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Understanding Sepsis-Associated Myocardial Dysfunction using Translational Research

Andrew J. Lautz, MD
Division of Critical Care Medicine
Cincinnati Children’s Hospital Medical Center

Sepsis, an extreme immune system response to serious infection that can damage the body’s organs, afflicts thousands of children each year in the United States, and new treatments are urgently needed to improve survival. The heart is commonly impacted in sepsis, a condition termed sepsis-associated myocardial dysfunction (SAMD). Our research has previously shown that children with SAMD are more likely to die despite treatment in the pediatric intensive care unit. SAMD occurs in children of all ages and affects both previously healthy children as well as those with chronic medical problems. It is currently unknown why some children develop SAMD while other children’s hearts remain healthy during sepsis. There also is no specific treatment for SAMD beyond supportive care and treatment of underlying infection. A better understanding of what causes SAMD would help us identify children at risk in the pediatric intensive care unit and lead to the development of new treatments for critically ill children.

Since we cannot directly collect samples from sick hearts of children with SAMD, we needed to create a new way to model how human heart cells respond in sepsis. Cincinnati Children’s Hospital Medical Center is a leader in induced pluripotent stem cell (iPSC) technology, in which blood cells can be collected from a small amount of blood and reprogrammed to become iPSCs. Then we can further program iPSCs to become different cell types, including cells that are difficult to collect, like heart cells. To study SAMD in children, we partner with the Pluripotent Stem Cell Facility to use iPSCs to make iPSC-cardiomyocytes, which are reprogrammed human heart cells that beat spontaneously. Leveraging the multicenter pediatric sepsis biorepository pioneered by the late Dr. Hector Wong, we expose iPSC-cardiomyocytes to blood banked from children with sepsis to learn how human heart cells respond to the sepsis environment. Mirroring what we see in the hearts of children with SAMD, we have found that iPSC-cardiomyocytes exposed to blood from children with SAMD do not beat as strongly compared to heart cells exposed to blood from children who have healthy hearts.

Our research laboratory is funded by the National Institutes of Health to study SAMD in children with sepsis using iPSC-cardiomyocytes. We are collecting blood from children with sepsis who have sick and healthy hearts (who do or do not have SAMD) from patients and families who consent to develop iPSC-cardiomyocytes. Since iPSC-cardiomyocytes retain the unique genetic material of each person, we can start to investigate how genetic factors might make some children more vulnerable to SAMD than others. Additionally, we are testing iPSC-cardiomyocytes to determine what proteins in the blood of children with sepsis injure heart cells with the goal of identifying potential new ways to treat SAMD. Ultimately, we hope that our research can be brought back to the bedside of children with sepsis in the pediatric intensive care unit to improve outcomes.

Understanding Sepsis-Associated Myocardial Dysfunction Using Translational Research
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