Abstract 18016: Maternal Age is a Modifiable Risk Factor for Congenital Heart Disease
INTRODUCTION: Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn. We previously reported the same risk for newborn mice that carry a mutation of the cardiac transcription factor NKX2-5. Whether the basis of the risk resides with the mother or oocyte is unknown. We describe here characteristics of the mechanism by which maternal age acts a risk factor for congenital heart disease in Nkx2-5+/- mice.
METHODS and RESULTS: First, we performed reciprocal ovarian transplants between young and old mothers in a C57BL/6N X FVB/N F1 hybrid background. The incidence of VSD in the Nkx2-5+/- offspring was associated with the age of the mother and not the ovary. This result clearly indicates the existence of an age-related maternal factor that interacts with embryonic cardiac development. Second, a high-fat diet did not increase the maternal age-based risk, so abnormal glucose metabolism and obesity do not simply explain the mechanism. Third, the risk associated with maternal aging is a quantitative genetic trait. It was highest in the inbred C57BL/6N background, intermediate in the C57BL/6N X FVB/N F1 hybrid, and insignficant in the C57BL/6N X A/J F1 hybrid. Maternal genetic polymorphisms must determine the activity of the factor that mediates the age-based risk. Finally and most surprisingly, voluntary exercise by mothers can abrogate the age-based risk. Running wheels in breeding cages reduced the incidence of VSD from 20 to 9% for the offspring of old mothers. The lower incidence is similar to that observed in the offspring of young, sedentary mothers.
CONCLUSION: A mother’s age, genes, and exercise influence a pathway that interacts with embryonic cardiac development. Interventions aimed at the mother could meaningfully reduce the risk of congenital heart disease in offspring who carry a deleterious mutation.
Author Disclosures: C.E. Schulkey: None. S.D. Regmi: None. R.A. Magnan: None. M.T. Danzo: None. A.K. Hutchinson: None. H. Luther: None. A.A. Panzer: None. D.B. Wilson: None. P.Y. Jay: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.