Evidence of cardiac involvement in the fetal inflammatory response syndrome: disruption of gene networks programming cardiac development in nonhuman primates

Am J Obstet Gynecol. 2018 Apr;218(4):438.e1-438.e16. doi: 10.1016/j.ajog.2018.01.009. Epub 2018 Feb 21.


Background: Most early preterm births are associated with intraamniotic infection and inflammation, which can lead to systemic inflammation in the fetus. The fetal inflammatory response syndrome describes elevations in the fetal interleukin-6 level, which is a marker for inflammation and fetal organ injury. An understanding of the effects of inflammation on fetal cardiac development may lead to insight into the fetal origins of adult cardiovascular disease.

Objective: The purpose of this study was to determine whether the fetal inflammatory response syndrome is associated with disruptions in gene networks that program fetal cardiac development.

Study design: We obtained fetal cardiac tissue after necropsy from a well-described pregnant nonhuman primate model (pigtail macaque, Macaca nemestrina) of intrauterine infection (n=5) and controls (n=5). Cases with the fetal inflammatory response syndrome (fetal plasma interleukin-6 >11 pg/mL) were induced by either choriodecidual inoculation of a hypervirulent group B streptococcus strain (n=4) or intraamniotic inoculation of Escherichia coli (n=1). RNA and protein were extracted from fetal hearts and profiled by microarray and Luminex (Millipore, Billerica, MA) for cytokine analysis, respectively. Results were validated by quantitative reverse transcriptase polymerase chain reaction. Statistical and bioinformatics analyses included single gene analysis, gene set analysis, Ingenuity Pathway Analysis (Qiagen, Valencia, CA), and Wilcoxon rank sum.

Results: Severe fetal inflammation developed in the context of intraamniotic infection and a disseminated bacterial infection in the fetus. Interleukin-6 and -8 in fetal cardiac tissues were elevated significantly in fetal inflammatory response syndrome cases vs controls (P<.05). A total of 609 probe sets were expressed differentially (>1.5-fold change, P<.05) in the fetal heart (analysis of variance). Altered expression of select genes was validated by quantitative reverse transcriptase polymerase chain reaction that included several with known functions in cardiac injury, morphogenesis, angiogenesis, and tissue remodeling (eg, angiotensin I converting enzyme 2, STEAP family member 4, natriuretic peptide A, and secreted frizzled-related protein 4; all P<.05). Multiple gene sets and pathways that are involved in cardiac morphogenesis and vasculogenesis were downregulated significantly by gene set and Ingenuity Pathway Analysis (hallmark transforming growth factor beta signaling, cellular morphogenesis during differentiation, morphology of cardiovascular system; all P<.05).

Conclusion: Disruption of gene networks for cardiac morphogenesis and vasculogenesis occurred in the preterm fetal heart of nonhuman primates with preterm labor, intraamniotic infection, and severe fetal inflammation. Inflammatory injury to the fetal heart in utero may contribute to the development of heart disease later in life. Development of preterm labor therapeutics must also target fetal inflammation to lessen organ injury and potential long-term effects on cardiac function.

Keywords: Escherichia coli; cardiac; fetal inflammatory response syndrome; fetus; group B streptococcus; heart; morphogenesis; neonate; pigtail macaque; pregnancy; preterm birth; preterm labor; vasculogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Natriuretic Factor / genetics
  • Biomarkers / metabolism
  • Chorioamnionitis / metabolism
  • Down-Regulation
  • Female
  • Fetal Diseases / metabolism*
  • Heart / microbiology
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Macaca nemestrina
  • Membrane Proteins / genetics
  • Microarray Analysis
  • Models, Animal
  • Myocardium / metabolism*
  • Obstetric Labor, Premature
  • Oxidoreductases / genetics
  • Peptidyl-Dipeptidase A / genetics
  • Pregnancy
  • Proto-Oncogene Proteins / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Systemic Inflammatory Response Syndrome / metabolism*
  • Up-Regulation


  • Biomarkers
  • Interleukin-6
  • Interleukin-8
  • Membrane Proteins
  • NPPA protein, human
  • Proto-Oncogene Proteins
  • SFRP4 protein, human
  • Atrial Natriuretic Factor
  • Oxidoreductases
  • STEAP4 protein, human
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2