which translates into a more reproducible and sensitive technique.20 Thus, in this work we aim to evaluate the utility of T1 mapping for detecting myocardial iron changes after IV iron administration. In a recent pilot study, our group reported an association between IV FCM administration and myocardial iron repletion assessed by T2* CMR. Interestingly, myocardial iron changes were strongly related to an improvement in left ventricular ejection fraction (LVEF).21

We sought to determine whether short‐term (7‐day and 30‐day) myocardial iron content changes after IV FCM, evaluated by T1* CMR, would correlate with simultaneous changes in parameters of HF severity.

2. METHODS

2.1. Overall study design

Changes in Myocardial Iron After Iron Administration (Myocardial‐IRON) is a multicenter, double‐blind, randomized, placebo‐controlled study designed to test the effect of IV FCM (Ferinject; Vifor Pharma, Glattbrugg, Switzerland) on myocardial iron content assessed by CMR in 5 academic centers in Spain (Hospital Clínico Universitario de Valencia, Hospital de Manises, Hospital General Universitari de Castelló, Hospital Universitario y Politécnico La Fe, and Consorci Hospital General Universitari de Valencia). After signing the informed consent, patients will be randomized 1:1 to receive FCM or placebo. Intramyocardial iron will be evaluated before its administration, and 7 and 30 days after. At 30 days, patients assigned to placebo will receive FCM if ID persists (Figure 1).

Figure 1.

Study design. Abbreviations: FCM, ferric carboxymaltose; HF, heart failure; ID, iron deficiency; R, randomization; V, visit

The study will be carried out in accordance with the principles of the Declaration of Helsinki (1996) and the Guideline for Good Clinical Practice of the International Council for Harmonisation. The study protocol was approved by Agencia Española del Medicamento y Productos sanitarios (AEMPS) on December 6, 2016, and by Comité Ético de Investigación Clínica (CEIC) del Hospital Clínico Universitario de Valencia on January 26, 2017, with an amendment on June 22, 2017. CMR studies will be performed by ERESA (Valencia, Spain), and laboratory parameters will be analyzed in local laboratories. The study is registered at http://www.clinicaltrials.gov (NCT03398681). For a complete list of Myocardial‐IRON investigators, see Supporting Information, Appendix 1, in the online version of this article.

2.2. Study population

Eligible patients are those with stable chronic HF (New York Heart Association [NYHA] class II–III), LVEF <50%, and ID, the latter defined as serum ferritin <100 μg/L or 100 to 299 μg/L with transferrin saturation (TSAT) <20% and hemoglobin (Hb) <15 g/dL. All patients must meet all inclusion and exclusion criteria (Table 1).

Table 1.

Inclusion and exclusion criteria

Inclusion criteria

Outpatients with chronic HF

Age > 18 years

NYHA class II–III with optimal medical treatment in the last 4 weeks, without dose changes of HF treatment in the last 2 weeks (except for diuretics)

NT‐proBNP >400 pg/mL

LVEF <50% in the last 12 months

ID, defined as serum ferritin <100 μg/L, or 100–299 μg/L if TSAT <20% and Hb <15 g/dL

Willing and able to give informed consent for participation in the study

Exclusion criteria

Known intolerance to FCM

History of acquired iron overload

Severe valve disease or cardiac surgery scheduled in the next 30 days

ACS, TIA, or ictus in the previous 3 months

CABG, major surgery, or cardiac, cerebrovascular, or aortic percutaneous intervention (diagnostic angiography is allowed) in the previous 3 months

Scheduled revascularization in the next 30 days

Scheduled CRT device implantation in the next 30 days

Active bleeding in the last 30 days

Active infection or malignancy

Immediate need for transfusion or Hb ≥15 g/dL

Anemia for reasons other than ID

Immunosuppressive therapy or dialysis

History of treatment with EPO, IV iron, or transfusion in the previous 12 weeks

Treatment with oral iron at doses >100 mg/d in the previous week

Contraindications to CMR, including noncompatible pacemakers or defibrillators, cochlear implants, cerebral aneurysm clips, claustrophobia, or large body size that does not allow the performance of the test

Pregnant or lactating females

Subject of childbearing age who is unwilling to use adequate contraceptive measures during the study and up to 5 half‐lives after the administration of study treatment

Participation in another trial at the time of inclusion or in the previous 30 days

Any disorder that compromises the ability to sign informed consent and/or comply with study procedures

Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CMR, cardiac magnetic resonance; CRT, cardiac resynchronization therapy; EPO, erythropoietin; FCM, ferric carboxymaltose; Hb, hemoglobin; HF, heart failure; ID, iron deficiency; IV, intravenous; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; NYHA, New York Heart Association; TIA, transient ischemic attack; TSAT, transferrin saturation.

2.3. Randomization

Patients will be randomly allocated into 1:1 ratio to receive FCM or placebo by means of a web‐based computer‐generated block sequence. Investigators and patients will be blinded to treatment allocations.

2.4. Study procedures

Study procedures are detailed in Table 2.

Table 2.

Study procedures

	Visit 0, Enrollment	Visit 1, 24 Hours	Visit 2, 7 Days	Visit 3, 30 Days	Additional Visits
Informed consent form	X
Medical history	X
Concomitant medications	X
Physical examination	X	X	X	X	X
Vital signs	X	X	X	X	X
Review of inclusion and exclusion criteria	X
Randomization		X
ECG	X			X
Echocardiography	X			X
Laboratory tests	X		X	X
NYHA functional class	X	X	X	X	X
6MWT	X		X	X
KCCQ	X		X	X
CMR	X		X	X
Adverse clinical events		X	X	X	X
Changes in treatment		X	X	X	X

Abbreviations: 6MWT, 6‐minute walking test; CMR, cardiac magnetic resonance; ECG, electrocardiography; KCCQ, Kansas City Cardiomyopathy Questionnaire; NYHA, New York Heart Association.

2.4.1. Cardiac magnetic resonance

CMR data will be blindly acquired and quantified offline by 2 experienced cardiologists (M.P.L.L. and J.V.M., both with 15 years' experience in CMR imaging) on a 1.5‐Tesla MR scanner (Magnetom Essenza or Avanto; Siemens, Erlangen, Germany). The 3 consecutive CMR studies of each patient will be analyzed by the same operator. No contrast media are used. All images are obtained with electrocardiographic gating and breathholding.

Cine images are acquired at rest in short‐axis views every 1 cm with steady‐state free precession imaging sequences (time resolution: 37 ms; voxel size: 1.7 × 1.7 × 7 mm). Right ventricular (RV) ejection fraction and LVEF (%), left ventricular (LV) end‐diastolic and end‐systolic volume index (mL/m²), and LV mass (g/m²) are calculated by semiautomatic planimetry of endocardial and epicardial borders in short‐axis‐view cine images.

The basic T2* pulse sequence is a breathhold, multiecho gradient echo T2* sequence (voxel size: 1.6 × 1.6 × 8 mm) with 8 echo times from 2.65 to 21 ms, in mid‐ventricular short axis. For T2* analysis, a region of interest (ROI) is chosen in the mid‐LV septum. The mean signal intensities of the ROI are measured in the series of increasing echo time images to give an exponential decay curve. The monoexponential decay model and the nonlinear curve fitting algorithm are used to fit the curve to obtain T2* measurement.

T1 mapping is performed with modified Look‐Locker inversion recovery (MOLLI) sequences with motion correction (voxel size: 1.5 × 1.5 × 7 mm) in 3 short axes (basal, medial, and apical). After T1 maps are generated, a ROI is chosen in the mid‐LV septum in the 3 short axes and the average T1 values are calculated.

For details of the CMR sequences used, see Supporting Information, Appendix 3, in the online version of this article. All measurements were made on the Syngo MR C15 (Siemens) platform. The same protocol will be repeated at 7 and 30 days.

2.4.2. Six‐minute walking test

The 6MWT is performed in a place well‐equipped for cardiopulmonary resuscitation. Subjects are advised not to have undertaken vigorous exercise within the previous 2 hours and are instructed to cover the maximum distance possible in 6 minutes, at a self‐graded walking speed. Pausing to rest will be allowed when needed.

2.4.3. Kansas City Cardiomyopathy Questionnaire

The KCCQ is a self‐administered instrument designed to evaluate health‐related quality of life in patients with chronic HF. It is composed of 23 items (15 questions) that form 7 domains: physical limitations, symptoms (frequency, severity, and change over time), self‐efficacy and knowledge, social interference, and quality of life. It is scored by assigning each response from 1 to 5, 6, or 7 points, with 1 the lowest. The sum of these items is subsequently converted to a scale of 0 to 100 points (see Supporting Information, Appendix 2, in the online version of this article).22 The Spanish version of the KCCQ23 will be completed by patients with the support of trained nurses.

2.4.4. Biomarkers

The results from laboratory data will be reviewed and signed by the investigator, who will record in the case‐report form whether results are normal, abnormal, and clinically significant. The following parameters will be assessed at baseline, 7, and 30 days: (1) hematology: Hb, hematocrit, red‐cell distribution width, mean corpuscular volume, and mean corpuscular Hb; (2) serum electrolytes: sodium, potassium, and chloride; (3) ID parameters: ferritin, TSAT, soluble transferrin receptor, and hepcidin; (4) renal function parameters: cystatin C, serum creatinine, blood urea nitrogen, and estimated glomerular filtration rate; (5) liver function parameters: alanine aminotransferase and aspartate aminotransferase; and (6) HF biomarkers: carbohydrate antigen 125, N‐terminal pro‐brain natriuretic peptide, galectin‐3, ST‐2, and high‐sensitivity troponin T.

2.4.5. Clinical visits

A summary of study procedures performed at each visit is detailed in Table 2. Visit 0 is the screening and eligibility assessment; after signing and dating the informed consent, the study procedures will be initiated. Scheduled follow‐up visits will be performed at 24 hours and at 7 and 30 days after randomization. Patients will be censored if they withdraw from the informed consent or die. Optional additional visits are permitted. The main reason for each optional visit, and for any laboratory test or procedure additionally performed, must be recorded on the case‐report form. Information on concomitant medications and clinical adverse events will be recorded.

2.5. Trial intervention

Eligible patients will be randomized to receive FCM or placebo.

2.5.1. Intravenous ferric carboxymaltose

FCM solution (Ferinject) will be given as an IV perfusion of 20 mL (equivalent to 1000 mg of iron) diluted in a sterile saline solution (0.9% NaCl) and administered over ≥15 minutes.

Because FCM is a dark‐brown solution and easily distinguishable, the personnel responsible for its preparation and administration will not be involved in any study assessments. To ensure that patients will be unaware of the study drug, the materials used in drug administration will be covered with aluminum foil or other opaque material and the injection site will be shielded from patient view.

2.5.2. Placebo

Normal saline (0.9% NaCl) will be administered as per the instructions in the placebo group.

2.5.3. Concomitant drugs

The indication for other HF drugs will be followed according to the current recommendations for clinical practice.

2.6. Endpoints

2.6.1. Primary endpoint

The main endpoint will be change in myocardial iron content from baseline at 7 and 30 days, assessed by T2* and T1‐mapping CMR sequences. The statistical comparisons for the primary efficacy objective will test the null hypotheses of no differences in changes in myocardial iron content from baseline as assessed by T2* and T1‐mapping CMR; the alternative hypotheses will indicate differences in either direction. Strictly speaking, the primary objective will be the 30‐day evaluation; the 7‐day evaluation will be considered a co–primary endpoint.

2.6.2. Secondary endpoints

The study has 3 secondary endpoints.

1. On the entire sample, to correlate these changes with the following clinical markers of HF disease severity: LVEF, functional capacity (6MWT and NYHA class), quality of life (KCCQ), and cardiac biomarkers.

2. On the sample stratified into 3 prespecified subgroups: age > 70 years vs ≤70 years; anemia vs no anemia (according to World Health Organization criteria); and ischemic vs nonischemic etiology.

3. On the entire sample, to correlate these changes with blood markers specific to iron biology/deficiency (ferritin, TSAT, soluble transferrin receptor, and hepcidin).

2.6.3. Safety endpoints

Based on previous studies,8, 9 a safety surveillance will be specifically focused on (1) general disorders and administration‐site conditions; (2) skin and subcutaneous tissue disorders; (3) nervous system disorders; (4) gastrointestinal disorders; (5) vascular disorders; (6) ear and labyrinth disorders; (7) injury, poisoning, and procedural complications; and (8) cardiac disorders.

2.7. Sample‐size calculation

The sample size was calculated based on the expected changes in T2*, according to the following parameters: (1) 2 treatment arms; (2) statistical power of the primary endpoint of 80%; and (3) α error of 0.05. We used repeated‐measures ANOVA using the Lawley‐Hotelling test to evaluate the effect of treatment. Based on studies from our group,21 we predict a mean difference of 9.25 ±8.69 in T2* at 30 days after treatment, and a correlation of 0.38 between T2* measurements at baseline and 1 month later. The correlation of T2* at baseline and 7 days would be 0.40, because we expect the correlation to decrease with time. For a desired power of 0.80 and a type I error of 0.025, we need to include 42 participants to detect a mean difference of 9.25 on T2* at 30 days, assuming no differences with placebo. Assuming a loss of 10% of patients, we increased the sample size to 50 patients (25 patients per arm).

2.8. Statistical analysis

All statistical comparisons will be made under an intention‐to‐treat principle. Continuous variables will be presented as mean ± SD for normally distributed variables and as median (interquartile range) otherwise. Discrete data will be expressed as percentages.

The primary and secondary endpoints will be tested using an analysis of covariance (ANCOVA) design within a framework of linear mixed model. The analysis will include a between (FMC vs placebo) and within comparison (changes at 7 and 30 days). The interaction term Tx*visit will be included if the omnibus P value is ≤0.05. The ANCOVA model for the primary analysis will include as dependent variable the myocardial T2* CMR values; the contrast among treatment groups at 30 days and 7 days will test the primary and co‐primary endpoint, respectively. As a prespecified analysis, no adjustment for multiple comparisons will be made. Baseline value of myocardial T2* CMR will be included as an obligated covariate. The use of other covariates will be dictated if important differences among treatment groups are observed after randomization. Based on the normality of residuals, a decision about transforming the outcome variable will be made. A similar approach will be taken for the secondary endpoints where LV and RV systolic function, KCCQ, NYHA class, and serum biomarkers will be the outcome variables.

A 2‐sided P value of 0.05 will be considered statistically significant for all analyses. Stata release 15.1 (StataCorp LP, College Station, TX) will be used for the analysis.

2.9. Current status

Patient enrollment started in May 2017. As of December 31, 2017, twenty‐five patients had been enrolled in the study (50% of the target). Baseline characteristics of these patients are described in Table 3.

Table 3.

Baseline characteristics (n = 25)

Variable	Value
Demographics and medical history
Age, years	72.5 (67–78.5)
Male sex	17 (68.0)
Hypertension	16 (64)
Dyslipidemia	15 (60)
DM	12 (48)
Smoker	3 (12.0)
Former smoker	13 (52.0)
CAD	9 (36.0)
Hospital admission for AHF in the last year	14 (56.0)
COPD	6 (24.0)
CKD	8 (32.0)
Stroke	5 (20.0)
NYHA functional class
II	23 (92.0)
III	2 (8.0)
Vital signs
Heart rate, bpm	70 (60–79)
SBP, mm Hg	118 (106–130)
ECG and echocardiography
AF	9 (36.0)
LVEF, %	40 (34–44)
Laboratory tests
Hb, g/dL	12 (12.1–13.3)
Anemia (WHO criteria)a	8 (32.0)
TSAT, %	14.9 (11–18.9)
Ferritin, ng/mL	78 (42–148)
Absolute ID	14 (56)
Relative ID	11 (44.0)
Lymphocyte count, ×103 cells/mL	1720 (1210–2130)
Sodium, mEq/L	140 (139–142)
Potassium, mEq/L	4.6 (4.3–4.9)
Urea, mEq/L	62 (50–82)
sCr, mg/dL	1.17 (0.94–1.57)
eGFR <60 mL/min/1.73 m2	62 (44–83)
NT‐proBNP, pg/mL	1690 (1117–2836)
Medical treatment
Diuretic	23 (92.0)
β‐Blocker	22 (80.0)
ACEI	6 (24.0)
ARB	6 (24.0)
Sacubitril/valsartan	6 (24.0)
MRI	13 (52.0)

Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; AF, atrial fibrillation; AHF, acute decompensated heart failure; ARB, angiotensin II receptor blocker; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; ID, iron deficiency; IQR, interquartile range; LOS, length of stay; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MRI, mineralocorticoid receptor inhibitor; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; sCr, serum creatinine; TSAT, transferrin saturation; WHO, World Health Organization. Data are presented as n (%) or median (IQR).

^aWHO criteria for anemia: adult male, Hb 13 g/dL; adult nonpregnant female, Hb 12 g/dL, adult pregnant female, Hb 11 g/dL. Absolute ID, ferritin <100 ng/mL; relative ID, ferritin 100–299 ng/mL and TSAT <20%.

2.10. Planned substudies

The following substudies are planned:

1. The correlation of basal T1 mapping and T2* with basal ferritin and TSAT.

2. Correlations of changes in T1 mapping and T2* with changes in ferritin and TSAT.

3. The effect of FCM on RV function.

4. The effect of FCM on LV tissue Doppler.

3. RESULTS

Once the study is finished, the changes in T2* and T1 mapping after FCM administration at 7 and 30 days will be documented. Furthermore, we will describe changes in laboratory data, functional capacity (6MWT, NYHA class), quality of life (KCCQ), LVEF, and ventricular diameters and volumes in echocardiography and CMR. Finally, we will relate the changes in T2* and T1 mapping with secondary endpoints mentioned above. We expect the results to be available in October 2018.

4. DISCUSSION

The prevalence of ID in chronic HF is approximately 50%. It is commonly associated with decreased functional capacity and quality of life, and increased risk of mortality and readmission, even in the absence of anemia.1, 2, 3, 4, 5, 6, 7 Indeed, the administration of FCM has been shown to reverse these changes within an acceptable safety profile.8, 9 Several studies have demonstrated clinical improvement after IV iron administration in patients with and without anemia, suggesting that its beneficial effect includes additional mechanisms independent of the erythropoietic pathway.10, 11

4.1. Iron and myocardial function

Iron plays a crucial role in oxygen transport, through the production of Hb; oxygen storage, through myoglobin; and as a component of the mitochondrial respiratory chain involved in energy production.1

An experimental study has shown that rats with iron‐deficiency anemia developed LV hypertrophy and dilation due to mitochondrial ultrastructural damage.12 Another study in nonanemic iron‐deficient mice showed that iron content in cardiomyocytes and mitochondrial function was restored by iron repletion.13 In humans, a small study showed a reduction in the iron content of cardiomyocytes in patients with HF and reduced ejection fraction (HFrEF) as compared with controls.14 More recently, Toblli et al., in a small randomized trial including 60 patients with HFrEF, ID, and chronic kidney disease, showed that iron sucrose administration translated into a significant 6‐month improvement in LVEF.24 More recently, findings from a cohort of 232 patients undergoing renal transplantation showed an increase of LVEF that was particularly notable in those with systolic dysfunction.25

This preliminary evidence has led us to postulate that myocardial ID may play a direct role in the pathogenesis and progression of HF. However, the clinical impact of myocardial ID on HF has not been thoroughly evaluated, mainly because of the lack of reliable and widely available noninvasive techniques for myocardial iron quantification.

4.2. CMR and myocardial iron assessment

CMR has emerged as a noninvasive accurate technique for evaluation of cardiac anatomy, function, and risk stratification.26, 27 More recently, this technique has been used to assess myocardial iron content.15 The T2* CMR sequence has been considered a reliable tool for myocardial iron overload assessment.16, 17 Nagao et al., in a small case–control study, found a significant decrease in myocardial iron concentration, assessed by T2* CMR, particularly in nonischemic HF patients.18 Later, these authors also reported that T2* CMR was related to an increased risk of adverse outcomes.18 In a pilot study of 8 patients with HFrEF, our group found that treatment with FCM was associated with significant 30‐day changes in T2* CMR, and they were associated with marked improvement in LVEF.21 Some new CMR techniques, such as T1 mapping, have emerged as potential alternatives for myocardial iron quantification.19 We postulate that the T1 mapping CMR sequence, a more sensitive and reproducible technique,20 could also identify myocardial ID and quantify changes in myocardial iron content after FCM administration.

In summary, preliminary evidence suggests that myocardial iron content plays a key pathophysiological role in HF. We speculate that with the new CMR sequences we will be able to reliably assess changes in myocardial iron content after IV iron administration, and, thereby, open a new modality of treatment for care of HF patients. In addition, these results will add new insights about the role of iron in the physiopathology of the disease. A randomized clinical trial is a necessary step forward to advance the knowledge in this area.

4.3. Study limitations

There is a possibility that large areas of fibrosis may modify T2* and T1 measurement, irrespective of iron status. As CMR are only performed on 1.5‐T machines, and T1 mapping is performed with the MOLLI sequence, the extrapolation of the findings to 3‐T machines or other T1‐mapping protocols is unknown.

Several factors inherent to the study design, such as lower dose (and 1‐time) administration of FCM, short trial duration (endpoint assessment at 30 days), and broad inclusion criteria (LVEF up to 50%; anemia not required), might reduce the expected response to therapy. In addition, the small number of patients leading to inadequate statistical power may become a potential limitation to reliably assess the clinical response.

5. CONCLUSION

We hypothesize that T2* and T1‐mapping CMR sequences will be sensitive enough to detect changes in myocardial iron content following administration of FCM, and that those changes will correlate with surrogates of HF severity.

Conflicts of interest

The authors declare no potential conflicts of interest.

Supporting information

Appendix 1. Complete list of Myocardial‐IRON investigators

Appendix 2. Kansas City Cardiomiopathy Questionnaire

Appendix 3. Details of the CMR sequences used

Miñana G, Cardells I, Palau P, et al. Changes in myocardial iron content following administration of intravenous iron (Myocardial‐IRON): Study design. Clin Cardiol. 2018;41:729–735. 10.1002/clc.22956