title: Evidence for a novel mechanism independent of myocardial iron in β-thalassemia cardiac pathogenesis.
abstract: Human β-thalassemia major is one of the most prevalent genetic diseases characterized by decrease/absence of β-globin chain production with reduction of erythrocyte number. The main cause of death of treated β-thalassemia major patients with chronic blood transfusion is early cardiac complications that have been attributed to secondary iron overload despite optimal chelation. Herein, we investigated pathophysiological mechanisms of cardiovascular dysfunction in a severe murine model of β-thalassemia from 6 to 15-months of age in the absence of confounding effects related to transfusion. Our longitudinal echocardiography analysis showed that β-thalassemic mice first display a significant increase of cardiac output in response to limited oxygen-carrying erythrocytes that progressed rapidly to left ventricular hypertrophy and structural remodeling. Following this compensated hypertrophy, β-thalassemic mice developed age-dependent deterioration of left ventricular contractility and dysfunction that led toward decompensated heart failure. Consistently, murine β-thalassemic hearts histopathology revealed cardiac remodeling with increased interstitial fibrosis but virtual absence of myocardial iron deposits. Importantly, development of thalassemic cardiac hypertrophy and dysfunction independently of iron overload has uncoupled these cardiopathogenic processes. Altogether our study on β-thalassemia major hemoglobinopathy points to two successive phases resulting from severe chronic anemia and from secondarily induced mechanisms as pathophysiologic contributors to thalassemic cardiopathy.
authors.affiliation: Institut de recherches cliniques de Montréal, Molecular Genetics and Development, Faculte de Medecine de L'Universite de Montreal, Montreal, Quebec, Canada.
authors.forename: Ekatherina
authors.initials: E
authors.lastname: Stoyanova
authors.forename: Guy
authors.initials: G
authors.lastname: Cloutier
authors.forename: Hady
authors.initials: H
authors.lastname: Felfly
authors.forename: Wafaa
authors.initials: W
authors.lastname: Lemsaddek
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ah-Son
authors.forename: Marie
authors.initials: M
authors.lastname: Trudel
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D006331:Heart Diseases / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017086:beta-Thalassemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism
chemical_list: D007501:Iron