ACCEL | Cardiovascular disease is the leading cause of death worldwide and originates in early life, although the exact mechanisms of this early-life origin are unclear. David Burgner, MBChB, PhD, thinks early life remains a largely overlooked window of opportunity to reduce the burden of adult CVD, so he has been investigating how childhood CV risk factors affect vascular function long before overt cardiovascular disease.

A particular interest of his is the role of inflammation that may occur in pregnancy (e.g., due to infection and inflammation of the placenta, hypertension, or diabetes) or in childhood (e.g., following childhood infection or due to common chronic inflammatory diseases). His research also includes Kawasaki disease, an inflammatory illness of infants and the most common cause of acquired heart disease in children.

Professor Burgner is currently conducting a first-of-its-kind investigation into how inflammation in pregnancy (chorioamnionitis) contributes to the early development of atherosclerosis from birth onwards. Chorioamnionitis is common, affecting about 15% of full-term and up to 75% of preterm deliveries, but there are usually no symptoms. He and his collaborators are investigating the mechanisms by which chorioamnionitis appears to accelerate and worsen atherosclerosis, ultimately, perhaps, allowing for the development of targeted prevention to reduce CVD in later life in those at highest risk.

There have been several studies examining the relationship between in utero exposure to maternal diabetes and the development of risk factors for CVD. The underlying biological mechanisms are likely to be multifactorial; these children may be at risk due to metabolic derangements or epigenetic changes, or via a direct effect on their vasculature.

In a recent review article,¹ Dr. Burgner and colleagues noted that while glucose can cross the placenta, insulin cannot; hence, diabetes mellitus during pregnancy may expose the fetus to an excessive glucose load that is associated with accelerated fetal weight gain, predominately as increased adiposity. These kids, known as macrosomic offspring, show increased LV mass and increased aortic intima-media thickness compared to controls.

A number of metabolic derangements have been reported in the offspring of diabetic women, including increased serum lipids, proatherosclerotic apolipoprotein A-I and B-100, and higher lipoprotein levels at birth when compared to controls. This proatherosclerotic state may persist into later life, possibly predisposing them to the development of the metabolic syndrome, although longitudinal studies are lacking.

Animal studies demonstrate hyperinsulinism during prenatal development can disrupt the neuroendocrine systems that regulate satiety. Exposure to hyperglycemia in utero may also program future disease risk via changes to critical developmental pathways as a result of altered gene expression.

Twin Studies

Dr. Burgner recently coauthored a review article on the value of twin studies for providing a unique opportunity to examine the influence of shared genetic and environmental influences on childhood CV function.² Identifying epigenetic changes associated with CVD-risk biomarkers in children, he said, will provide new opportunities to unravel the underlying biological mechanism of the origins of CVD and enable the identification of those at risk for early-life interventions to alter the risk trajectory and potentially reduce CVD incidence later in life.

In August 2014, he and his colleagues reported the relationship between birth parameters, markers of adiposity, insulin resistance, lipid profile, and blood pressure on carotid-femoral pulse wave velocity (PWV), a noninvasive measure of arterial stiffness.³ They studied a healthy population-based cohort of 147 twin pairs aged 7-11 years. There were positive associations between both markers of higher adiposity, insulin resistance, elevated triglycerides, and PWV. Professor Burgner said their results support both the genetic and environmental contribution to higher PWV as a marker of arterial stiffness. Importantly, he said, it emphasizes the significance of preventing metabolic syndrome from childhood and perhaps targeting it once it exists.

Ultimately, Dr. Burgner’s goal is to understand factors that promote early atherosclerosis and cardiovascular risk, develop new treatments and means of preventing early CVD initiation, and identify individuals at greatest risk.

(Editor’s note: At the end of October 2014, Dr. Burgner joined the Department of Pediatrics at Monash Health as an Adjunct Professor. Previously, he was the clinical lead for pediatric infectious diseases and refugee child health, Child and Adolescent Health Services, Western Australia and an Associate Professor of Pediatrics at the University of Western Australia.)

References

1. Marco LJ, McCloskey K, Vuillermin PJ, Burgner D, Said J, Ponsonby AL. Exp Diabetes Res. 2012;2012:565160.
2. Sun C, Burgner DP, Ponsonby AL, et al. Pediatr Res. 2013;73:523-30.
3. McCloskey K, Sun C, Pezic A, et al. J Dev Orig Health Dis. 2014;5:307-13.

Keywords: ACC Publications, CardioSource WorldNews

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