Vaughan, O. R.; Goodspeed, A.; Sucharov, C. C.; Powell, T. L.; Jansson, T.

Aim: Obesity in pregnant women increases offspring cardiovascular risk and causes fetal cardiac dysfunction. The underpinning mechanisms remain unclear. We hypothesised that circulating factors in serum from fetuses of women with obesity induce pathological cardiomyocyte hypertrophy. Methods: Pregnant women with obesity or healthy weight were recruited at term and provided umbilical cord serum and placentas, which were used for isolation of primary trophoblast cells. Primary cardiomyocytes were isolated from neonatal rats. Results: Compared to serum-free medium, supplementing cardiomyocytes with umbilical cord serum increased their mRNA expression of atrial natriuretic factor (Anf) and brain natriuretic peptide (Bnp), hallmarks of pathological hypertrophy, but did not alter their size. Cord serum from women with obesity further upregulated cardiomyocyte Anf and Bnp, and increased the ratio of beta- to alpha-myosin heavy chain expression (Myh7:Myh6), compared to cord serum from healthy weight women. This effect was prevented by treating the cord serum with heat-freeze cycling and DNase or RNase digestion. Conditioned medium from trophoblast cells from women with obesity also increased cardiomyocyte Anf, Bnp and Myh7:Myh6 expression. MicroRNAs miR-142 and miR-17, which are associated with cardiac function, were increased in abundance in extracellular vesicles isolated from cord serum from women with obesity. However, miR-142-3p, miR-142-5p and miR-17-5p did not increase Anf, Bnp or Myh7:Myh6 expression when they were transfected into cardiomyocytes. Conclusion: The results show that human fetal circulating and placenta-derived factors induce hallmarks of pathological hypertrophy in cardiomyocytes and may mediate cardiac dysfunction in children of women with obesity.