Maternal infection: A critical driver of offspring cardiac dysfunction

Cardiac development is an intricately regulated process, and maternal infections during pregnancy are known to significantly increase the risk of congenital heart defects in offspring. However, the precise molecular pathways through which these infections disrupt fetal cardiac growth and differentiation have largely remained unexplored.

This new research, published in Genes & Diseases by a team from The Second Affiliated Hospital of Chongqing Medical University, investigated the profound impact of maternal exposure to bacterial and viral mimics on the metabolic profiles and mitochondrial function of the developing heart.

Through comprehensive untargeted metabolomics and transcriptome sequencing of neonatal mouse hearts, alongside in vitro human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) models, the researchers discovered that maternal exposure to lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid [Poly(I:C)] drastically alters cardiac metabolic pathways.

Maternal infection

The data revealed that maternal infection causes severe metabolic disturbances within the offspring’s heart, most notably enriching differentially expressed genes in lipid, energy, and amino acid metabolism. Additionally, the infection heavily suppressed cardiac cell proliferation, drastically reducing the expression of key proliferation markers like KI67 and ultimately restricting postnatal heart growth and size.

Extensive molecular and structural analyses deciphered the underlying intracellular mechanisms, revealing that both LPS and Poly(I:C) exposure significantly impair mitochondrial morphology and function, leading to abnormal membrane potential and depleted ATP production.

This severe mitochondrial dysfunction is fundamentally driven by a massive intracellular accumulation of reactive oxygen species (ROS) and a notable elevation in polyunsaturated fatty acids. Together, these factors aggressively trigger lipid peroxidation, generating toxic oxidative byproducts such as malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) that profoundly disrupt cardiomyocyte maturation.

Counteracting oxidative stress

Remarkably, in vitro and in vivo models confirmed that administering the antioxidant N-acetylcysteine (NAC) or the specific lipid peroxidation inhibitor ferrostatin-1 (Fer-1) successfully counteracted oxidative stress, fundamentally rescuing the mitochondria from infection-induced damage and restoring ATP levels.

While these collective data robustly highlight the critical influence of oxidative stress and lipid peroxidation in mediating fetal cardiac abnormalities, additional clinical studies are necessary to translate these targeted interventions into human therapies.

In conclusion, targeting the lipid peroxidation and oxidative stress pathways triggered by maternal infections offers a powerful strategy to protect mitochondrial function and preserve healthy metabolic signaling in the developing fetal heart. This profound finding positions antioxidants and specific lipid peroxidation inhibitors as compelling therapeutic candidates for preventing congenital heart defects and improving long-term cardiovascular outcomes in affected offspring.