Transgenerational cardiology: One way to a baby's heart is through the mother

Abstract

Despite decades of progress, congenital heart disease remains a major cause of mortality and suffering in children and young adults. Prevention would be ideal, but formidable biological and technical hurdles face any intervention that seeks to target the main causes, genetic mutations in the embryo. Other factors, however, significantly modify the total risk in individuals who carry mutations. Investigation of these factors could lead to an alternative approach to prevention. To define the risk modifiers, our group has taken an “experimental epidemiologic” approach via inbred mouse strain crosses. The original intent was to map genes that modify an individual’s risk of heart defects caused by an Nkx2-5 mutation. During the analysis of >2000 Nkx2-5+/− offspring from one cross we serendipitously discovered a maternal-age associated risk, which also exists in humans. Reciprocal ovarian transplants between young and old mothers indicate that the incidence of heart defects correlates with the age of the mother and not the oocyte, which implicates a maternal pathway as the basis of the risk. The quantitative risk varies between strain backgrounds, so maternal genetic polymorphisms determine the activity of a factor or factors in the pathway. Most strikingly, voluntary exercise by the mother mitigates the risk. Therefore, congenital heart disease can in principle be prevented by targeting a maternal pathway even if the embryo carries a causative mutation. Further mechanistic insight is necessary to develop an intervention that could be implemented on a broad scale, but the physiology of maternal-fetal interactions, aging, and exercise are notoriously complex and undefined. This suggests that an unbiased genetic approach would most efficiently lead to the relevant pathway. A genetic foundation would lay the groundwork for human studies and clinical trials.

Maternal hyperglycemia and fetal cardiac development: Clinical impact and underlying mechanisms

“…Placental dysfunction can also lead to inflammation and oxidative stress to impede signaling cascades that affect different aspects of embryonic development including heart development (Maslen, 2018; Courtney et al, 2018). Lastly, other modifiable risk factors like maternal age and exercise have complex effects on physiology and metabolism and therefore could also play a functional role in mitigating the risk of CHD in offspring carrying a pathogenic sequence variant (Ramírez-Vélez et al, 2009; Schulkey et al, 2015; Jay et al, 2016).…”

Associations of Assisted Reproductive Technology and Twin Pregnancy With Risk of Congenital Heart Defects

“…Congenital heart defect is a serious disease burden not only in infants but also in adolescents and adults . The pathophysiologic findings and pathogenesis of CHD are complicated and often are very different from other congenital anomalies . The American Institute of Ultrasound in Medicine, in collaboration with other professional organizations, has developed the Fetal Echocardiography Practice Parameter, and the American College of Radiology has endorsed this document.…”

Risk Assessment of the Increased Occurrence of Congenital Cardiac and Non-Cardiac Defects in Fetuses with a Normal Karyotype after Assisted Fertilization in Comparison to Natural Fertilization Based on Ultrasound Diagnostics

“…First, the possibility of a relationship existing between using assisted reproduction techniques and the occurrence of congenital heart defects was assessed, as such defects form a significant troublesome disease that burdens the developing fetus [ 23 , 24 ]; for instance, the most commonly diagnosed heart defect during ultrasound examination was a defect of the interventricular septum.…”