Disordered Iron Homeostasis in Chronic Heart Failure: Prevalence, Predictors, and Relation to Anemia, Exercise Capacity, and Survival

Study Questions:

How is iron metabolized in patients with chronic heart failure (HF), and what are the implications for abnormal iron metabolism?

Methods:

Iron indices were evaluated in 157 patients with chronic HF (ejection fraction ≤45% for 6 months) and 22 age- and sex-matched controls with no illnesses and normal cardiac function. Serum iron, total iron binding capacity (TIBC), ferritin, and soluble transferrin receptor (sTFR) concentrations were measured. Anemia was defined as a hemoglobin <13 g/dl for males and <12 g/dl in females. Iron deficiency anemia (IDA) was defined as an iron saturation (TSAT) <20%, and absolute IDA (AIDA) required a TSAT <20% with a ferritin <30 μg/L. Functional iron deficiency was defined as a TSAT <20% with a ferritin >30 μg/L. Anemia of chronic disease (ACD) with concomitant IDA was defined as TSAT <20%, ferritin >30 μg/L, and elevated TIBC and sTFR.

Results:

Compared with controls, individuals with HF had more renal dysfunction and lower hemoglobin, serum iron, and TSAT levels (all p < 0.05). There was no difference in median [interquartile range] ferritin level between control (85 [47-136]) and HF (87 [43-149]) patients. In the HF group, the mean age was 71 ± 12 years, and mean ejection fraction and serum hemoglobin was 32 ± 9% and 13.1 ± 1.6 g/dl, respectively. Anemia was present in 61 (39%) patients. There were 89 (57%) HF patients with a TSAT ≥20%, and 68 (43%) with a TSAT <20%. Patients with a TSAT <20% had higher New York Heart Association (NYHA) class, higher C-reactive protein, and worse anemia than those with a TSAT ≥20% (all p < 0.05). Progression from NYHA class I to IV was associated with a decrease in ferritin levels (analysis of variance, p = 0.04). Likewise, patients with NYHA class III and IV HF were more likely to have iron deficiency substrates (ACD or IDA). On cardiopulmonary stress testing, patients with a TSAT <20% had lower pulmonary venous oxygen tension (11.4 ± 2.1 vs. 14.9 ± 1.7 ml/kg/min, p = 0.03) and higher slope ventilatory equivalent of carbon dioxide (54.8 ± 10.6 vs. 44.1 ± 1, p = 0.02) than those with higher TSATs. There were 27 deaths (17%) over 743 medians days of follow-up. A TSAT <20% was associated with a 3.4-fold [1.5, 7.7] increased risk of death on univariable analysis. Nonanemic patients with iron deficiency had a two-fold higher risk of death than anemic iron-replete patients.

Conclusions:

The authors concluded that abnormal iron metabolism is associated with worse exercise capacity and survival in HF.

Perspective:

This was a very complex and thorough evaluation of iron metabolism in patients with HF. The authors demonstrated a high burden of anemia and iron deficiency in patients with HF. Interestingly, patients with NYHA class I/II HF tended to have greater evidence of anemia of chronic (ACD) disease, but this progressed to IDA (with or without ACD) as NYHA class progressed. The authors suggest that cytokine elevation in HF may be responsible for the development of ACD. Perhaps poor dietary intake of iron and reduced gastrointestinal absorption lead to the development of absolute iron deficiency in advanced HF. Further, the long-term impact of repeated hospitalizations and testing/interventions that may deplete iron stores in advancing HF needs to be considered. Regardless, abnormal iron metabolism was associated with higher mortality in this cohort. Questions remain regarding the impact of iron repletion in HF and whether abnormal iron metabolism is a marker of advancing HF, a direct cause of HF progression, or a result of HF progression.

Clinical Topics: Cardiac Surgery, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Cardiac Surgery and Heart Failure, Lipid Metabolism, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Heart Transplant

Keywords: Exercise Tolerance, Iron, Missouri, Heart Transplantation, Heart Diseases, Oligodeoxyribonucleotides, Ferritins, C-Reactive Protein, Flavins, Heart Failure, Luciferases, Anemia, Iron-Deficiency, Hospitalization, Receptors, Transferrin


< Back to Listings