Source: Lothar Schulz/Getty Images
Source: Lothar Schulz/Getty Images

Using preterm animal models, researchers at the University of Washington School of Medicine in Seattle have developed new evidence that inflammation due to infection can disrupt the pre-birth activity of genes crucial for normal development of the heart. The research, which appeared in the American Journal of Obstetrics & Gynecology, suggested the altered gene activity may also be linked to adult-onset cardiac disease.

“This study connects the dots between preterm birth and heart disease in adult life by defining the gene networks disrupted by infection and inflammation that program normal heart development,” explained lead study investigator Kristina Adams Waldorf, M.D., a professor of obstetrics and gynecology at the University of Washington School of Medicine who specializes in maternal and fetal infections. “When I was in training, we talked to women in preterm labor about the risk to their infants of lung and brain injury. We now know that long-term health risks of a preterm birth extend beyond the developing lungs and brain to involve vision, hearing, kidney, and even heart function.”

In the current study, the investigators looked at the heart tissue from fetal pigtail macaque monkeys whose mothers' uteruses had been infected with bacteria, namely group B Streptococcus and Escherichia coli. These often cause infections in human mothers and trigger preterm birth. The investigators compared gene expression patterns from fetal heart tissues infected with bacteria to normal heart tissues. The animals were chosen because macaques are considered one of the closest animal models to human pregnancy. They also are ideal for the development of vaccines and treatments to protect pregnant women from bacterial infections.

“This study is the first to show that the gene program for heart development in preterm babies is interrupted in preterm babies exposed to fetal infection and inflammation, which may lead to incomplete heart development,” noted study co-author Timothy Mitchell, M.D., an obstetrician specializing in high-risk pregnancies and a former UW Medicine fellow in maternal and fetal medicine. “This incomplete development, in turn, may be lead to the higher risk of abnormal heart rhythms and heart failure seen when preterm babies reach adulthood.”

The infections in the current study were severe, a scenario that is typical of early preterm births, which occur in approximately 2% of all U.S. births. Infection triggered a marked inflammatory response in the fetus. Inflammation was also present in the heart tissues and characterized by elevations in inflammatory proteins, like interleukin-6 and interleukin 8.

Many of the genes with altered expression—NPPA, MYH6, and ACE2—have known functions in heart development or are linked to heart disease. For example, the gene NPPA, which encodes natriuretic peptide A, is essential for the formation and expansion of the walls of the heart.

Interestingly, the researchers also found significant alteration in the expression of gene networks involved in heart and blood vessel formation, including the movement and migration of cells, growth of smooth and cardiac muscle, and the migration of endothelial cells that line the inside of the heart and blood vessels.

“These findings suggest that many pathways related to fetal heart development may be impacted by inflammation and infection,” remarked Mitchell.

“We are only beginning to understand the health risks that infection and inflammation pose to the developing fetus, particularly in the setting of an early preterm birth,” added study co-author Lakshmi Rajagopal, Ph.D., an associate professor of pediatrics at the University of Washington School of Medicine and expert on newborn infectious diseases at Seattle Children's Research Institute and UW Medicine. “We need a better understanding of how bacteria invade the uterus to cause preterm birth so that we can develop therapies to prevent fetal infections. Ultimately, we must also develop an effective vaccine for group B Streptococcus to protect pregnant women and their fetuses.”

“Future research should investigate whether combining antibiotics to treat the infection and anti-inflammatory drugs can lessen inflammation and damage to the fetal heart,” concluded Adams Waldorf. “If we can better understand how to prevent infections that cause preterm birth, we can protect fetuses and enhance their long-term health into adulthood.”

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