Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology
Significance Sickle cell anemia (SCA) is a common monogenic disorder associated with significant morbidity and mortality and a high incidence of unexplained sudden death in young adults. With the prevention of infections, there is an increasing appreciation for cardiopulmonary complications and a cardiac phenotype that cannot be solely attributed to chronic anemia. We used mouse models of SCA and iron deficient anemia to show distinct functional, pathological, ultrastructural, and molecular cardiac features causing a unique restrictive cardiomyopathy in SCA that predisposed the myocardium to electrophysiological abnormalities and sudden death. This is a comprehensive longitudinal analysis in preclinical mouse models that unifies the previously reported diverse cardiac phenotypes in SCA, and opens new avenues for early diagnostics and targeted therapies for human SCA related cardiac disease. 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.
Proceedings of the National Academy of Sciences