Published online June 1, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. 1204-1206 (doi:10.1542/peds.2007-0833)
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COMMENTARY

Pediatric Prevention of Atherosclerosis: Targeting Early Variation in Vascular Biology

Paul Leeson, PhD, MRCP

Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

Atherosclerosis first appears during childhood.1 Therefore, interventions may need to be started much earlier, and targeted at biological pathways that determine disease susceptibility, to prevent adult cardiovascular disease. In this issue of Pediatrics, Martin et al2 put forward the hypothesis that folic acid intake during in utero and early postnatal life may be relevant to longer-term risk of cardiovascular disease. This suggestion is based on their observation that folate levels in the immediate postnatal period are associated with endothelial function.

The endothelium has a key biological influence on the development of cardiovascular disease. Endothelial responses relate to an individual's risk of cardiovascular events,3 and in animal models, loss of endothelial function leads to accelerated atherogenesis and the development of hypertension and glucose intolerance.4,5 Approximately 10 years ago it was observed that there was significant variation in endothelial function between individuals during childhood.6,7 This variation did not relate to levels of classical cardiovascular risk factors, an important determinant of function in adults and those at high risk,8 but did relate to patterns of early growth. Reduced in utero growth was associated with impaired endothelial function, and this relationship has been consistently demonstrated in cohorts aged from a few days of life to early adulthood.9–11 Interestingly, this observation is strikingly similar to the associations between reduced in utero growth, increased mortality from atherosclerotic cardiovascular disease,12 and the development of risk factors such as hypertension13 and glucose intolerance14 derived from large population studies.

These findings have led to the hypothesis that early growth and endothelial function are biologically interrelated during early life and that "programmed" variation in endothelial function determines long-term risk of cardiovascular disease6 (Fig 1). In support of this hypothesis, animal models have demonstrated that environmental15 and genetic16 influences can determine both early growth and endothelial function.


Figure 1
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  		FIGURE 1 The "vascular biology" model, which explains the relation between early growth and later cardiovascular risk.

 

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If early variation in endothelial function does determine risk of later cardiovascular disease, then the endothelium is a novel target for pediatric prevention strategies. There has been particular interest in folic acid as an intervention. It is a simple nutritional supplement that influences endothelial function by having either an effect on homocysteine metabolism or a more direct effect on endothelial nitric oxide synthase function.17,18 Interestingly, low folic acid levels in the mother are also associated with a reduced birth weight in some studies,19 and animal data have demonstrated that vascular dysfunction in infants (secondary to maternal malnutrition15) can be prevented by supplementation with folic acid during pregnancy.20

Martin et al2 have demonstrated, for the first time in humans, that folate levels of both the mother and infant relate to endothelial function in the infant during the early postnatal period. Furthermore, they demonstrated that low folate levels in the mother, but not the infant, are related to reduced birth weight. However, they did not demonstrate that variation in folate levels accounts for the relation between birth weight and endothelial function, and it remains probable that there are other important modifiable pathways.


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Martin et al have provided data to focus attention on folic acid biology as a potentially simple target for pediatric prevention of atherosclerosis. However, at present, advice for folic acid supplements during pregnancy should be based on their known benefits for neurologic development and not on any hypothesized long-term cardiovascular protection to the offspring, because there remain at least 2 key issues. First, there are no data available to confirm that variation in endothelial function during the first decades of life has a long-term impact on structural atherosclerosis or emergence of risk factors in humans. Second, the influence of folic acid on endothelial function is known to be transient, with acute changes in levels associated with acute changes in function. This contrasts with the relations between in utero growth, endothelial function, and cardiovascular disease, which are fixed over decades.7,12 Therefore, we still need to unravel the underlying biology to determine if transient changes in folic acid intake can lead to long-term "programmed" variation in endothelial function and cardiovascular risk.

Over the next few years, these issues will be addressed by current longitudinal studies of the impact of early endothelial function on the vasculature combined with basic research into the effect of interventions on endothelial function and disease susceptibility. Together, a growing body of research into the effect of early variation in vascular biology on long-term risk of cardiovascular disease will generate a scientific evidence base to allow us to design robust proposals for novel pediatric prevention strategies for atherosclerosis.


   FOOTNOTES
 
Accepted Mar 15, 2007.

Address correspondence to Paul Leeson, PhD, MRCP, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. E-mail: paul.leeson{at}cardiov.ox.ac.uk

The author has indicated he has no financial relationships relevant to this article to disclose.

Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.


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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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