Adaptive response of the heart to long-term anemia induced by iron deficiency

Am J Physiol Heart Circ Physiol. 2009 Mar;296(3):H585-93. doi: 10.1152/ajpheart.00463.2008. Epub 2009 Jan 9.


Anemia is common in patients with chronic heart failure and an independent predictor of poor prognosis. Chronic anemia leads to left ventricular (LV) hypertrophy and heart failure, but its molecular mechanisms remain largely unknown. We investigated the mechanisms, including the molecular signaling pathway, of cardiac remodeling induced by iron deficiency anemia (IDA). Weanling Sprague-Dawley rats were fed an iron-deficient diet for 20 wk to induce IDA, and the molecular mechanisms of cardiac remodeling were evaluated. The iron-deficient diet initially induced severe anemia, which resulted in LV hypertrophy and dilation with preserved systolic function associated with increased serum erythropoietin (Epo) concentration. Cardiac STAT3 phosphorylation and VEGF gene expression increased by 12 wk of IDA, causing angiogenesis in the heart. Thereafter, sustained IDA induced upregulation of cardiac hypoxia inducible factor-1alpha gene expression and maintained upregulation of cardiac VEGF gene expression and cardiac angiogenesis; however, sustained IDA promoted cardiac fibrosis and lung congestion, with decreased serum Epo concentration and cardiac STAT3 phosphorylation after 20 wk of IDA compared with 12 wk. Upregulation of serum Epo concentration and cardiac STAT3 phosphorylation is associated with a beneficial adaptive mechanism of anemia-induced cardiac hypertrophy, and later decreased levels of these molecules may be critical for the transition from adaptive cardiac hypertrophy to cardiac dysfunction in long-term anemia. Understanding the mechanism of cardiac maladaptation to anemia may lead to a new strategy for treatment of chronic heart failure with anemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Anemia, Iron-Deficiency / complications
  • Anemia, Iron-Deficiency / metabolism
  • Anemia, Iron-Deficiency / physiopathology*
  • Animals
  • Blood Pressure
  • Body Weight
  • Disease Models, Animal
  • Erythropoietin / blood
  • Heart / physiopathology*
  • Heart Failure / etiology*
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Heart Rate
  • Hypertrophy, Left Ventricular / etiology*
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Iron / blood
  • Kidney / physiopathology
  • Male
  • Myocardial Contraction
  • Myocardium / metabolism
  • Myocardium / pathology
  • Neovascularization, Physiologic
  • Phosphorylation
  • Pulmonary Edema / etiology
  • Pulmonary Edema / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Erythropoietin / metabolism
  • STAT3 Transcription Factor / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / blood
  • Vascular Endothelial Growth Factor A / metabolism
  • Ventricular Function, Left*
  • Ventricular Pressure
  • Ventricular Remodeling*


  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Erythropoietin
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Erythropoietin
  • Iron