Programming of Adult Cardiovascular Disease following Exposure to Late-Gestation Hyperglycemia

Abstract

Background: In utero exposure to hyperglycemia is becoming increasingly prevalent as the number of women entering pregnancy with type II diabetes, or developing gestational diabetes, increases. Both animal studies and epidemiologic investigations have found cardiovascular abnormalities in adult offspring of hyperglycemic mothers (OHM). Objective: We hypothesized that adult OHM would have abnormal cardiac function in vivo and increased susceptibility to ischemia. Methods: Pregnant rats were made diabetic on day 12 of gestation. Serum glucose was monitored twice daily and insulin provided to maintain serum glucose at 200–400 mg/dl. Offspring were fostered to normal mothers after birth. Adult OHM were studied at 8–10 months of age with echocardiography to assess in vivo cardiac function and isolated hearts to determine the response to ischemia. Results: Echocardiography found significant diastolic dysfunction in male OHM compared to male controls. In isolated hearts, baseline cardiac function and left ventricular compliance was significantly diminished in male OHM compared to controls. Ischemia caused a significant decline in heart function in controls and female OHM, while function in male OHM remained unchanged. Conclusions: Adult male OHM demonstrate programmed cardiac dysfunction. Given the growing number of pregnancies complicated by hyperglycemia, additional assessment of cardiac function of adults born to diabetic mothers may be warranted.

Increased renal sympathetic nerve activity leads to hypertension and renal dysfunction in offspring from diabetic mothers

“…Representative photomicrographs of renal cortex [immunoreaction for tyrosine hydroxylase (TH); positive reaction in dark brown: OC-Sham ϭ offspring from control mother -sham; OC-dn ϭ offspring from control mother -denervated; OD-Sham ϭ offspring from diabetic mother, sham; OD-dn ϭ offspring from diabetic mother, denervated]; and comparison of tyrosine hydroxylase protein expression in renal tissues by Western blot (WB) analysis (*P Յ 0.05 compared offspring from control mothers sham, †P Յ 0.05 compared offspring from diabetic mothers sham). (2,11,12,40,51,52,67). Hypertension develops early in life, before 2 mo in rats, and blood pressure increases by up to 30 mmHg.…”

“…Offspring of diabetic mothers have an increased risk of cardiovascular disease and diabetes in adulthood (2,13,42). A recent meta-analysis concluded that offspring of diabetic mothers have higher systolic blood pressure than controls (1).…”

Abnormal Expression of MST1 and YAP1 in Fetal Heart Tissue in a Hyperglycemic Environment and Their Roles in Mediating Apoptosis

“…Indeed, increasing evidence shows that exposure to hyperglycemia in utero induces not only short-term consequences, but also long-term effects such as congenital birth defects and metabolic syndrome (Metzger et al 2008;Simeoni et al 2009). These defects are most common and severe in the central nervous and cardiovascular systems (Agoudemos et al 2011;Zhao et al 2010). The molecular basis of CHD pathogenesis in pregestational diabetes remains largely uncharacterized.…”

Intrauterine programming of lipid metabolic alterations in the heart of the offspring of diabetic rats is prevented by maternal diets enriched in olive oil

“…Both alterations in the expression of PPARα and overaccumulation of lipids have been found in the heart in the experimental models of adverse intrauterine programming due to protein restriction . Besides, studies have shown that diabetes experimentally induced in rats during late gestation leads to the programming of cardiovascular alterations in the offspring . Damage in the offspring's heart has also been found in severe models of pregestational diabetes .…”