Iron deficiency and cardiovascular disease

Abstract

Iron deficiency (ID) is common in patients with cardiovascular disease. Up to 60% of patients with coronary artery disease, and an even higher proportion of those with heart failure (HF) or pulmonary hypertension have ID; the evidence for cerebrovascular disease, aortic stenosis and atrial fibrillation is less robust. The prevalence of ID increases with the severity of cardiac and renal dysfunction and is probably more common amongst women. Insufficient dietary iron, reduced iron absorption due to increases in hepcidin secondary to the low-grade inflammation associated with atherosclerosis and congestion or reduced gastric acidity, and increased blood loss due to anti-thrombotic therapy or gastro-intestinal or renal disease may all cause ID. For older people in the general population and patients with HF with reduced ejection fraction (HFrEF), both anaemia and ID are associated with a poor prognosis; each may confer independent risk. There is growing evidence that ID is an important therapeutic target for patients with HFrEF, even if they do not have anaemia. Whether this is also true for other HF phenotypes or patients with cardiovascular disease in general is currently unknown. Randomized trials showed that intravenous ferric carboxymaltose improved symptoms, health-related quality of life and exercise capacity and reduced hospitalizations for worsening HF in patients with HFrEF and mildly reduced ejection fraction (<50%). Since ID is easy to treat and is effective for patients with HFrEF, such patients should be investigated for possible ID. This recommendation may extend to other populations in the light of evidence from future trials.

Keywords: Anaemia; Cerebrovascular disease; Coronary artery disease; Heart failure; Iron deficiency; Pulmonary hypertension.

Graphical Abstract

Iron deficiency in cardiovascular disease. CAD, coronary artery disease; CBV, cerebrovascular disease; 6MWD, 6 min walking distance; HRQoL, health-related quality of life; NYHA, New York Heart Association; NT-proBNP, N-terminal pro-B-type natriuretic peptide; RV, right ventricular; FDI, ferric derisomaltose.

Figure 1

Iron homeostasis. Heme-bound iron is transported from the gut lumen into the mucose cell through the heme carrier protein 1 (HCP1) and here Fe2 + is released by the activity of the heme-oxidase. Additionally, in the gut lumen Fe3 + is converted to Fe2 + by the ferri-reductase or through reduction by dietary ascorbate and then transported into the mucose cell through the divalent metal transporter 1 (DMT1). Fe2 + can be then converted again to Fe3 + and stored as ferritin, or exported to the bloodstream through ferroportin where it is converted to Fe3 + by hephaestin and binds to transferrin whose role is to transport iron where there is metabolic need. Macrophages contribute to iron homeostasis by taking up transferrin-bound iron by receptor-mediated endocytosis. In the macrophages iron can be stored as ferritin and released when needed through ferroportin. Inflammation leads to an increased release of hepcidin from the liver which downregulates ferroportin and therefore the transport of dietary intake from the inside of the mucosa cells in the small intestine to the bloodstream and also the release of recycled iron from macrophages in the spleen and the liver, potentially leading to iron deficiency. Created with BioRender.com Adapted from Nat Rev Cardiol 2015; 12: 659–669.

Figure 2

Effect of empagliflozin (panel A) and dapagliflozin (panel B) on erythropoietin levels and iron status. Panel A (A) EPO levels in patients receiving empagliflozin 10 mg daily or placebo. (B) RBC indices, hemoglobin and hematocrit values, and iron status at baseline and after 6 months of empagliflozin or placebo. (C) Potential renal mechanisms for increased EPO with sodium-glucose cotransporter 2 (SGLT2) inhibition. Reprint permissions from Mazer et al.Panel B: Plasma levels of erythropoietin and ferritin before and following 12 weeks of treatment with placebo or 10 mg daily of dapagliflozin. * = P < 0.05 compared to baseline in dapagliflozin group using ANOVA and paired t-test and #=P < 0.05 compared to placebo using two-way ANOVA and t-test. Adapted from J Clin Endocrinol Metab. 2020; 105:e1056-e1063.

Figure 3

Risk of cardiovascular outcomes with intravenous iron vs. placebo. Data from Graham et al. pooling data from seven randomized controlled trials on intravenous iron supplementation in HF with iron deficiency. HF, heart failure; CV, cardiovascular; OR, odds ratio; CI, confidence interval.