title: Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology.
abstract: Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.
authors: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Nihal
authors: N
authors: Bakeer
authors: Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Jeanne
authors: J
authors: James
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Swarnava
authors: S
authors: Roy
authors: Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Physics, University of Colombo, Colombo 03, Sri Lanka;
authors: Janaka
authors: J
authors: Wansapura
authors: Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Shiva Kumar
authors: SK
authors: Shanmukhappa
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267;
authors: John N
authors: JN
authors: Lorenz
authors: Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Hanna
authors: H
authors: Osinska
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Kurt
authors: K
authors: Backer
authors: Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Anne-Cecile
authors: AC
authors: Huby
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Archana
authors: A
authors: Shrestha
authors: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Omar
authors: O
authors: Niss
authors: Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Robert
authors: R
authors: Fleck
authors: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Charles T
authors: CT
authors: Quinn
authors: Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Michael D
authors: MD
authors: Taylor
authors: Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Enkhsaikhan
authors: E
authors: Purevjav
authors: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors: Bruce J
authors: BJ
authors: Aronow
authors: Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors: Jeffrey A
authors: JA
authors: Towbin
authors: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; punam.malik@cchmc.org.
authors: Punam
authors: P
authors: Malik
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000503:physiopathology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000379:methods; D020869:Gene Expression Profiling; D054144:Heart Failure, Diastolic / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology
keywords: arrhythmias; cardiomyopathy; restrictive physiology; sickle cell anemia; sudden death