The following are key points to remember from this state-of-the-art review on iron deficiency and cardiovascular disease:

1. Iron deficiency (ID) is characterized by: a) depleted iron stores linked with a decrease in the total body iron supply due to insufficient nutritional iron intake, impaired absorption, or chronic blood loss (i.e., absolute ID); and/or b) reduced circulating iron, which can be linked to a persistent inflammatory state as in many cardiovascular diseases (CVDs) (i.e., functional ID) and is common in patients with CVD.
2. Up to 60% of patients with coronary artery disease (CAD), and an even higher proportion of those with heart failure (HF) or pulmonary hypertension, have ID, while the evidence for cerebrovascular disease, aortic stenosis, and atrial fibrillation (AF) is less robust.
3. The prevalence of ID increases with the severity of cardiac and renal dysfunction and is probably more common among 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 antithrombotic therapy or gastrointestinal or renal disease may all cause ID.
4. For older people in the general population and patients with HF with reduced ejection fraction (HFrEF), both anemia and ID are associated with a poor prognosis; each may confer independent risk.
5. There is now growing evidence that ID is an important therapeutic target for patients with HFrEF, even if they do not have anemia. Whether this is also true for other HF phenotypes or patients with CVD in general is currently unknown.
6. Randomized trials have shown that intravenous ferric carboxymaltose (FCM) improved symptoms, health-related quality of life and exercise capacity, and reduced hospitalizations for worsening HF in patients with HFrEF and mildly reduced EF (<50%). Since ID is easy to treat and is effective for patients with HFrEF, such patients should be investigated for possible ID.
7. The 2021 European Society of Cardiology (ESC) guidelines on HF provide a Class I, Level of Evidence C recommendation for periodical screening for ID and anemia with a full blood count, serum ferritin concentration, and transferrin saturation for HF patients. They also provide a Class IIa, Level of Evidence A recommendation for FCM use in symptomatic HF patients with EF <45% for alleviating patients’ symptoms, and to improve exercise capacity and quality of life; and a Class IIa, Level of Evidence B recommendation for FCM in patients with HF recently hospitalized for HF and EF <50% to reduce the risk of HF hospitalization.
8. The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guideline on HF provides a Class IIa, Level of Evidence B recommendation that in patients with HFrEF and ID with or without anemia, intravenous iron replacement is reasonable to improve functional status and quality of life.
9. Although there could be a potential role for ID in other CVDs, such as CAD, valvular heart disease, cerebrovascular disease, AF, and pulmonary hypertension, evidence is fragmentary, often conflicting, and the underlying pathophysiological mechanisms are often unknown.
10. Since ID can be easily treated, future research should aim for a full characterization of patients with CVDs for ID, and to identify those phenotypes or patients who are more likely to benefit from iron supplementation.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Nonstatins, Acute Heart Failure, Pulmonary Hypertension, Diet, Hypertension

Keywords: Anemia, Iron-Deficiency, Aortic Valve Stenosis, Atherosclerosis, Atrial Fibrillation, Cardiovascular Diseases, Cerebrovascular Disorders, Coronary Artery Disease, Dietary Supplements, Exercise Tolerance, Ferritins, Fibrinolytic Agents, Functional Status, Geriatrics, Heart Failure, Heart Valve Diseases, Hypertension, Pulmonary, Inflammation, Iron, Iron, Dietary, Kidney Diseases, Phenotype, Quality of Life, Secondary Prevention, Stroke Volume, Thrombosis, Transferrins

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