Iron deficiency is one of the most prevalent comorbidities in chronic heart failure (HF), affecting more than half of all HF patients. The detrimental clinical and prognostic consequences of iron deficiency have been stressed by numerous studies.1 However, the pathophysiology of iron deficiency in HF is largely unclear. Although anemia, as a consequence of iron deficiency, may seem a reasonable explanation for the adverse effects, iron deficiency without anemia was also strongly and independently associated with impaired quality of life, exercise intolerance, and mortality.1 Furthermore, the beneficial effects of intravenous iron in iron-deficient HF patients (ie, improvement in exercise tolerance, New York Heart Association Functional Classification, and quality of life) were irrespective of attained hemoglobin levels.2,3 These findings shifted the focus from hemoglobin toward more direct effects of iron itself on nonhematopoietic tissues that are important for exercise capacity, such as skeletal and cardiac muscle. It has also been acknowledged that the exercise intolerance of chronic HF patients is not solely explained by peripheral muscle underperfusion associated with cardiac dysfunction. Several in vitro studies showed direct detrimental effects of iron deficiency on mitochondrial function and morphology, among others in human cardiomyocytes and myoblasts.4–6 Impaired mitochondrial respiration and contractility of iron-deficient human cardiomyocytes could be rescued by adding transferrin-bound iron to these cells.4 A more direct way to study the effects of iron status on exercise tolerance is to analyze mitochondrial respiratory function in skeletal muscle biopsies.7 However, this method provides static results and is associated with excessive burden to the patients, especially when multiple biopsies are taken.
To study the consequences of iron deficiency on exercise capacity, a more dynamic approach is needed. Phosphorus-31 magnetic resonance spectroscopy (31P MRS) is such a method, allowing noninvasive, real-time, in vivo measurement of oxidative skeletal muscle metabolism, both at rest and during exercise. With a phosphorus-31 coil, phosphorus-containing metabolites such as phosphocreatine (PCr), inorganic phosphate, and adenosine triphosphate (ATP) can be detected and quantified in human tissue. The high-energy bond between creatine and a phosphate group makes PCr a rapidly available anaerobic store of chemical energy in skeletal muscle cells. During exercise, PCr is depleted by donating high-energy phosphate groups to ADP, which converts into ATP, and the tight balance between ATP use and production is therefore kept intact. This process, facilitated by the enzyme creatine kinase, is later reverted in postexercise rest to regenerate the PCr pool from creatine and ATP. The largest portion of all ATP is derived by mitochondrial processes, of which many are iron-dependent. Iron is directly involved in several complexes of the respiratory chain, containing iron–sulfur clusters, but is also a critical component of multiple other heme-containing enzymes involved in energetic machinery.8 When applying 31P MRS in a dynamic exercise protocol, PCr kinetics can be assessed before, during, and after exercise.9
To date, no randomized clinical trial has been performed focusing on the effect of intravenous iron administration on oxidative skeletal muscle metabolism in HF patients. Therefore, the results of the Ferric Iron in Heart Failure II Trial (FERRIC-HF II), which are published in the current issue of this journal, are important to better understand the mode of action of iron repletion in HF patients.10 In this randomized, double-blind, placebo-controlled trial, Charles-Edwards et al prospectively studied the influence of intravenous iron therapy on PCr kinetics in HF patients using 31P MRS. They enrolled 40 patients with symptomatic chronic HF, at least a moderately reduced left ventricular ejection fraction (≤45%) and iron deficiency (ferritin <100 µg/L or ferritin <300 µg/L with transferrin saturation <20%). Patients were randomized to either a single dose of intravenous iron (iron isomaltoside) or matching placebo. Using 31P MRS, the authors studied several aspects of oxidative metabolism of the quadriceps muscle, both at rest and during low-intensity exercise. These measurements were performed at baseline (predose) and 2 weeks postdose of either intravenous iron or placebo. The primary end point of the study was the change in PCr recovery half-time postexercise 2 weeks after iron administration. Patients receiving iron isomaltoside showed a significant improvement in PCr recovery halftime during follow-up. Other, secondary parameters reflecting PCr kinetics (eg, resting and exercise PCr, inorganic phosphate, and pH) were not affected by administration of iron isomaltoside (see the Figure). In subgroup analyses (ie, anemic versus nonanemic patients), PCr recovery rate improved significantly in anemic patients, whereas a trend toward improvement was observed in patients without anemia. However, no formal test for interaction was provided and nonanemic patients generally received a lower iron repletion dose.
Several other research groups have studied PCr kinetics as a noninvasive and in vivo proxy for mitochondrial function in chronic HF patients using 31P MRS. Observational studies on skeletal muscle energetics from the past century showed that symptomatic HF patients had impaired oxidative mitochondrial capacity of the forearm flexor muscle compared to healthy controls.11 More recently, Weiss et al12 studied calf muscle energetics using 31P MRS in both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) patients. Compared to healthy controls and HFrEF patients, HFpEF patients showed the most impaired oxidative skeletal muscle metabolism, already at low exercise intensity. Moreover, the PCr recovery rate in both HFrEF and HFpEF patients was markedly longer, with most delay in HFpEF patients.12 Another study confirmed these findings in a cohort of chronic HF patients who underwent 31P MRS of the calf muscle. HF patients had lower PCr at baseline, lower pH during exercise, and more impaired PCr recovery postexercise, compared with healthy controls. The HF cohort was further stratified based on the presence or absence of iron deficiency using the conventional definition. Compared with chronic HF without iron deficiency, muscle energetics in iron-deficient patients were even more impaired, reflected by the largest PCr depletion and lower intracellular pH. The PCr recovery time was not affected by iron deficiency in the HF cohort (44 patients), although this study might have been underpowered to assess this component of the PCr kinetics.13
The findings from FERRIC-HF II add valuable pieces to the iron puzzle. Interestingly, hemoglobin levels only marginally increased in the iron isomaltoside arm; this increase was not correlated to the change in PCr recovery rate. This was in contrast with the change in ferritin levels during follow-up, which was inversely related to PCr recovery. Taken together, this study provides additional evidence that exercise intolerance in iron-deficient HF patients is at least partly independent of hemoglobin. Second, the data from Charles-Edwards et al show a substantial improvement in PCr kinetics in patients receiving only a single dose of iron isomaltose, comparable with several weeks of exercise training.14 Finally, both resting and exercise PCr levels were comparable between treatment arms; only PCr regeneration was affected by administration of iron isomaltoside. This finding is not entirely surprising; it is this step that is critically dependent on adequate oxidative mitochondrial function for ATP resynthesis postexercise, in which iron plays a crucial role.8
However, many questions remain to be answered in the pathophysiology of iron deficiency in HF and its treatment. Rather than a negative iron balance leading to absolute iron deficit, iron deficiency in HF can also develop because of altered distribution of systemic iron as a consequence of inflammation, neurohumoral activation, or tissue stress associated with mechanical overload or ischemia. Whereas iron metabolism was mapped in great detail in hematopoietic organs (bone marrow, spleen, liver), cellular iron uptake and intracellular homeostasis on nondividing cells, such as skeletal or cardiac myocytes, were rarely studied and are poorly understood.15 There is a paucity of data about distinct differences between various intravenous iron preparations, about persistence of clinical improvement in HF patients receiving intravenous iron, and about possible direct effects of intravenous iron on cardiac muscle. It is also unclear which cellular component of the bioenergetic machinery is mostly affected by HF-related iron deficiency and its response to iron administration. From a clinical standpoint, patients with HFpEF were excluded in the FERRIC-HF II. Particularly HFpEF patients seem to have even worse oxidative skeletal muscle metabolism compared with HFrEF patients, which may be attributable to coexisting muscle steatosis.12 Unfortunately, the study was not powered to detect differences between anemic and nonanemic patients; anemic patients received a clinically significant higher dose of iron isomaltoside. Adequately powered studies should be conducted in a nonanemic cohort to completely rule out the possible confounding effect of low hemoglobin levels. Moreover, PCr kinetics should be assessed at multiple time points after intravenous iron administration to better understand the effect on skeletal muscle energetics over time.
No adequately powered randomized clinical trial has been published showing that correction of iron deficiency using intravenous iron supplementation leads to a reduction of (cardiovascular) mortality and morbidity in iron-deficient HF patients, although such trials are currently ongoing with different iron preparations (AFFIRM-AHF [Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency], NCT02937454; FAIR-HF2 [Intravenous Iron in Patients With Systolic Heart Failure and Iron Deficiency to Improve Morbidity and Mortality], NCT03036462; HEART-FID [Randomized Placebo-controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency], NCT03037931; IRONMAN [Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency], NCT02642562). While the results of these major outcome trials are eagerly awaited, mechanistic studies such as the FERRIC-HF II provide very useful insights into the mode of action of intravenous iron.
Dr van der Meer received speaker’s fees and grant support from Vifor Pharma. The other authors report no conflicts.