Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Nihal Bakeer, Jeanne James, Swarnava Roy, Janaka Wansapura, Shiva Kumar Shanmukhappa, John N. Lorenz, Hanna Osinska, Kurt Backer, Anne Cecile Huby, Archana Shrestha, Omar Niss, Robert Fleck, Charles T. Quinn, Michael D. Taylor, Enkhsaikhan Purevjav, Bruce J. Aronow, Jeffrey A. Towbin, Punam Malik

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E5182-E5191
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
StatePublished - Aug 30 2016
Externally publishedYes


  • Arrhythmias
  • Cardiomyopathy
  • Restrictive physiology
  • Sickle cell anemia
  • Sudden death

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology'. Together they form a unique fingerprint.

Cite this