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Adult onset atherosclerosis may have its origin in the foetal state in utero

Mukherjee, Sagarika

Current Opinion in Lipidology: April 2009 - Volume 20 - Issue 2 - p 155–156
doi: 10.1097/MOL.0b013e3283295713
Bimonthly update: Edited by Alan Rees

Department of Diabetes and Endocrinology, Advanced Medicare Research Institute, Kolkata, West Bengal, India

Correspondence to Dr Sagarika Mukherjee, Consultant Physician, 795 D/2 Lake Town, Block A, Kolkata 700089, West Bengal, India Tel: +91 9830746146; fax: +91 33 24404803; e-mail:

Increasing prevalence of obesity and associated disorders suggest a perpetuating cycle of more obesity, insulin resistance and abnormal lipid metabolism, which has ominous consequences for future generations. Extensive epidemiological evidence supports link between metabolic derangements during pregnancy and later development of adulthood dysmetabolic conditions like insulin resistance, type 2 diabetes, cardiovascular disease and hypertension [1••]. The original Barker hypothesis focused on low birth weight as primary indicator of postnatal risk, but low birth weight may arise from other nonmetabolic conditions [2]. Recently, focus has shifted to the impact of specific maternal risk factors like obesity, metabolic syndrome and diabetes, on cardiovascular risk of the offspring. The development of metabolic syndrome in children with increasing age is related to maternal gestational diabetes, glycaemia in third trimester, obesity, neonatal macrosomia, and childhood obesity [3••].

Factors responsible for these risks are not fully understood. Foetal hyperinsulinaemia is a risk factor for development of both obesity and abnormal glucose metabolism and might be implicated in the pathophysiology [4•].

There is a J shaped or U shaped relationship between birth weight and adult fat mass with higher prevalence of obesity occurring at low and high birth weights [5••]. The influence of maternal weight on the relationship between birth weight and subsequent BMI may operate through an impact of high maternal and hence foetal nutrient supply [6]. Low birth weight infants who had experienced a period of rapid childhood growth, later in adulthood were more vulnerable to becoming obese [7].

There is a long lag period between onset and clinical manifestation of atherosclerosis and very early stages of atherosclerotic lesions are already formed during foetal development [8]. Malfunctioning of arterial endothelial layer in the offspring occur with both maternal undernutrition and overnutrition [9••]. Fatty streaks containing accumulation of lipids, products of perioxidation and monocyte/macrophages occur in the aorta and coronary arteries of human foetuses [10], and maternal hypercholesterolaemia play a role in foetal lesion formation [11]. A strong influence of maternal hypercholesteolaemia on foetal sterol metabolism has been estasblished in animal models [12]. Once started, atherosclerotic lesions progresses under the influence of risk factors that promote vascular inflammation and plaque rupture. Foetal lesions occur at the same sites as lesions in adolescents and adults, but are of minute size and they partially regress during final stages of gestation or early infancy, when cholesterol levels are low [13].

The fate of Early Leisons in Children (Foelic) study [13] showed that the progression of atherosclerosis was markedly faster in offspring of hypercholesterolaemic mothers than in those with normal cholesterol. Conventional risk factors in children and their mothers could not explain this. There may be a genetic influence in the children of hypercholesterolaemic mothers that contributed to the faster progression of the disease. Numerous signalling pathways are affected by increased oxidation of LDL or intracellular formation of reactive species [14].

The marked increase of lipid peroxidation in maternal and foetal plasma and prevalence of oxidized LDL in lesions of human foetuses, conclude that many genes regulated by oxidation-sensitive pathways will be up or downregulated in the foetuses of hypercholesterolaemic mothers. After birth, when placental passage of oxidized fatty acids ceases and acute oxidative stress is low, such regulation disappears for a while [15]. Accumulation of oxidized LDL in fatty streaks and increased oxidative stress in plasma activate multiple oxidation sensitive pathways in the arterial wall of the fetus, which modulate the expression of many regulatory genes affecting endothelial function and lesion formation. This influences the molecular memory in the arterial wall that determines later atherogenesis in response to trigger by classical risk factors, that is, as seen in the metabolic syndrome [16].

Human population is genetically heterogenous and both diet and risk factors are also variable. Role of maternal hypercholesterolaemia in foetal lesion formation and enhanced susceptibility to postnatal atherogenesis could only be obtained in genetically more homogeneous experimental models [17•]. If maternal hypercholesterolaemia is responsible at least in part for a chain of events leading to increased foetal lesion formation, susceptibility to atherosclerosis later in life, and to clinical manifestations, then pharmacological interventions in mothers during pregnancy that prevent or reduce the onset of these pathogenic events in the foetus could be expected to provide lifelong benefits.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

1•• Palinski W, Yamashita T, Freigang S, Napoli C. Developmental programming: maternal hypercholesterolaemia and immunity influence susceptibility to atherosclerosis. Nutr Rev 2007; 65(12 Pt 2):S182–S187. This paper discusses on the effects of maternal hypercholesterolaemia in promoting fetal atherosclerosis. It has focused on the influence of inflammation and immune mechanisms on progress of fetal atherosclerosis.
2 Barker DJP, Hales CN, Fall CHD, et al. Type 2 Diabetes mellitus, hypertension and hyperlipidaemia (syndrome x): relation to reduced fetal growth. Diabetologia 1993; 36:62–67.
3•• Vohr BR, Boney CM. Gestational diabetes: the fore runner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Fetal Neonatal Med 2008; 21:149–157. This paper mentions about effects of gestational diabetes on the offspring's risk for development of cardiovascular disease in later life.
4• Metzger BE. Long-term outcomes in mothers diagnosed with gestational diabetes mellitus and their offspring. Clin Obstet Gynecol 2007; 50:972–979.
5•• Yajnik CS, Deshmukh US. Maternal nutrition, intrauterine programming and consequential risks in the offspring. Rev Endocr Metab Disord 2008; 9:203–211. Epub 2008 Jul 26. This paper discusses on the effects of maternal nutrition on effects of fetal programming of future metabolic fisorders nad focuses on aspects of micronutrients.
6 Singhal A, Wells J, Cole TJ, et al. Programming of lean body mass: a link between birth weight, obesity and cardiovascular disease? Am J Clin Nutr 2003; 77:726–730.
7 Ong KK, Dunger DB. Perinatal growth failure: road to obesity, insulin resistance and cardiovascular disease in adults. Best Pract Res Clin Endocrinol Metab 2002; 16:191–207.
8 Napoli C, Witztum JL, de Nigris F, et al. Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation than extracranial arteries. Circulation 1999; 99:2003–2010.
9•• Poston L. Influences of maternal nutritional status on vascular function in the offspring. Curr Drug Targets 2007; 8:914–922. This paper discusses about intrauterine influence on the future development of cardiovascular disease. There are detailed discussions about malfunctioning of arterial endothelial layer in association with both overnutrition and undernutrition of the mother.
10 Pathobiological Determinants of Atherosclerosis in Youths (PDAY) Research Group Natural history of aortic and coronary atherosclerotic lesions in youth. Findings from the PDAY study. Arterioscler Thromb 1993; 13: 1291–1298.
11 Napoli C, D' Armiento FP, Mancini FP, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: intimal accumulation of LDL and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 1997; 100:2680–2690.
12 Woollett SA. The origins and roles of cholesterol and fatty acids in the fetus. Curr Opin Lipidol 2001; 12:305–312.
13 Napoli C, Glass CK, Witztum JL, et al. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 1999; 354:1234–1241.
14 de Nigris F, Youssef T, Ciafré SA, et al. Evidence for oxidative activation of c-Myc-dependent nuclear signaling pathways in cultured human coronary SMC and in early atherosclerotic lesions of WHHL rabbits: protective effects of vitamin E. Circulation 2000; 102:2111–2117.
15 Collins T, Cybulsky M. NF-κB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 2001; 107:255–264.
16 Radunovic N, Kuczynski E, Rosen T, et al. Plasma apolipoprotein A-I and B concentrations in growth-retarded fetuses: a link between low birth weight and adult atherosclerosis. J Clin Endocrinol Metab 2000; 85:85–88.
17• Pallinski W, Napoli C. The fetal origins of atherosclerosis: maternal hypercholesterolemia, and cholesterol-lowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis. The FASEB Journal 2002; 16:1348–1360.
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Further recommended reading

• Yajnik CS, Godbole K, Otiv SR, Lubree HG. Fetal programming of type 2 diabetes: is sex important? Diabetes Care 2007; 30:2754–2755.
• Liguori A, D'Armiento FP, Palagiano A, Palinski W, Napoli C. Maternal C-reactive protein and developmental programming of atherosclerosis. Am J Obstet Gynecol 2008; 198:281.e1–281.e5.
• Palinski W, Napoli C. Impaired fetal growth, cardiovascular disease, and the need to move on. Circulation 2008; 117:341–343.
© 2009 Lippincott Williams & Wilkins, Inc.