Noninvasive Imaging Estimation of Myocardial Iron Repletion Following Administration of Intravenous Iron: The Myocardial‐IRON Trial

Núñez, Julio; Miñana, Gema; Cardells, Ingrid; Palau, Patricia; Llàcer, Pau; Fácila, Lorenzo; Almenar, Luís; López‐Lereu, María P.; Monmeneu, José V.; Amiguet, Martina; González, Jessika; Serrano, Alicia; Montagud, Vicente; López‐Vilella, Raquel; Valero, Ernesto; García‐Blas, Sergio; Bodı́, Vicent; Espriella, Rafael de la; Lupón, Josep; Navarro, Jorge; Górriz, José Luis; Sanchís, Juan; Chorro, Francisco J.; Comín‐Colet, Josep; Bayés‐Genís, Antoni; Soler, Meritxell; Villaescusa, Amparo; Civera, Jose; Mollar, Anna; Moreno, María Isabel Benito; Vidal, Verónica

doi:10.1161/jaha.119.014254

Cited by 66 publications

(78 citation statements)

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“…1). After excluding 12 reports [6][7][8][9][10][11][12][13][14][15][16][17], mainly because they were not randomisedcontrolled trials or did not report relevant outcomes (Supplementary Table S1), seven trials (Table 1) that enrolled 2,166 patients (n = 1168 assigned to IV iron; n = 998 assigned to the control/placebo) were included in the primary analysis [4,[18][19][20][21][22][23]. The most common definition of ID was a ferritin < 100 µg/L and/or, if ferritin was 100-300 µg/L, a TSAT of < 20%.…”

Section: Resultsmentioning

confidence: 99%

Intravenous iron for heart failure with evidence of iron deficiency: a meta-analysis of randomised trials

et al. 2021

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Background The recent AFFIRM-AHF trial assessing the effect of intravenous (IV) iron on outcomes in patients hospitalised with worsening heart failure who had iron deficiency (ID) narrowly missed its primary efficacy endpoint of recurrent hospitalisations for heart failure (HHF) or cardiovascular (CV) death. We conducted a meta-analysis to determine whether these results were consistent with previous trials. Methods We searched for randomised trials of patients with heart failure investigating the effect of IV iron vs placebo/control groups that reported HHF and CV mortality from 1st January 2000 to 5th December 2020. Seven trials were identified and included in this analysis. A fixed effect model was applied to assess the effects of IV iron on the composite of first HHF or CV mortality and individual components of these. Results Altogether, 2,166 patients were included (n = 1168 assigned to IV iron; n = 998 assigned to control). IV iron reduced the composite of HHF or CV mortality substantially [OR 0.73; (95% confidence interval 0.59–0.90); p = 0.003]. Outcomes were consistent for the pooled trials prior to AFFIRM-AHF. Whereas first HHF were reduced substantially [OR 0.67; (0.54–0.85); p = 0.0007], the effect on CV mortality was uncertain but appeared smaller [OR 0.89; (0.66–1.21); p = 0.47]. Conclusion Administration of IV iron to patients with heart failure and ID reduces the risk of the composite outcome of first heart failure hospitalisation or cardiovascular mortality, but this outcome may be driven predominantly by an effect on HHF. At least three more substantial trials of intravenous iron are underway. Graphic abstract

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Section: Resultsmentioning

confidence: 99%

Intravenous iron for heart failure with evidence of iron deficiency: a meta-analysis of randomised trials

et al. 2021

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“…Mean ± standard deviation LVEF and RVEF were 40.3 ± 10.4% and 56.3 ± 11.4%, and median (inter‐quartile range) were 39% (33–47) and 58% (49–63), respectively. Detailed baseline characteristics of the patients in the two study groups have been reported elsewhere 12,16 . At enrolment, LVSD 1 and LVSD 2 were found in 27 (50.9%) and 38 (71.7%) patients, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…At 30 days, patients assigned to placebo received intravenous FCM if ID persisted. The study design, protocol, and main results have been published and are available elsewhere 12,16 …”

Section: Methodsmentioning

confidence: 99%

“…The Myocardial-IRON trial of patients with chronic HF and ID showed that treatment with FCM causes short-term changes in cardiac magnetic resonance (CMR) sequences suggestive of myocardial iron repletion. 12 Promising data from small clinical studies suggest that iron therapy may improve left ventricular ejection fraction (LVEF) on echocardiography, 13,14 but conflicting results have also been published. 15 Also, little is known about changes in the right ventricular ejection fraction (RVEF), especially on CMR, as a gold-standard cardiac imaging technique.…”

Section: Introductionmentioning

confidence: 99%

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Short‐term changes in left and right systolic function following ferric carboxymaltose: a substudy of the Myocardial‐IRON trial

et al. 2020

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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 ventricular 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% (LVSD 1) or <45% (LVSD 2), respectively, and 10 (18.9%) and 17 (32.1%) patients had RVEF < 45% (RVSD 1) or <51% in women and <52% in men (RVSD 2) , respectively. Treatment with FCM was associated with a significant improvement in LVEF at 30 days (LVSD 1 : Δ2.3%, P < 0.001; LVSD 2 : Δ4.1, P = 0.014). FCM was also associated with a significant and early improvement in RVEF at 7 days (RVSD 1 : Δ6.9%, P = 0.003; RVSD 2 : Δ3.2%, P = 0.003) that persisted at 30 days (RVSD 1 : Δ8.1%, P < 0.001; RVSD 2 : 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.

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“…Although the unequivocal benefits of intravenous iron may be related to a peripheral effect [ 14 , 28 ], recent studies support a cardiac-centered hypothesis. First, ferric carboxymaltose administration was associated with cardiac iron repletion in cardiac magnetic resonance T2* and T1 mapping sequences [ 29 ]. Second, Doppler and strain rate echocardiography parameters were significantly improved after intravenous iron administration in patients with stable systolic HF and ID without anemia [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells

et al. 2021

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Background Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells. Methods HF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production. Results Hearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells. Conclusions HF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF.

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Noninvasive Imaging Estimation of Myocardial Iron Repletion Following Administration of Intravenous Iron: The Myocardial‐IRON Trial

Cited by 66 publications

References 27 publications

Intravenous iron for heart failure with evidence of iron deficiency: a meta-analysis of randomised trials

Intravenous iron for heart failure with evidence of iron deficiency: a meta-analysis of randomised trials

Short‐term changes in left and right systolic function following ferric carboxymaltose: a substudy of the Myocardial‐IRON trial

Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells

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