(134) Maternal Immune Activation Meets Down syndrome: A Perfect Storm for Congenital Heart Defects?

Maternal Immune Activation Meets Down Syndrome: A Perfect Storm for Congenital Heart Defects?

Authors: Abhik Saha¹, Lexe West¹, Greta Foye¹, Sunita Vargheese¹, Jian Huang², Tom Packard, Olivia Veatch³ and Katherine Waugh.  ¹Department of Cell Biology and Physiology, ²Cardiovascular Core, Department of Cardiovascular Medicine, and ³Department of Psychiatry & Behavioral Sciences, The University of Kansas Medical Center.

Abstract Text:

Congenital heart defects (CHDs) represent the leading cause of infant morbidity and mortality worldwide, with most cases having an unspecified etiology. The remaining cases are broadly attributed to broad genetic or environmental causes, often exhibiting incomplete penetrance through largely unknown mechanisms. For example, fetal aneuploidy and maternal exposure to Influenza A independently increase risk of CHDs. Infants with trisomy 21 (T21), also known as Down syndrome (DS), are 50 times more likely to develop CHDs, with nearly half of the progeny affected by this condition. This genetic disorder is also characterized by autoinflammation beginning en utero and hypersensitivity to inflammatory insults, with evidence supporting immunomodulation across chromosomal anomalies that vary with genetic content. Mechanistically dissecting the dual burden of inflammation and CHDs in individuals with DS has the potential to reshape the known landscape of mammalian cardiovascular development. We posit that the penetrance and severity of heart defects will be heightened in offspring genetically predisposed to the deleterious impacts of maternal immune activation (MIA), due to gene dosage of cytokine receptors orthologous to those on human chromosome 21. This study utilizes medical histories from >37,000 pregnancies at KUMC, focusing on 2405 progeny with chromosomal anomalies, of which 1923 have documented MIA. We also present preliminary data here from our cause-effect investigations using a mouse model of DS and MIA driven by viral mimetic exposure to elucidate the impacts of heightened inflammation on fetal demise, placental dysfunction, and abnormal heart morphogenesis among genetically distinct littermates. Dissecting the interplay between environmental and genetic risk factors for heart malformations could inform targeted therapeutic strategies for high-risk pregnancies with implications that extend well beyond the scope of DS.