Effects of Simvastatin on Fetal Cardiac Impairment in the Diaphragmatic Experimental Hernia Model

Fetal Diagn Ther. 2019;46(1):28-37. doi: 10.1159/000490144. Epub 2018 Sep 10.


Background: Statins and sildenafil have been shown to exert beneficial effects in cardiac injury. We hypothesized that antenatal maternal administration of simvastatin and/or sildenafil might also promote benefits in cardiac remodeling of congenital diaphragmatic hernia (CDH). Therefore, we performed micro-CT image analysis and histology of the heart after antennal treatment in experimental nitrofen-induced CDH.

Methods: At 9.5 days post conception (dpc), pregnant rats were exposed to nitrofen. At 16 and 20 dpc fetuses were treated with simvastatin and/or sildenafil. At 21 dpc postmortem micro-CT and autopsy were performed.

Results: All nitrofen-treated fetuses had a lower birth weight compared to controls; in the simvastatin-treated group, a significant improvement in CDH was noted. Impairment of the lung and liver was also noted in CDH. Compared to controls, CDH rats showed lower ventricular mass, with greater left ventricular thickness; simvastatin decreased the ventricular mass and improved wall thickness. CDH rats exhibited myocardial hypotrophy, severe vascular depression in the left ventricle, and intense interstitial edema compared to controls and nitrofen-exposed animals without CDH. In CDH, the cardiac morphology appeared deformed with left ventricular wall verticalization. Simvastatin improved cardiac myocyte appearance and heart morphology.

Conclusion: The potential to treat CDH with antenatal simvastatin may improve the management of this malformation.

Keywords: Cardiac remodeling; Congenital diaphragmatic hernia; Fetal growth; Simvastatin; Treatment.

MeSH terms

  • Animals
  • Female
  • Fetal Development
  • Hernias, Diaphragmatic, Congenital / chemically induced
  • Hernias, Diaphragmatic, Congenital / diagnostic imaging
  • Hernias, Diaphragmatic, Congenital / drug therapy*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Phosphodiesterase 5 Inhibitors / adverse effects
  • Phosphodiesterase 5 Inhibitors / therapeutic use*
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Sildenafil Citrate / adverse effects
  • Sildenafil Citrate / therapeutic use*
  • Simvastatin / administration & dosage
  • Simvastatin / adverse effects
  • Simvastatin / therapeutic use*
  • X-Ray Microtomography


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Phosphodiesterase 5 Inhibitors
  • Simvastatin
  • Sildenafil Citrate