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with sickle cell anemia
Image courtesy of the
University of Michigan
Preclinical research has revealed malfunctioning molecular pathways associated with cardiac anomalies in sickle cell anemia (SCA) that lead to sudden death.
Researchers used a mouse model of SCA and identified a unique “restrictive cardiomyopathy” that is superimposed on the anemia-associated heart enlargement.
They also found upregulated gene expression that fuels myocardial fibrosis and electrophysiological changes.
The researchers believe these findings, published in PNAS, will aid the development of new targeted therapies to treat cardiac dysfunction in patients with SCA.
“Sickle cell anemia is associated with significant morbidity and mortality, including a high incidence of unexplained, sudden death in young adults,” said study author Punam Malik, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings may provide a unifying cardiac pathophysiology that explains reported cardiac abnormalities and sudden death seen in humans with SCA.”
To find pathologies specific to SCA, Dr Malik and his colleagues compared mice bred to have SCA and wild-type mice with experimentally induced chronic anemia.
The mice underwent serial comprehensive cardiac analysis, including detailed cardiac imaging (MRI), electrocardiography, and microscopic cross-section analysis of heart tissues (histopathology and electron microscopy).
The researchers said that, in the SCA mice, they observed a distinctive sickle cardiomyopathy in which restrictive physiology was superimposed on chronic anemia and predisposed the mice to sudden death.
The SCA mice had progressive left atrial enlargement and diastolic dysfunction but preserved systolic function. This restrictive physiology appeared to be caused by ischemic-scattered cardiomyocyte loss, myocardial fibrosis, and cardiac remodeling.
The researchers also conducted transcriptome analysis. This revealed that SCA mice had upregulation of genes that cause increased oxidation, hypoxia, and fibrosis in heart tissues. It also showed a downregulation of genes associated with electrophysiological function.
Finally, the team observed progressive corrected QT prolongation, arrhythmias, and ischemic changes in the SCA mice shortly before a significant number of the animals experienced sudden death.
The researchers are continuing to study the molecular mechanisms and pathways that trigger myocardial fibrosis in SCA, using a variety of knockout mice.
In addition, the successful use of noninvasive cardiac imaging techniques in this study inspired the researchers to launch a clinical trial to test these early diagnostic techniques on people with SCA. Enrollment in that study is now complete.
“It is incredibly exciting to see that this work has inspired clinical trials and other research studies,” said study author Nihal Bakeer, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
“Our goal has always been [to] find the underling pathobiology of cardiac complications in sickle cell anemia and help find new diagnostics and therapeutics to decrease the morbidity and rate of sudden cardiac death in young adults with SCA.” 
with sickle cell anemia
Image courtesy of the
University of Michigan
Preclinical research has revealed malfunctioning molecular pathways associated with cardiac anomalies in sickle cell anemia (SCA) that lead to sudden death.
Researchers used a mouse model of SCA and identified a unique “restrictive cardiomyopathy” that is superimposed on the anemia-associated heart enlargement.
They also found upregulated gene expression that fuels myocardial fibrosis and electrophysiological changes.
The researchers believe these findings, published in PNAS, will aid the development of new targeted therapies to treat cardiac dysfunction in patients with SCA.
“Sickle cell anemia is associated with significant morbidity and mortality, including a high incidence of unexplained, sudden death in young adults,” said study author Punam Malik, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings may provide a unifying cardiac pathophysiology that explains reported cardiac abnormalities and sudden death seen in humans with SCA.”
To find pathologies specific to SCA, Dr Malik and his colleagues compared mice bred to have SCA and wild-type mice with experimentally induced chronic anemia.
The mice underwent serial comprehensive cardiac analysis, including detailed cardiac imaging (MRI), electrocardiography, and microscopic cross-section analysis of heart tissues (histopathology and electron microscopy).
The researchers said that, in the SCA mice, they observed a distinctive sickle cardiomyopathy in which restrictive physiology was superimposed on chronic anemia and predisposed the mice to sudden death.
The SCA mice had progressive left atrial enlargement and diastolic dysfunction but preserved systolic function. This restrictive physiology appeared to be caused by ischemic-scattered cardiomyocyte loss, myocardial fibrosis, and cardiac remodeling.
The researchers also conducted transcriptome analysis. This revealed that SCA mice had upregulation of genes that cause increased oxidation, hypoxia, and fibrosis in heart tissues. It also showed a downregulation of genes associated with electrophysiological function.
Finally, the team observed progressive corrected QT prolongation, arrhythmias, and ischemic changes in the SCA mice shortly before a significant number of the animals experienced sudden death.
The researchers are continuing to study the molecular mechanisms and pathways that trigger myocardial fibrosis in SCA, using a variety of knockout mice.
In addition, the successful use of noninvasive cardiac imaging techniques in this study inspired the researchers to launch a clinical trial to test these early diagnostic techniques on people with SCA. Enrollment in that study is now complete.
“It is incredibly exciting to see that this work has inspired clinical trials and other research studies,” said study author Nihal Bakeer, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
“Our goal has always been [to] find the underling pathobiology of cardiac complications in sickle cell anemia and help find new diagnostics and therapeutics to decrease the morbidity and rate of sudden cardiac death in young adults with SCA.”
with sickle cell anemia
Image courtesy of the
University of Michigan
Preclinical research has revealed malfunctioning molecular pathways associated with cardiac anomalies in sickle cell anemia (SCA) that lead to sudden death.
Researchers used a mouse model of SCA and identified a unique “restrictive cardiomyopathy” that is superimposed on the anemia-associated heart enlargement.
They also found upregulated gene expression that fuels myocardial fibrosis and electrophysiological changes.
The researchers believe these findings, published in PNAS, will aid the development of new targeted therapies to treat cardiac dysfunction in patients with SCA.
“Sickle cell anemia is associated with significant morbidity and mortality, including a high incidence of unexplained, sudden death in young adults,” said study author Punam Malik, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings may provide a unifying cardiac pathophysiology that explains reported cardiac abnormalities and sudden death seen in humans with SCA.”
To find pathologies specific to SCA, Dr Malik and his colleagues compared mice bred to have SCA and wild-type mice with experimentally induced chronic anemia.
The mice underwent serial comprehensive cardiac analysis, including detailed cardiac imaging (MRI), electrocardiography, and microscopic cross-section analysis of heart tissues (histopathology and electron microscopy).
The researchers said that, in the SCA mice, they observed a distinctive sickle cardiomyopathy in which restrictive physiology was superimposed on chronic anemia and predisposed the mice to sudden death.
The SCA mice had progressive left atrial enlargement and diastolic dysfunction but preserved systolic function. This restrictive physiology appeared to be caused by ischemic-scattered cardiomyocyte loss, myocardial fibrosis, and cardiac remodeling.
The researchers also conducted transcriptome analysis. This revealed that SCA mice had upregulation of genes that cause increased oxidation, hypoxia, and fibrosis in heart tissues. It also showed a downregulation of genes associated with electrophysiological function.
Finally, the team observed progressive corrected QT prolongation, arrhythmias, and ischemic changes in the SCA mice shortly before a significant number of the animals experienced sudden death.
The researchers are continuing to study the molecular mechanisms and pathways that trigger myocardial fibrosis in SCA, using a variety of knockout mice.
In addition, the successful use of noninvasive cardiac imaging techniques in this study inspired the researchers to launch a clinical trial to test these early diagnostic techniques on people with SCA. Enrollment in that study is now complete.
“It is incredibly exciting to see that this work has inspired clinical trials and other research studies,” said study author Nihal Bakeer, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
“Our goal has always been [to] find the underling pathobiology of cardiac complications in sickle cell anemia and help find new diagnostics and therapeutics to decrease the morbidity and rate of sudden cardiac death in young adults with SCA.”