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 Towbin, Punam Malik

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E5182-E5191
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number35
DOIs
StatePublished - Aug 30 2016
Externally publishedYes

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Restrictive Cardiomyopathy
Sickle Cell Anemia
Sudden Cardiac Death
Sudden Death
Anemia
Long QT Syndrome
Cardiac Volume
Sarcomeres
Ion Transport
Gene Expression Profiling
Circadian Rhythm
Ion Channels
Pulmonary Hypertension
Cardiac Myocytes
Extracellular Matrix
Cardiac Arrhythmias
Electrocardiography
Oxidative Stress
Fibrosis
Up-Regulation

All Science Journal Classification (ASJC) codes

  • General

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Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology. / Bakeer, Nihal; James, Jeanne; Roy, Swarnava; Wansapura, Janaka; Shanmukhappa, Shiva Kumar; Lorenz, John N.; Osinska, Hanna; Backer, Kurt; Huby, Anne Cecile; Shrestha, Archana; Niss, Omar; Fleck, Robert; Quinn, Charles T.; Taylor, Michael D.; Purevjav, Enkhsaikhan; Aronow, Bruce J.; Towbin, Jeffrey; Malik, Punam.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 35, 30.08.2016, p. E5182-E5191.

Research output: Contribution to journalArticle

Bakeer, N, James, J, Roy, S, Wansapura, J, Shanmukhappa, SK, Lorenz, JN, Osinska, H, Backer, K, Huby, AC, Shrestha, A, Niss, O, Fleck, R, Quinn, CT, Taylor, MD, Purevjav, E, Aronow, BJ, Towbin, J & Malik, P 2016, 'Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 35, pp. E5182-E5191. https://doi.org/10.1073/pnas.1600311113
Bakeer, Nihal ; James, Jeanne ; Roy, Swarnava ; Wansapura, Janaka ; Shanmukhappa, Shiva Kumar ; Lorenz, John N. ; Osinska, Hanna ; Backer, Kurt ; Huby, Anne Cecile ; Shrestha, Archana ; Niss, Omar ; Fleck, Robert ; Quinn, Charles T. ; Taylor, Michael D. ; Purevjav, Enkhsaikhan ; Aronow, Bruce J. ; Towbin, Jeffrey ; Malik, Punam. / Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 35. pp. E5182-E5191.
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AU - Bakeer, Nihal

AU - James, Jeanne

AU - Roy, Swarnava

AU - Wansapura, Janaka

AU - Shanmukhappa, Shiva Kumar

AU - Lorenz, John N.

AU - Osinska, Hanna

AU - Backer, Kurt

AU - Huby, Anne Cecile

AU - Shrestha, Archana

AU - Niss, Omar

AU - Fleck, Robert

AU - Quinn, Charles T.

AU - Taylor, Michael D.

AU - Purevjav, Enkhsaikhan

AU - Aronow, Bruce J.

AU - Towbin, Jeffrey

AU - Malik, Punam

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N2 - 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.

AB - 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.

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