EXPRESS: Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features.

Abstract

Sickle cell anemia (SCA) and β-thalassemia intermedia are very different genetically determined hemoglobinopathies predisposing to pulmonary hypertension (PH). The etiologies responsible for the associated development of PH in both diseases are multi-factorial with extensive mechanistic contributors described. Both SCA and β-thalassemia intermedia present with intra and extravascular hemolysis, and because SCA and β-thalassemia intermedia share features of extravascular hemolysis, macrophage iron excess and anemia we sought to characterize the common features of the PH phenotype, cardiac mechanics, and function as well as lung and right ventricular metabolism. Within the concept of iron, we have defined a unique pulmonary vascular iron accumulation in lungs of SCA PH patients at autopsy. This observation is unlike findings in idiopathic or other forms of pulmonary arterial hypertension. In this study we hypothesized that a common pathophysiology would characterize the PH phenotype in SCA and β-thalassemia intermedia murine models, but because unlike SCA, β-thalassemia is also a disease of dyserythropoiesis, with increased iron absorption and cellular iron extrusion mediated by high erythroferrone and low hepcidin levels as well as dysregulated iron transport due transferrin saturation, there may be differences as well. Herein we describe common and divergent features of PH in aged Berk-ss (SCA) and Hbbth/3+ (intermediate β-thalassemia) mice and suggest translational utility as proof-of-concept models to study PH therapeutics specific to genetic anemias.