Iron deficiency and cardiovascular disease

 
von Haehling S, Ewa A. Jankowska, Dirk J. van Veldhuisen et al
Nature Reviews Cardiology Published online 21 July 2015 doi:10.1038/nrcardio.2015.109.
 

Introduction

Iron deficiency is a very common condition, particularly in young people and in the elderly, and in those with chronic inflammation.
Iron is not only involved in erythropoiesis, but it has many other physiological roles, including in oxygen transport and storage, synthesis and degradation of proteins, lipids and ribonucleic acids, mitochondrial function, myocardial and skeletal muscle metabolism, and function of the thyroid gland, central nervous system and immune system. Erythropoiesis has priority over other metabolic processes for iron use. Given the wide implication of iron in many organ systems, the effects of iron deficiency are broad, including impaired intellectual functioning.
The impact of iron and iron deficiency on patients with cardiovascular disease (CVD) receives increasing attention. Several studies have shown that patients with heart failure (HF) and iron deficiency can benefit from iron supplementation, irrespective of the presence of anaemia. Iron deficiency also appears relevant in other CVD such as coronary artery disease (CAD) or pulmonary hypertension.

 
Pathophysiology of iron metabolism

Iron is an essential trace element, which exists in different forms (Fe²⁺ and Fe³⁺). The different characteristics are required for oxygen transport, but also a potential source of toxic free radicals.
Daily intake in developed countries is about 12-15 mg, of which 1-2 mg is ultimately absorbed; the same amount that we loose via blood, skin, urine and gut mucosa per day. It is estimated that a total of about 3-5 g of iron is normally present in the body. About 2/3 is contained in haemoglobin, another part is bound to ferritin. Both absolute and functional iron deficiency can occur, with the latter meaning that iron is stored but cannot be mobilised. Serum ferritin can serve as a surrogate marker of the stored iron, and in patients with HF iron deficiency can be diagnosed when serum ferritin is <100 µg/L or when serum ferritin is <300 µg/L and transferrin saturation (TSAT) is <20% of iron binding sites occupied.
Oral administration to treat iron deficiency often contains Fe²⁺, with limited effectiveness since little iron is absorbed by the gut, because of its the metallic taste and since it often causes gastrointestinal adverse effects. Parenteral iron preparations allow higher doses to be administered, thus iron stores can be replenished rapidly. Different intravenous (IV) preparations are available, with the use of iron sucrose and ferric carboxymaltose being most common in the context of CVD.
 

Iron in CAD

A hypothesis formulated in 1981 suggested that stored iron is toxic to the heart, which would explain the increased incidence of heart disease in men and postmenopausal women as compared with premenopausal women. However, most studies testing this hypothesis failed to find a positive association between CAD and serum ferritin levels. A meta-analysis on the other hand, found a significant negative association between TSAT and CAD, indicating that high body iron stores could confer protection against development of CHD. This link has been confirmed in several studies, showing a higher risk of CAD in the lowest quartiles of TSAT, ferritin and soluble transferrin receptor (sTfR) levels. A U-shaped relationship between serum ferritin and mortality was observed.
Iron deficiency was determined in bone marrow of patients with stable CAD who qualified for CABG surgery. Among circulating biomarkers of iron deficiency, high levels of serum sTfR yielded the strongest association with depleted extracellular iron stores in bone marrow.
Iron deficiency seems common in CAD and associated with a higher risk of death, especially in high-risk patients. It is to date, however, unknown whether replenishing iron stores in CAD is beneficial.

 
Iron in HF

Ample evidence is available on iron deficiency in HF. Several studies have demonstrated that a substantial proportion (up to 60%) of patients with HF have iron deficiency. Anaemia is also common in HF and its pathophysiology involves iron deficiency. The two conditions show independent, and sometimes opposing associations with HF.
Initially, it was attempted to improve CV health in HF by treating anaemia with erythropoietin plus iron sucrose. This strategy indeed yielded symptomatic and functional improvements. No positive effects were seen, however, in the RED-HF study in which HF patients with anaemia were randomly assigned to darbepoetin alfa or placebo. The rather high threshold for initiation of iron supplementation was suggested as a possible explanation for the neutral effect.
Better results were obtained in studies testing IV iron sucrose supplementation without erythropoietin. Also, after treatment with IV ferric carboxymaltose in the FAIR-HF trial, HF patients reported improvement of symptoms, and showed better NYHA class and 6-minute walk distance. This effect was seen both in anaemic and nonanaemic patients.
After publication of the FAIR-HF results, the 2012 ESC guidelines for the management of HF included a class 1c recommendation for the assessment of blood biochemistry parameters to enable detection of reversible and treatable causes of HF (such as hypocalcaemia and thyroid dysfunction) and comor­bidities (for example iron deficiency). The guidelines also state that iron therapy can be considered as a treatment in patients with iron deficiency. A 2011 update of the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines for the management of HF contained a grade B recommendation to identify and treat iron deficiency in patients with chronic HF, aiming to reduce symptoms and improve exercise tolerance and quality of life. The 2013 joint HF guidelines of the ACC and AHA did not consider the results of the FAIR‑HF study to be sufficient to make a recommenda­tion.
The CONFIRM-HF study results have strengthened the evidence. Treatment dose of ferric carboxymaltose or placebo was based on haemoglobin values and body weight, in patients with symptomatic chronic HF and iron deficiency and anaemia. Patients receiving ferric carboxymaltose showed greater 6-min walk distance at week 24, which was maintained until week 52. Patients reported improvement of symptoms and the risk of hospitalisation for worsening HF was more than halved. A clinical outcomes study evaluating ferric carboxymaltose (FAIR-HF2) is currently underway, and its effect in patients with HF with preserved EF (FAIR-HFpEF) will also be examined.
 

Iron in PAH

Many features of pulmonary arterial hypertension (PAH) overlap with chronic HF, for instance subclinical inflammation and clinical symptoms. Also in PAH, iron deficiency is common, with prevalences ranging from 30 to 63%, depending on the definition used. Patients show lower exercise capacity than PAH patients without iron deficiency. The value of iron deficiency as a therapeutic target has been explored in a pilot study. Patients with iron deficiency who were treated with ferric carboxymaltose increased their 6-min walking distance after 8 weeks, and reported improved quality of life.
 

Iron in heart transplantation

Even years after cardiac transplantation, anaemia is common. In cardiac transplantation, iron administration needs to be considered with caution. Animal experiments showed that reducing iron levels with deferoxamine was beneficial with regard to graft viability and patient evidence suggests that iron overload should be avoided. In patients awaiting transplantation, treatment of iron deficiency may, however, improve patient outcomes.
 

Iron in nontransplant cardiac surgery

In patients undergoing nontransplant cardiac surgery, unlike in heart transplantation, anaemia is an independent predictor of mortality. Functional iron deficiency, and to a lesser extent absolute deficiencies, are common in preoperatively anaemic patients. Patients with preoperative iron deficiency showed lower preoperative haemoglobin levels and higher perioperative transfusion rates in the first week and higher physical fatigue score at 7 days post-surgery. Studies evaluating the value of oral or IV iron administration in these patients did not significantly affect haemoglobin levels or transfusion needs. Mobility and well-being were not assessed in these studies.

 
Conclusion

Anaemia is an independent predictor of death in patients with HF, but the prognostic value of iron deficiency is less clear. Evidence is accumulating that iron supplementation improves symptoms in patients with HF and assessment of the potential benefit on morbidity and mortality after correction of iron deficiency is currently underway.
In CAD and PAH, iron administration can be beneficial, but its value for patients undergoing cardiac surgery requires further study, with a focus on quality of life or earlier mobility after surgery. Patients undergoing transplantation can benefit from IV iron while waiting for surgery, but after transplantation it seems contraindicated.
Ongoing and future research should further define patient groups that may benefit from iron supplementation as well as the optimal treatment regimen.  
 
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