title: Myocardial and systemic iron depletion in heart failure implications for anemia accompanying heart failure.
abstract: OBJECTIVE
  This study sought to determine the potential pathophysiological link between anemia and disease severity, and adverse outcome in heart failure (HF).
  
  
  BACKGROUND
  Anemia frequently accompanies advanced HF; however, the pathophysiological mechanism responsible for the association between anemia and more severe HF remains uncertain. We hypothesized that a depletion of myocardial iron content may provide the biological link.
  
  
  METHODS
  Complementary clinical and basic studies were performed. Hemodynamic, biochemical, and echocardiographic investigations were performed in 9 healthy controls and 25 patients with advanced HF (left ventricular ejection fraction: 23 ± 10%). Tissue iron content and type 1 transferrin receptor (Tfr1) expression were assessed in human myocardial tissue, and the regulation of Tfr1 expression was studied in isolated cardiomyocytes.
  
  
  RESULTS
  HF patients displayed evidence of iron deficiency as measured by lower serum iron (p < 0.05) and transferrin saturation (TFS) (p < 0.05). When subclassified according to the presence of anemia, TFS was lower in anemic compared with nonanemic HF patients, whereas TFS in nonanemic HF patients was intermediate. In association, myocardial iron content was reduced in HF versus non-HF samples (0.49 ± 0.07 μg/g vs. 0.58 ± 0.09 μg/g, p < 0.05), and there was a significant reduction (p < 0.05) in the myocardial mRNA expression of Tfr1, which plays a key role in cellular iron transport. In the context of HF, catecholamines and aldosterone both down-regulated Tfr1 expression in isolated cardiomyocytes.
  
  
  CONCLUSIONS
  This study suggests the presence of iron depletion in the failing human heart, providing a potential link for the association between anemia and adverse prognosis in HF.
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, St. Kilda Road Central, Melbourne, Australia.
authors.forename: Micha T
authors.initials: MT
authors.lastname: Maeder
authors.forename: Ouda
authors.initials: O
authors.lastname: Khammy
authors.forename: Cris
authors.initials: C
authors.lastname: dos Remedios
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000450:Aldosterone / Q000494:pharmacology; D018798:Anemia, Iron-Deficiency / Q000175:diagnosis*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D015703:Antigens, CD; C068126:CD71 antigen; D006454:Hemoglobins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D010656:Phenylephrine; D000450:Aldosterone; D007501:Iron; D007545:Isoproterenol; D009638:Norepinephrine