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In utero programming and early detection of cardiovascular disease in the offspring of mothers with obesity

  • Karolien Van De Maele
    Correspondence
    Corresponding author. Department of Pediatrics, Division of Pediatric Endocrinology, University Hospital of Brussels, Laarbeeklaan 101, 1090 Jette, Belgium.
    Affiliations
    Department of Pediatrics, Division of Pediatric Endocrinology, University Hospital of Brussels, Laarbeeklaan 101, 1090, Jette, Belgium

    Research unit Organ Systems, Department of Development and Regeneration, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium

    Research unit GRON, Free University of Brussels, Laarbeeklaan 103, 1090 Jette, Belgium
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  • Roland Devlieger
    Affiliations
    Department of Obstetrics and Gynecology, University Hospital of Leuven, Herestraat 49, 3000, Leuven, Belgium

    Research unit Organ Systems, Department of Development and Regeneration, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium
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  • Inge Gies
    Affiliations
    Department of Pediatrics, Division of Pediatric Endocrinology, University Hospital of Brussels, Laarbeeklaan 101, 1090, Jette, Belgium

    Research unit GRON, Free University of Brussels, Laarbeeklaan 103, 1090 Jette, Belgium
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Open AccessPublished:June 09, 2018DOI:https://doi.org/10.1016/j.atherosclerosis.2018.06.016

      Highlights

      • Obesity during pregnancy poses the offspring at risk for cardiovascular disease.
      • Pre-conception period and early pregnancy are critical periods for an intervention.
      • Non-invasive assessment of endothelial function in children opens possibilities.
      • Pediatricians should pay attention to maternal weight status during pregnancy.

      Abstract

      The offspring of women with obesity during their pregnancy are exposed to an altered intra-uterine environment. A subsequent influence on the cardiovascular development during fetal life is assumed. In the present thematic review, we report on the current knowledge about this early development of cardiovascular disease from fetal life until adolescence. Based on animal studies, different contributing mechanisms have been hypothesized that still need confirmation in human subjects. Insulin resistance, increased levels of leptin, chronic inflammatory state, perturbation of sympathetic tone and epigenetic modifications contribute to a suboptimal nutrient environment and changed hemodynamics. The ensuing aberrant cardiomyocyte development, impaired endothelial cell relaxation and atherogenic lipid profile put these children at risk for the development of endothelial cell dysfunction. Increasing possibilities for early detection of this preliminary stage of atherosclerotic disease offer new insights into future prevention and treatment strategies. Future research should focus on further unraveling the effect of moderate intense, aerobic exercise. Since it is used to treat the condition in children and adolescents with good results, it might be a contributor to tackling endothelial cell dysfunction at its cradle when applied in early pregnancy.

      Keywords

      1. Introduction

      Ischemic cardiovascular events remain the global leading cause of death and an important contributor to premature deaths [
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • Lim S.
      • Shibuya K.
      • Aboyans V.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Moran A.E.
      • Forouzanfar M.H.
      • Roth G.A.
      • Mensah G.A.
      • Ezzati M.
      • Murray C.J.
      • et al.
      Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: the Global Burden of Disease 2010 study.
      ,

      World Health Organization. Fact sheet on Cardiovascular Diseases. (Fact Sheet 317) 2016 [updated September 2016. Available from:: http://www.who.int/mediacentre/factsheets/fs317/en/.

      ]. Strategies for the improvement of these figures focus on the identification and treatment of cardiovascular diseases and associated risk factors in its early stages [
      • Shay C.M.
      • Gooding H.S.
      • Murillo R.
      • Foraker R.
      Understanding and improving cardiovascular health: an update on the American heart Association's concept of cardiovascular health.
      ]. Childhood obesity is a known risk factor and one of the major global public health challenges of this century [

      World Health Organization. Fact sheet on Obesity and Overweight. (Fact Sheet 311) 2016 [updated June 2016. Available from:: http://www.who.int/mediacentre/factsheets/fs311/en/.

      ]. A specific population of children at risk for the development of (childhood) obesity and/or cardiovascular diseases is the offspring of pregnant women with obesity. There is a growing body of literature that recognizes adverse outcomes of obesity during pregnancy in short- and long-term. Short-term complications include an increased risk of delivery by caesarean section, macrosomia or large-for-gestational-age infants at birth, admission to a neonatal care unit and stillbirth [
      • Devlieger R.
      • Benhalima K.
      • Damm P.
      • Van Assche A.
      • Mathieu C.
      • Mahmood T.
      • et al.
      Maternal obesity in Europe: where do we stand and how to move forward?: A scientific paper commissioned by the European Board and College of Obstetrics and Gynaecology (EBCOG).
      ,
      • Tanvig M.
      Offspring body size and metabolic profile - effects of lifestyle intervention in obese pregnant women.
      ]. Long-term complications induce an unfavorable metabolic profile in later life with a tendency to insulin resistance, adverse body composition and lipid profile and chronic state of low-grade inflammation [
      • Wankhade U.D.
      • Thakali K.M.
      • Shankar K.
      Persistent influence of maternal obesity on offspring health: mechanisms from animal models and clinical studies.
      ,
      • O'Reilly J.R.
      • Reynolds R.M.
      The risk of maternal obesity to the long-term health of the offspring.
      ,
      • Galjaard S.
      • Devlieger R.
      • Van Assche F.A.
      Fetal growth and developmental programming.
      ,
      • Santangeli L.
      • Sattar N.
      • Huda S.S.
      Impact of maternal obesity on perinatal and childhood outcomes.
      ,
      • Godfrey K.M.
      • Reynolds R.M.
      • Prescott S.L.
      • Nyirenda M.
      • Jaddoe V.W.
      • Eriksson J.G.
      • et al.
      Influence of maternal obesity on the long-term health of offspring.
      ,
      • Woo Baidal J.A.
      • Locks L.M.
      • Cheng E.R.
      • Blake-Lamb T.L.
      • Perkins M.E.
      • Taveras E.M.
      Risk factors for childhood obesity in the first 1,000 Days: a systematic review.
      ]. The adverse metabolic consequences put these children at risk for the early development of atherosclerosis and cardiovascular disease. Epidemiological studies link maternal obesity to cardiovascular disease and premature death in later life in the offspring [
      • Reynolds R.M.
      • Allan K.M.
      • Raja E.A.
      • Bhattacharya S.
      • McNeill G.
      • Hannaford P.C.
      • et al.
      Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years.
      ,
      • Eriksson J.G.
      • Sandboge S.
      • Salonen M.K.
      • Kajantie E.
      • Osmond C.
      Long-term consequences of maternal overweight in pregnancy on offspring later health: findings from the Helsinki Birth Cohort study.
      ]. This review sheds light on the in utero programming of cardiovascular disease in the offspring of women with obesity, the subsequent clinical implications of its detection in the earliest stages and valuable perspectives on prevention strategies.

      2. Maternal obesity and in utero programming of cardiovascular disease

      A higher (pre)pregnancy maternal weight is associated with altered cardiovascular development in the offspring causing a greater risk for congenital heart defects and myocardial hypertrophy, hypertension, an atherogenic lipid profile and higher circulating levels of vascular and cellular adhesion molecules [
      • O'Reilly J.R.
      • Reynolds R.M.
      The risk of maternal obesity to the long-term health of the offspring.
      ,
      • Roberts V.H.
      • Frias A.E.
      • Grove K.L.
      Impact of maternal obesity on fetal programming of cardiovascular disease.
      ,
      • Thornburg K.L.
      The programming of cardiovascular disease.
      ,
      • Penfold N.C.
      • Ozanne S.E.
      Developmental programming by maternal obesity in 2015: outcomes, mechanisms, and potential interventions.
      ,
      • Musa M.G.
      • Torrens C.
      • Clough G.F.
      The microvasculature: a target for nutritional programming and later risk of cardio-metabolic disease.
      ,
      • Gaillard R.
      • Welten M.
      • Oddy W.H.
      • Beilin L.J.
      • Mori T.A.
      • Jaddoe V.W.
      • et al.
      Associations of maternal prepregnancy body mass index and gestational weight gain with cardio-metabolic risk factors in adolescent offspring: a prospective cohort study.
      ]. An abnormal in utero environment and placental development, resulting in a suboptimal nutritional climate and changed hemodynamics play a central role (see Fig. 1). One of the pioneers in this research field was David Barker with the development of the hypothesis of fetal programming, following studies in malnourished pregnant women over 30 years ago. [
      • Barker D.J.
      Fetal origins of coronary heart disease.
      ] This relationship between a poor nutritional intra-uterine environment in malnourished women during pregnancy and cardiovascular disease in the offspring at adult age, has been suggested in the offspring of mothers with obesity during pregnancy as well [
      • Reynolds R.M.
      • Allan K.M.
      • Raja E.A.
      • Bhattacharya S.
      • McNeill G.
      • Hannaford P.C.
      • et al.
      Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years.
      ]. The still ongoing follow-up studies of the Dutch Hunger Winter (1944–1945) families' cohort provide valuable additional information on these correlations [
      • Lumey L.H.
      • Stein A.D.
      • Kahn H.S.
      • van der Pal-de Bruin K.M.
      • Blauw G.J.
      • Zybert P.A.
      • et al.
      Cohort profile: the Dutch Hunger Winter families study.
      ,
      • Schulz L.C.
      The Dutch Hunger Winter and the developmental origins of health and disease.
      ].Most of the evidence regarding the underlying programming mechanisms arises from animal studies.
      Fig. 1
      Fig. 1This figure provides an overview of the major contributors in the programming process putting the offspring at risk for the development of cardiovascular disease.

      2.1 Data from animal studies

      To assess the consequences of a poor intra-uterine nutritional climate, animal studies with maternal high-fat diet (HFD) during pregnancy in rodents, sheep and nonhuman primates are used (Table 1). The offspring of HFD fed animals demonstrates an impaired endothelial cell relaxation in combination with a raised intimal wall thickness and increased expression of vascular inflammatory markers [
      • Wankhade U.D.
      • Thakali K.M.
      • Shankar K.
      Persistent influence of maternal obesity on offspring health: mechanisms from animal models and clinical studies.
      ,
      • Fan L.
      • Lindsley S.R.
      • Comstock S.M.
      • Takahashi D.L.
      • Evans A.E.
      • He G.W.
      • et al.
      Maternal high-fat diet impacts endothelial function in nonhuman primate offspring.
      ]. Underlying insulin resistance and higher levels of leptin are thought to contribute. Raised leptin levels, secreted by the adipose tissue, inhibit the in vitro proliferation of smooth muscle cells and could impede the angiogenesis process in vivo, but this assumption needs scientific validation in humans [
      • Bohlen F.
      • Kratzsch J.
      • Mueller M.
      • Seidel B.
      • Friedman-Einat M.
      • Witzigmann H.
      • et al.
      Leptin inhibits cell growth of human vascular smooth muscle cells.
      ]. The high circulating levels of lipids induce a pro-inflammatory cascade which can up- or down regulate the placental nutrient transporters and influence placental (vascular) development and function [
      • Roberts V.H.
      • Frias A.E.
      • Grove K.L.
      Impact of maternal obesity on fetal programming of cardiovascular disease.
      ].
      Table 1Overview of different diet-induced obesity animal studies with focus on the cardiovascular phenotype of the offspring.
      Study (year)Type of animalDiet control groupHigh fat dietMain findings in hfd-offspring
      Ghosh et al. (2001) [
      • Ghosh P.
      • Bitsanis D.
      • Ghebremeskel K.
      • Crawford M.A.
      • Poston L.
      Abnormal aortic fatty acid composition and small artery function in offspring of rats fed a high fat diet in pregnancy.
      ]
      Sprague-Dawley rats

      N = 20 dam s
      4% fat20% animal lardAssessment at 160 days of age (on standard chow): ONLY ♀
      • -
        ↓ endothelium-dependent relaxation in femoral artery
      • -
        ↑ triglyceride levels and ↓ HDL levels
      • -
        abnormal composition of fatty acids in aorta
      22% protein18% protein
      51% carbohydrate 5% fiber41% carbohydrate 3% fiber
      Khan et al. (2004) [
      • Khan I.
      • Dekou V.
      • Hanson M.
      • Poston L.
      • Taylor P.
      Predictive adaptive responses to maternal high-fat diet prevent endothelial dysfunction but not hypertension in adult rat offspring.
      ]
      Sprague-Dawley rats

      N = 20 dam s
      5.3% fat (corn oil)25.7% fatAssessment at 6 months of age (on standard chow or HFD):
      • -
        ↑ blood pressure in ♀ on standard chow and HFD
      • -
        No difference in endothelium-independent relaxation
      • -
        ↓ endothelium-dependent relaxation in small mesenteric artery in ♀ & ♂ on standard chow
      • -
        ↓ triglyceride level in ♂ on HFD
      21.2% protein19.5% protein
      57.4% carbohydrate41.3% carbohydrate
      4.6% fiber3.5% fiber
      Armitage et al. (2005) [
      • Armitage J.A.
      • Lakasing L.
      • Taylor P.D.
      • Balachandran A.A.
      • Jensen R.I.
      • Dekou V.
      • et al.
      Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy.
      ]
      Sprague-Dawley rats

      N = 23 offspring
      5.3% fat (corn oil)24.3% fatAssessment at 160 days of age (on standard chow):
      • -
        ↓aortic endothelial cell layer volume & smooth muscle cell number
      • -
        No difference in aortic medial thickness
      • -
        ↑aortic stiffness and ↓ endothelium-dependent relaxation
      21.6% protein19.5% protein
      54.2% carbohydrate41.2% carbohydrate
      4.5% fiber4.5% fiber
      Khan et al. (2005) [
      • Khan I.Y.
      • Dekou V.
      • Douglas G.
      • Jensen R.
      • Hanson M.A.
      • Poston L.
      • et al.
      A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring.
      ]
      Sprague-Dawley rats

      N = 21 dam s
      5.3% fat (corn oil)25.7% fatAssessment at 6 months of age (all on standard chow):
      • -
        ↑ blood pressure in ♀
      • -
        No difference in endothelium-independent relaxation or lipid profile
      • -
        ↓ endothelium-dependent relaxation in mesenteric arteries in ♀ & ♂
      21.2% protein19.5% protein
      49.2% carbohydrate34.7% carbohydrate
      4.6% fiber3.5% fiber
      Samuelsson et al. (2008) [
      • Samuelsson A.M.
      • Matthews P.A.
      • Argenton M.
      • Christie M.R.
      • McConnell J.M.
      • Jansen E.H.
      • et al.
      Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming.
      ]
      C57BL/6 J mice

      N = 50 dam s
      7% simple sugars10% simple sugars 20% animal lardAssessments at 3 and 6 months of age (all on standard chow):
      • -
        ↑ triglyceride levels in ♀ & ♂ at 3 months
      • -
        ↑ blood pressure in ♀ & ♂ at 3 and 6 months (effect ♀>♂)
      • -
        ↓ endothelium-dependent relaxation in ♀ & ♂ at 3 months
      • -
        No difference in endothelium-independent relaxation
      3% fat28% polysaccharide
      50% polysaccharide 15% protein23% protein
      Elahi et al. (2009)

      [
      • Elahi M.M.
      • Cagampang F.R.
      • Mukhtar D.
      • Anthony F.W.
      • Ohri S.K.
      • Hanson M.A.
      Long-term maternal high-fat feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids and fatty liver in mice.
      ]
      C57BL/6 J mice5.3% fat (maize oil)17.8% fat (lard)Assessment at 9 months of age (on standard chow or HFD):
      • -
        ↑ blood pressure in ♀ & ♂ on standard chow and HFD (effect ♂>♀)
      • -
        ↑ cholesterol levels in ♂ on standard chow and HFD
      • -
        ↑ cholesterol levels in ♀ on HFD
      21.2% protein26.5% protein
      49.2% carbohydrate28.3% carbohydrate

      10.4% sucrose
      Huang et al. (2010) [
      • Huang Y.
      • Yan X.
      • Zhao J.X.
      • Zhu M.J.
      • McCormick R.J.
      • Ford S.P.
      • et al.
      Maternal obesity induces fibrosis in fetal myocardium of sheep.
      ]
      Multiparous Rambouillet/Columbia ewes

      N = 12 ewes
      Highly palatable diet 100% of National Research Council recommendationsHighly palatable diet 150% of National Research Council recommendationsFetal assessment at day 75 or 135 of gestation:
      • -
        Presence of Myocardial fibrosis
      • -
        ↑fetal heart connective tissue accumulation
      Wang et al. (2010) [
      • Wang J.
      • Ma H.
      • Tong C.
      • Zhang H.
      • Lawlis G.B.
      • Li Y.
      • et al.
      Overnutrition and maternal obesity in sheep pregnancy alter the JNK-IRS-1 signaling cascades and cardiac function in the fetal heart.
      ]
      Multiparous Rambouillet/Columbia ewes

      N = 16 ewes
      Highly palatable diet 100% of National Research Council recommendationsHighly palatable diet 150% of National Research Council recommendationsFetal assessment at day 135 of gestation:
      • -
        ↑ ratio Left Ventricular mass to heart weight without signs of cardiac hypertrophy or fibrogenesis
      • -
        ↓contractile functioning of fetal heart in high workload stress
      Fernandez-Twinn et al. (2012)

      [
      • Fernandez-Twinn D.S.
      • Blackmore H.L.
      • Siggens L.
      • Giussani D.A.
      • Cross C.M.
      • Foo R.
      • et al.
      The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinemia, AKT, ERK, and mTOR activation.
      ]
      C57BL/6 J mice

      N = 16 dam s
      7% simple sugars10% simple sugarsAssessment at 8 weeks of age (all on standard chow):
      • -
        ↑ heart mass (absolute cardiac weight and % of body mass)
      • -
        ↑ thickness left ventricular wall (intraventricular septum and free wall)
      • -
        ↑ expression of molecular markers of cardiac hypertrophy
      3% fat20% animal lard
      Fan et al. (2013) [
      • Fan L.
      • Lindsley S.R.
      • Comstock S.M.
      • Takahashi D.L.
      • Evans A.E.
      • He G.W.
      • et al.
      Maternal high-fat diet impacts endothelial function in nonhuman primate offspring.
      ]
      Japanese macaques (Macaca fuscata)

      N = 52 offspring
      14% fat36% fatAssessment at 13 months of age (on standard diet or HFD):
      • -
        ↓ endothelium-dependent relaxation in abdominal aortic rings on HFD
      • -
        No difference in renal endothelial response
      • -
        ↑ intima wall thickness + abnormal vascular morphology when on HFD
      Blackmore et al. (2014) [
      • Blackmore H.L.
      • Niu Y.
      • Fernandez-Twinn D.S.
      • Tarry-Adkins J.L.
      • Giussani D.A.
      • Ozanne S.E.
      Maternal diet-induced obesity programs cardiovascular dysfunction in adult male mouse offspring independent of current body weight.
      ]
      C57BL/6 J mice

      N = 20 dam s
      7% simple sugars10% simple sugarsAssessment at 3,5, 8 and 12 weeks of age (all on standard chow): ONLY ♂
      • -
        ↑ heart weight and Left + Right ventricular volumes
      • -
        re-expression of fetal cardiac genes
      • -
        ventricular wall thickening & cardiomyocyte hypertrophy
      • -
        severe systolic and diastolic dysfunction + cardiac sympathetic dominance in young adulthood
      3% fat20% animal lard
      Wakana et al. (2015) [
      • Wakana N.
      • Irie D.
      • Kikai M.
      • Terada K.
      • Yamamoto K.
      • Kawahito H.
      • et al.
      Maternal high-fat diet exaggerates atherosclerosis in adult offspring by augmenting periaortic adipose tissue-specific proinflammatory response.
      ]
      C57BL/6 J mice12.0% fat62% fatAssessment at 20 weeks of age (on HFD from the age of 8 weeks):
      • -
        ↑atherosclerotic lesion in aorta in ♂
      • -
        ↑ inflammatory expression in thoracic periaortic tissue
      • -
        ↑ increased expression of macrophage colony-stimulating factor
      28.9% protein18.2% protein
      59.1% carbohydrate19.6% carbohydrate
      Xue et al. (2015) [
      • Xue Q.
      • Chen P.
      • Li X.
      • Zhang G.
      • Patterson A.J.
      • Luo J.
      Maternal high-fat diet causes a sex-dependent increase in AGTR2 expression and cardiac dysfunction in adult male rat offspring.
      ]
      Sprague-Dawley rats4.3% fat35% fatAssessment at 3 months of age (all on standard chow):
      • -
        No difference in heart weight
      • -
        ↑ thickness left ventricular wall and ↓Left Ventricular ejection fraction in
      • -
        No effect on systolic and diastolic functioning
      • -
        ↑ susceptibility to ischemia-reperfusion injury in ♂
      20% protein26% protein
      49% carbohydrate

      4.8% fiber
      26% carbohydrate
      Loche et al. (2018) [
      • Loche E.
      • Blackmore H.L.
      • Carpenter A.A.M.
      • Beeson J.H.
      • Pinnock A.
      • Ashmore T.J.
      • et al.
      Maternal diet-induced obesity programmes cardiac dysfunction in male mice independently of post-weaning diet.
      ]
      C57BL/6 J mice

      N = 16 dam s
      7% simple sugars10% simple sugarsAssessment at 8 weeks of age (on standard chow or HFD): ONLY ♂
      • -
        ↑ heart weight and dimensions (highest when on HFD)
      • -
        re-expression of fetal cardiac genes independent of offspring diet
      • -
        ↑ thickness interventricular septum and left ventricular area independent of offspring diet
      • -
        ↓Left Ventricular ejection fraction
      • -
        ↑ blood pressure (highest when on HFD)
      3% fat20% animal lard
      15% protein23% protein
      Chronic inflammation in mothers with obesity causes a combination of vasoconstriction, platelet aggregation and lipid storage in the placenta. This contributes to a suboptimal trophoblast invasion and aberrant vascular development with hypoxia and decreased blood flow [
      • Hayes E.K.
      • Tessier D.R.
      • Percival M.E.
      • Holloway A.C.
      • Petrik J.J.
      • Gruslin A.
      • et al.
      Trophoblast invasion and blood vessel remodeling are altered in a rat model of lifelong maternal obesity.
      ,
      • Frias A.E.
      • Morgan T.K.
      • Evans A.E.
      • Rasanen J.
      • Oh K.Y.
      • Thornburg K.L.
      • et al.
      Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition.
      ]. A decreased foetal:placental weight ratio is observed in combination with the development of atherosclerosis–like plaques in the placental arterioles and occurrence of infarcts [
      • Roberts V.H.
      • Frias A.E.
      • Grove K.L.
      Impact of maternal obesity on fetal programming of cardiovascular disease.
      ,
      • Musa M.G.
      • Torrens C.
      • Clough G.F.
      The microvasculature: a target for nutritional programming and later risk of cardio-metabolic disease.
      ,
      • Lager S.
      • Samulesson A.M.
      • Taylor P.D.
      • Poston L.
      • Powell T.L.
      • Jansson T.
      Diet-induced obesity in mice reduces placental efficiency and inhibits placental mTOR signaling.
      ]. These placental abnormalities cause hemodynamic changes leading to a shift in fetal blood supply which most affects, for reasons yet unknown, the blood vessels, kidneys and heart ([
      • Thornburg K.L.
      The programming of cardiovascular disease.
      ]).
      The fetal cardiomyocytes are influenced through different pathways. Insulin-like growth factor-1 (IGF-1) stimulates the proliferation of cardiomyocytes and is suppressed when placental insufficiency is present, leading to less proliferation and maturation of the cardiomyocytes [
      • Thornburg K.L.
      The programming of cardiovascular disease.
      ,
      • Sundgren N.C.
      • Giraud G.D.
      • Schultz J.M.
      • Lasarev M.R.
      • Stork P.J.
      • Thornburg K.L.
      Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes.
      ,
      • Thornburg K.L.
      • O'Tierney P.F.
      • Louey S.
      Review: the placenta is a programming agent for cardiovascular disease.
      ]. The observed ventricular hypertrophy and myocardial fibrosis are possibly caused by the activation of protein kinase B, sympathetic dominance, lipotoxicity and/or increased mechanical systolic load to the fetal heart [
      • Briffa J.F.
      • McAinch A.J.
      • Romano T.
      • Wlodek M.E.
      • Hryciw D.H.
      Leptin in pregnancy and development: a contributor to adulthood disease?.
      ,
      • Louey S.
      • Jonker S.S.
      • Giraud G.D.
      • Thornburg K.L.
      Placental insufficiency decreases cell cycle activity and terminal maturation in fetal sheep cardiomyocytes.
      ,
      • Baschat A.A.
      Fetal responses to placental insufficiency: an update.
      ]. The combination of the aforementioned hypertrophy and immaturity predispose the offspring to cardiac dysfunction and premature cardiac failure at adult age [
      • Roberts V.H.
      • Frias A.E.
      • Grove K.L.
      Impact of maternal obesity on fetal programming of cardiovascular disease.
      ].

      2.2 Data from human studies

      Human data on long-term cardiovascular effects of maternal obesity mostly arise from epidemiological studies and are based on associations. Therefore, they cannot be used to confirm or contradict the aforementioned programming hypotheses. A Finnish study by Forsen et al. from 1997 [
      • Forsén T.
      • Eriksson J.G.
      • Tuomilehto J.
      • Teramo K.
      • Osmond C.
      • Barker D.J.
      Mother's weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study.
      ] is repeatedly referred to as a pioneering study. It links an increased death from cardiovascular disease in adult men with their mothers suffering from obesity during pregnancy. Other contributory studies link gestational weight gain and maternal obesity during pregnancy to an elevated blood pressure at childhood, adolescent and adult age and even demonstrate increased incidence of adverse cardiovascular outcomes and premature death [
      • Godfrey K.M.
      • Forrester T.
      • Barker D.J.
      • Jackson A.A.
      • Landman J.P.
      • Hall J.S.
      • et al.
      Maternal nutritional status in pregnancy and blood pressure in childhood.
      ,
      • Laor A.
      • Stevenson D.K.
      • Shemer J.
      • Gale R.
      • Seidman D.S.
      Size at birth, maternal nutritional status in pregnancy, and blood pressure at age 17: population based analysis.
      ,
      • Moraeus L.
      • Lissner L.
      • Yngve A.
      • Poortvliet E.
      • Al-Ansari U.
      • Sjöberg A.
      Multi-level influences on childhood obesity in Sweden: societal factors, parental determinants and child's lifestyle.
      ]. So far only the aberrant pro-inflammatory and lipotoxic state of pregnant women with obesity has been confirmed in humans [
      • Wankhade U.D.
      • Thakali K.M.
      • Shankar K.
      Persistent influence of maternal obesity on offspring health: mechanisms from animal models and clinical studies.
      ,
      • Saben J.
      • Lindsey F.
      • Zhong Y.
      • Thakali K.
      • Badger T.M.
      • Andres A.
      • et al.
      Maternal obesity is associated with a lipotoxic placental environment.
      ]. But since it is known that maternal hyperlipidemia during pregnancy is associated with increased formation of fetal atherosclerotic lesions and their progression in childhood, indications for the underlying mechanisms might be closer than we think [
      • Palinski 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.
      ,
      • Palinski W.
      • Nicolaides E.
      • Liguori A.
      • Napoli C.
      Influence of maternal dysmetabolic conditions during pregnancy on cardiovascular disease.
      ].
      Some issues remain when translating animal findings based on HFD to humans, since the used HFD are not standardized (as illustrated in Table 1) and diverse animal phenotypes are obtained. In order to overcome these issues, a new promising animal diet has been developed by Bortolin et al., in 2017 based on the human Western diet [
      • Bortolin R.C.
      • Vargas A.R.
      • Gasparotto J.
      • Chaves P.R.
      • Schnorr C.E.
      • Martinello K.B.
      • et al.
      A new animal diet based on human Western diet is a robust diet-induced obesity model: comparison to high-fat and cafeteria diets in term of metabolic and gut microbiota disruption.
      ]. Further research should be undertaken to investigate the accuracy of the formulated programming mechanisms, extrapolated from animal studies and eventual adaptations based on new animal diets.

      2.3 Epigenetic alterations

      Increasing evidence supports epigenetic alterations by the preceding stressors through the critical periods of fetal life and identifies them as a possible persistent factor across different generations if germ cells are affected as well [
      • Godfrey K.M.
      • Reynolds R.M.
      • Prescott S.L.
      • Nyirenda M.
      • Jaddoe V.W.
      • Eriksson J.G.
      • et al.
      Influence of maternal obesity on the long-term health of offspring.
      ,
      • Thornburg K.L.
      The programming of cardiovascular disease.
      ]. Epigenetic modifications could be present from the fetal period and/or caused by differences in flow or shear-stress and play a role in up-regulation of atherogenic genes or down-regulation of enzyme activities protecting against oxidative stress [
      • Boulanger C.M.
      ]. Unraveling the transgenerational epigenetic modifications is still in its early stage, but promising for future treatment strategies.
      Previously described alterations consist of post-translational histone modifications, gene promoter DNA methylation and expression of non-coding micro RNA [
      • Galjaard S.
      • Devlieger R.
      • Van Assche F.A.
      Fetal growth and developmental programming.
      ,
      • Thornburg K.L.
      The programming of cardiovascular disease.
      ,
      • Wankhade U.D.
      • Thakali K.M.
      • Shankar K.
      Persistent influence of maternal obesity on offspring health: mechanisms from animal models and clinical studies.
      ]. Several studies used a genome wide methylation technique to detect associations in DNA methylation at CpG sites (cytosine-guanine dinucleotides) between mothers with obesity and their offspring. The results have been conflicting so far. Some studies report no associations between the maternal pre-pregnancy BMI and global methylation or methylation at CpG sites [
      • Morales E.
      • Groom A.
      • Lawlor D.A.
      • Relton C.L.
      DNA methylation signatures in cord blood associated with maternal gestational weight gain: results from the ALSPAC cohort.
      ,
      • Michels K.B.
      • Harris H.R.
      • Barault L.
      Birthweight, maternal weight trajectories and global DNA methylation of LINE-1 repetitive elements.
      ]. Others did identify methylation differences at birth and at the age of three when comparing the offspring of mothers with obesity to healthy subjects [
      • Godfrey K.M.
      • Reynolds R.M.
      • Prescott S.L.
      • Nyirenda M.
      • Jaddoe V.W.
      • Eriksson J.G.
      • et al.
      Influence of maternal obesity on the long-term health of offspring.
      ,
      • Herbstman J.B.
      • Wang S.
      • Perera F.P.
      • Lederman S.A.
      • Vishnevetsky J.
      • Rundle A.G.
      • et al.
      Predictors and consequences of global DNA methylation in cord blood and at three years.
      ,
      • Liu X.
      • Chen Q.
      • Tsai H.J.
      • Wang G.
      • Hong X.
      • Zhou Y.
      • et al.
      Maternal preconception body mass index and offspring cord blood DNA methylation: exploration of early life origins of disease.
      ,
      • Sharp G.C.
      • Lawlor D.A.
      • Richmond R.C.
      • Fraser A.
      • Simpkin A.
      • Suderman M.
      • et al.
      Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: findings from the Avon Longitudinal Study of Parents and Children.
      ]. Two sibling cohorts comparing DNA methylation before and after bariatric surgery in the mother showed differences in methylation patterns in the offspring, strengthening the hypothesis that maternal obesity during pregnancy can definitely alter general methylation patterns in the offspring [
      • Guénard F.
      • Tchernof A.
      • Deshaies Y.
      • Cianflone K.
      • Kral J.G.
      • Marceau P.
      • et al.
      Methylation and expression of immune and inflammatory genes in the offspring of bariatric bypass surgery patients.
      ,
      • Berglind D.
      • Müller P.
      • Willmer M.
      • Sinha I.
      • Tynelius P.
      • Näslund E.
      • et al.
      Differential methylation in inflammation and type 2 diabetes genes in siblings born before and after maternal bariatric surgery.
      ].
      A different approach through detection of candidate genes demonstrates auspicious results. The AHRR gene in particular seems a methylation hotspot and has therefore been suggested as a candidate imprinted gene playing a possible role in the imprinting of the offspring's adiposity [
      • Burris H.H.
      • Baccarelli A.A.
      • Byun H.M.
      • Cantoral A.
      • Just A.C.
      • Pantic I.
      • et al.
      Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight.
      ]. Other mentioned candidate genes are PPARGC1A gene promoter region, IGF 2 and/or H19 region, PLAGL1 region and MEG region. However, caution must be applied, as most of the findings are found in cord blood and confirmation of a link between these methylation differences and long-term consequences of maternal obesity is needed [
      • Godfrey K.M.
      • Reynolds R.M.
      • Prescott S.L.
      • Nyirenda M.
      • Jaddoe V.W.
      • Eriksson J.G.
      • et al.
      Influence of maternal obesity on the long-term health of offspring.
      ,
      • Block T.
      • El-Osta A.
      Epigenetic programming, early life nutrition and the risk of metabolic disease.
      ].
      For the time being, the transgenerational impact of these alterations in methylation patterns are only shown in animal studies with HFD animals. In this respect the paternal influence also comes forward. Alterations in methylation at the spermatozoa of male rats fed with a HFD were shown in combination with transgenerational metabolic effects, mainly on the female offspring [
      • de Castro Barbosa T.
      • Ingerslev L.R.
      • Alm P.S.
      • Versteyhe S.
      • Massart J.
      • Rasmussen M.
      • et al.
      High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring.
      ]. Methylation alterations in spermatozoa were also found in the male offspring of dams fed with HFD during their pregnancy [
      • Ge Z.J.
      • Liang Q.X.
      • Hou Y.
      • Han Z.M.
      • Schatten H.
      • Sun Q.Y.
      • et al.
      Maternal obesity and diabetes may cause DNA methylation alteration in the spermatozoa of offspring in mice.
      ]. Consequent effects on the phenotype where again only shown in female offspring (until third generation) [
      • Dunn G.A.
      • Bale T.L.
      Maternal high-fat diet effects on third-generation female body size via the paternal lineage.
      ].
      A transgenerational inheritance through the female germline by mitochondrial inheritance has been suggested. A recent, small study in humans found altered mitochondrial functioning in the male offspring of overweight woman [
      • Abraham M.
      • Collins C.A.
      • Flewelling S.
      • Camazine M.
      • Cahill A.
      • Cade W.T.
      • et al.
      Mitochondrial inefficiency in infants born to overweight African-American mothers.
      ]. A finding that has been confirmed in mice studies with a persistence of this transfer of aberrant oocyte mitochondria into the third generation [
      • Saben J.L.
      • Boudoures A.L.
      • Asghar Z.
      • Thompson A.
      • Drury A.
      • Zhang W.
      • et al.
      Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations.
      ].
      The identification of a number of alterations in active cardiovascular micro RNA species in the offspring of animals with obesity offer promising perspectives for the future [
      • Roberts V.H.
      • Frias A.E.
      • Grove K.L.
      Impact of maternal obesity on fetal programming of cardiovascular disease.
      ,
      • Thornburg K.L.
      The programming of cardiovascular disease.
      ,
      • Eulalio A.
      • Mano M.
      • Dal Ferro M.
      • Zentilin L.
      • Sinagra G.
      • Zacchigna S.
      • et al.
      Functional screening identifies miRNAs inducing cardiac regeneration.
      ,
      • Hata A.
      Functions of microRNAs in cardiovascular biology and disease.
      ]. Specific micro-RNAs are expressed in the endothelial cells and could be a promising target in the management of early stage cardiovascular disease, once more human data are available.

      3. Endothelial cell (dys)function:pathophysiology – contributing factors

      According to the abovementioned programming mechanisms, the offspring of mothers with obesity during pregnancy is at risk for the early development of cardiovascular disease. Endothelial cell dysfunction is associated with future cardiovascular events, so it can be used as indicator for the cardiovascular system in an individual [
      • Skilton M.R.
      • Celermajer D.S.
      Endothelial dysfunction and arterial abnormalities in childhood obesity.
      ].
      The endothelial cells take part in a well-orchestrated vascular and inflammatory homeostasis and are subject to very diverse mechanical and metabolic influences [
      • Boulanger C.M.
      ,
      • Gimbrone M.A.
      • García-Cardeña G.
      Endothelial cell dysfunction and the pathobiology of atherosclerosis.
      ,
      • Bruyndonckx L.
      • Hoymans V.Y.
      • Van Craenenbroeck A.H.
      • Vissers D.K.
      • Vrints C.J.
      • Ramet J.
      • et al.
      Assessment of endothelial dysfunction in childhood obesity and clinical use.
      ]. Nitric Oxide (NO) is one of the main regulators in the control of vascular tone and protection against thrombogenic influences [
      • Boulanger C.M.
      ,
      • Bruyndonckx L.
      • Hoymans V.Y.
      • Van Craenenbroeck A.H.
      • Vissers D.K.
      • Vrints C.J.
      • Ramet J.
      • et al.
      Assessment of endothelial dysfunction in childhood obesity and clinical use.
      ]. A perturbation of the complex equilibrium results in endothelial cell dysfunction, a broad concept for diverse nonadaptive alterations [
      • Skilton M.R.
      • Celermajer D.S.
      Endothelial dysfunction and arterial abnormalities in childhood obesity.
      ,
      • Gimbrone M.A.
      • García-Cardeña G.
      Endothelial cell dysfunction and the pathobiology of atherosclerosis.
      ,
      • Bruyndonckx L.
      • Hoymans V.Y.
      • Van Craenenbroeck A.H.
      • Vissers D.K.
      • Vrints C.J.
      • Ramet J.
      • et al.
      Assessment of endothelial dysfunction in childhood obesity and clinical use.
      ]. As a result the protection against thrombogenic processes is lost and a pathogenic cascade is triggered to form an atherosclerotic plaque. Therefore endothelial cell dysfunction is considered the preliminary stage of atherosclerotic cardiovascular disease [
      • Skilton M.R.
      • Celermajer D.S.
      Endothelial dysfunction and arterial abnormalities in childhood obesity.
      ,
      • Gimbrone M.A.
      • García-Cardeña G.
      Endothelial cell dysfunction and the pathobiology of atherosclerosis.
      ].
      A diverse amount of molecular substances and mechanical stressors can contribute to an imbalance in the atheroprotective function of the endothelial cells as illustrated in Fig. 2. A number of them are characteristically seen in children or adults suffering from overweight or obesity. Hypertension is commonly present and is caused by mechanisms (e.g. Renin Angiotensin Aldosteron System) that directly influence endothelial function as well. Research shows a correlation between an elevated systolic blood pressure in adolescence and endothelial cell dysfunction at adult age through the affection of eNOS (endothelial Nitric Oxide Synthase [
      • Herouvi D.
      • Karanasios E.
      • Karayianni C.
      • Karavanaki K.
      Cardiovascular disease in childhood: the role of obesity.
      ,
      • Bruyndonckx L.
      • Hoymans V.Y.
      • Van Craenenbroeck A.H.
      • Vissers D.K.
      • Vrints C.J.
      • Ramet J.
      • et al.
      Assessment of endothelial dysfunction in childhood obesity and clinical use.
      ,
      • Chudek J.
      • Wiecek A.
      Adipose tissue, inflammation and endothelial dysfunction.
      ]. Adiponectin, has a relaxing influence on the smooth muscle cells by stimulating NO production and lowering the production of cytokines and expression of vascular adhesion molecules following inflammatory stimuli [
      • Boulanger C.M.
      ,
      • Chudek J.
      • Wiecek A.
      Adipose tissue, inflammation and endothelial dysfunction.
      ]. Since the plasma concentration of Adiponectin is low in individuals with obesity, the antithrombogenic effects are impaired. The chronic inflammatory state causes elevated levels of C-Reactive Protein (CRP) and pro-inflammatory cytokines (Interleukin-6, Tumor Necrosis Factor α), resulting in a higher permeability of the endothelial cells, a stimulation of fibrinogen and platelet activity and decreased eNOS activity with subsequent impaired vasodilatory response [
      • Boulanger C.M.
      ,
      • Herouvi D.
      • Karanasios E.
      • Karayianni C.
      • Karavanaki K.
      Cardiovascular disease in childhood: the role of obesity.
      ,
      • Chudek J.
      • Wiecek A.
      Adipose tissue, inflammation and endothelial dysfunction.
      ]. Circulating lipids are a well-known risk factor for the development of atheroscelosis. Low-Density Lipoprotein (LDL) in its oxidized form and free fatty acids impair eNOS function [
      • Bruyndonckx L.
      • Hoymans V.Y.
      • Van Craenenbroeck A.H.
      • Vissers D.K.
      • Vrints C.J.
      • Ramet J.
      • et al.
      Assessment of endothelial dysfunction in childhood obesity and clinical use.
      ,
      • Chudek J.
      • Wiecek A.
      Adipose tissue, inflammation and endothelial dysfunction.
      ].
      Fig. 2
      Fig. 2Comparison of normal endothelial cell function on the left site with endothelial cell dysfunction on the right site.
      The normal endothelial cells react to fluctuations in blood flow and other agonists such as insulin with the activation of endothelial Nitric Oxide Synthase (eNOS). This endothelial isoform of the NO synthase is activated through the phosphoinositol 3 kinase (PI3K)/akt pathway and forms NO by metabolizing l-Arginine with formation of l-Citrulline as a byproduct. Adiponectin, an insulin-sensitizing and anti-atherogenic protein, contributes to the normal endothelial cell function by suppressing the production of cytokines, expression of adhesion molecules and stabilization of eNOS RNA. The produced NO disseminates and acts by activating guanylyl cyclase, which leads to relaxation of smooth muscle cells, inhibition of leukocyte adhesion and platelet activation and aggregation.
      When the normal function of the endothelial cells is disturbed, there is decreased vascular relaxation and formation of a pro-inflammatory endothelial phenotype. Different stressors can affect the normal function of the endothelial cells. An altered blood flow due to hypertension, insulin resistance and decreased Adiponectin concentrations, TNF-α and other cytokines as well as oxidized LDL affect eNOS activity leading to a decreased production of NO. Consequently a pro-inflammatory environment is created, mostly through the nuclear factor-κB pathway, leading to expression of adhesion molecules at cell surface and secretion of chemokines. These events put pressure on the natural barrier function of the endothelial cell layer (symbolized by the small squares). Loss of this barrier function in the pro-inflammatory environment leads to migration and adhesion of leukocytes and macrophages, platelet adhesion and an eventual chronical inflammatory state which predisposes for the formation of atherosclerotic plaques.

      4. Endothelial cell (dys)function: assessment

      Since endothelial cell dysfunction is a reversible process, it offers a window of opportunity for a health care intervention. The oldest investigations of endothelial cell function were invasive and were performed by administering Achetylcholine into the coronary arteries to assess vasodilatory response [
      • Ludmer P.L.
      • Selwyn A.P.
      • Shook T.L.
      • Wayne R.R.
      • Mudge G.H.
      • Alexander R.W.
      • et al.
      Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.
      ]. Since this invasive procedure is not applicable in (healthy) children, innovative and non-invasive techniques were developed since the 1990s. Flow-mediated dilatation (FMD) was the first developed non-invasive technique. FMD is based on the measurement of the vasodilatory response of an artery after occlusion by using an ultrasound to assess the difference in diameter in a relatively superficial artery, mostly the brachial artery. This technique is elegant to use but requires expensive technical material, intense operator training and still remains operator-dependent making it subject to a low reproducibility [
      • Bruyndonckx L.
      • Hoymans V.Y.
      • Van Craenenbroeck A.H.
      • Vissers D.K.
      • Vrints C.J.
      • Ramet J.
      • et al.
      Assessment of endothelial dysfunction in childhood obesity and clinical use.
      ,
      • Herouvi D.
      • Karanasios E.
      • Karayianni C.
      • Karavanaki K.
      Cardiovascular disease in childhood: the role of obesity.
      ,
      • Bruyndonckx L.
      • Radtke T.
      • Eser P.
      • Vrints C.J.
      • Ramet J.
      • Wilhelm M.
      • et al.
      Methodological considerations and practical recommendations for the application of peripheral arterial tonometry in children and adolescents.
      ].
      To tackle these disadvantages, a novel technique based on peripheral arterial tonometry was developed. This approach enables the investigator to assess the endothelial cell function on a microvascular level. The peripheral wave amplitude measurements occur at the level of the fingertips. The technique is feasible and has a high reproducibility (assessed in adults and adolescents). Different outcomes are analyzed in wave amplitude after a period of occlusion, with the Reactive Hyperemia Index (RHI) being the most reported one [
      • Liu J.
      • Wang J.
      • Jin Y.
      • Roethig H.J.
      • Unverdorben M.
      Variability of peripheral arterial tonometry in the measurement of endothelial function in healthy men.
      ,
      • McCrea C.E.
      • Skulas-Ray A.C.
      • Chow M.
      • West S.G.
      Test-retest reliability of pulse amplitude tonometry measures of vascular endothelial function: implications for clinical trial design.
      ,
      • Selamet Tierney E.S.
      • Newburger J.W.
      • Gauvreau K.
      • Geva J.
      • Coogan E.
      • Colan S.D.
      • et al.
      Endothelial pulse amplitude testing: feasibility and reproducibility in adolescents.
      ,
      • Brant L.C.
      • Barreto S.M.
      • Passos V.M.
      • Ribeiro A.L.
      Reproducibility of peripheral arterial tonometry for the assessment of endothelial function in adults.
      ]. A broad overview of different studies using peripheral arterial tonometry measurements in children and adolescents is presented in Table 2. In healthy, normal weight subjects an increase in RHI with age and pubertal development is reported consistently, whereas associations with BMI and other cardiovascular risk factors remain controversial. In subjects with an unfavorable body composition and possible metabolic comorbidities, a persistent decrease in RHI is noticed. Corresponding with the healthy subjects, correlations with other cardiovascular risk factors differ across the studies. Besides studies in subjects suffering from overweight and obesity, the endothelial cell function of children with other pathologic conditions has been investigated as well. Children with Turner syndrome, Sickle Cell disease with recurrent crises, Fontan circulation and adolescents with Type 1 Diabetes Mellitus all demonstrate impaired RHI.
      Table 2Assessment of endothelial cell function in children and adolescents by using peripheral arterial tonometry (no interventions).
      Study (year)Population (mean age ± SD)Study groups BMI (kg/m2)Main findings
      Healthy children and adolescentsChen et al. (2010) [
      • Chen Y.
      • Osika W.
      • Dangardt F.
      • Gan L.M.
      • Strandvik B.
      • Friberg P.
      High levels of soluble intercellular adhesion molecule-1, insulin resistance and saturated fatty acids are associated with endothelial dysfunction in healthy adolescents.
      ]
      14.5 ± 1.0 years

      N = 257 (138♀)
      Healthy adolescents

      (♀ BMI 21.2 ± 3.3 and ♂ BMI 21.0 ± 3.6)
      • -
        No gender difference in RHI
      • -
        Inverse correlation between RHI and fasting insulin level, HOMA-IR, ICAM-1 and proportion of saturated fatty acids
      • -
        No correlation between RHI and BMI/lipid profile/blood pressure
      Bhangoo et al. (2011)

      [
      • Bhangoo A.
      • Sinha S.
      • Rosenbaum M.
      • Shelov S.
      • Ten S.
      Endothelial function as measured by peripheral arterial tonometry increases during pubertal advancement.
      ]
      Min 12.06 ± 0.6

      Max 12.96 ± 0.7

      N = 89 (45♀)
      Healthy children
      • 1
        Tanner I (n = 21) BMI 18.9 ± 3.1
      • 2
        Tanner II-III (n = 35) BMI 21.9 ± 4.5
      • 3
        Tanner IV-V (n = 33) BMI 23.1 ± 4.9
      • -
        ↑ RHI with age (similar in both sexes): group 3 (1.92 ± 0.38). > group 2 (1.71 ± 0.35) > group 1 (1.42 ± 0.44) (p = 0.02 & p < 0.001)
      • -
        Positive correlation between RHI and ↑ estradiol (r2 = 0.10; p < 0.05) and DHEAS levels (r2 = 0.12; p < 0.05) and age (r2 = 0.04; p < 0.05)
      • -
        Negative correlation with total cholesterol (r2 = 0.03: p < 0.05)
      Osika et al. (2011) [
      • Osika W.
      • Montgomery S.M.
      • Dangardt F.
      • Währborg P.
      • Gan L.M.
      • Tideman E.
      • et al.
      Anger, depression and anxiety associated with endothelial function in childhood and adolescence.
      ]
      14.0 ± 1.0 years

      N = 248 (136♀)
      Healthy school children

      BMI SDS 0.48 ± 1.11
      • -
        No gender difference in RHI (mean 1.82 ± 0.55)
      • -
        No correlation between RHI and height/BMI z score
      • -
        ♀: Association between ↓ RHI and ↑ scores for anger (B coefficient = −0.100, p = 0.040), depression (−0.108, p = 0.009) and anxiety (−0.138, p = 0.039)
      • -
        ♂: Association between ↑ RHI and disruptive behavior (0.09, p = 0.006).
      Radtke et al. (2012) [
      • Radtke T.
      • Khattab K.
      • Eser P.
      • Kriemler S.
      • Saner H.
      • Wilhelm M.
      Puberty and microvascular function in healthy children and adolescents.
      ]
      14.0 (3.0) yearsf

      N = 94 (55♀)
      Healthy children and adolescents
      • 1
        Tanner I (n = 42) BMI 17.6 ± 3.0
      • 2
        Tanner II-III (n = 10) BMI 18.8 ± 2.8
      • 3
        Tanner IV-V (n = 42) BMI 20.4 ± 2.4
      • -
        ↑ RHI with ↑ Tanner stage (group 3 > group 2>group 1; p ≤ 0.001)
      • -
        Positive correlation between RHI and Tanner stage (r = 0.569; p< 0.001), age (r = 0.567; p < 0.001), stature (r = 0.553; p < 0.001), systolic BP (r = 0.494; p < 0.001), and BMI (r = 0.309; p =0 .001)
      Radtke et al. (2013) [
      • Radtke T.
      • Kriemler S.
      • Eser P.
      • Saner H.
      • Wilhelm M.
      Physical activity intensity and surrogate markers for cardiovascular health in adolescents.
      ,
      • Radtke T.
      • Eser P.
      • Kriemler S.
      • Saner H.
      • Wilhelm M.
      Adolescent blood pressure hyperreactors have a higher reactive hyperemic index at the fingertip.
      ]
      14.5 ± 0.7 years

      N = 52(28♀)
      Healthy adolescents BMI19.8 ± 2.4
      • 1
        Low physical activity
      • 2
        High physical activity
      • -
        No significant differences in RHI between both groups
      • -
        ↑RHI at rest in BP-hyperreactors (n = 16) compared to normal reactors (2.1 ± 0.4 versus 1.6 ± 0.4; p = 0.003)
      Odanaka et al. (2017) [
      • Odanaka Y.
      • Takitani K.
      • Katayama H.
      • Fujiwara H.
      • Kishi K.
      • Ozaki N.
      • et al.
      Microvascular endothelial function in Japanese early adolescents.
      ]
      13.7 ± 0.9 years

      N = 157 (82♀)
      Healthy young adolescents
      • -
        No gender difference in RHI
      • -
        No correlation between RHI and age/anthropometric measurements
      • -
        Negative correlation with systolic blood pressure (r = −2.48; p = 0.01) and diastolic blood pressure (r = −4.26; p < 0.0001)
      Overweight & obeseMahmud et al. (2009)

      [
      • Mahmud F.H.
      • Hill D.J.
      • Cuerden M.S.
      • Clarson C.L.
      Impaired vascular function in obese adolescents with insulin resistance.
      ]
      13.4 ± 1.7 years

      N = 77 (31♀)
      • 1
        adolescents with obesityb and insulin resistance (n = 26) BMI 34.8 ± 4.5
      • 2
        normal weight adolescents (n = 51) BMI 19.7 ± 3.0
      • -
        ↓ mean RHI in obese adolescents (1.51 ± 0.4 versus 2.06 ± 0.4; p = 0.002)
      • -
        Association between BMI and waist circumference with RHI in both groups; lower RHI in subjects with ↑ direct measures of adiposity
      • -
        No gender differences in RHI
      • -
        ↑ RHI with age in normal weight
      • -
        In univariate linear regression, BMI, waist circumference, total cholesterol, Triglycerides and LDL-cholesterol negatively association with RHI
      Tryggestad et al. (2012) [
      • Tryggestad J.B.
      • Thompson D.M.
      • Copeland K.C.
      • Short K.R.
      Obese children have higher arterial elasticity without a difference in endothelial function: the role of body composition.
      ]
      13.9 ± 2.5 years

      N = 124 (62♀)
      • 1
        adolescents with obesityb (n = 63)
      • 2
        normal weight children (n = 61)
      • -
        No significant differences in RHI between both groups
      • -
        ↑ RHI with age in normal weight
      • -
        RHI not correlated with anthropometry, family history, BP or serum biochemical outcomes
      Agarwal et al. (2013) [
      • Agarwal C.
      • Cohen H.W.
      • Muzumdar R.H.
      • Heptulla R.A.
      • Renukuntla V.S.
      • Crandall J.
      Obesity, hyperglycemia and endothelial function in inner city Bronx adolescents: a cross-sectional study.
      ]
      15.45 ± 0.0.42 years

      N = 51 (36♀)
      • 1
        adolescents with obesityb and normal glucose tolerance (n = 22) BMI 36.37 ± 1.89
      • 2
        adolescents with obesityb and impaired glucose tolerance (n = 15) BMI 37.44 ± 1.25
      • 3
        lean controls (n = 14) BMI 22.69 ± 0.77
      • -
        ↓RHI in the obese group (1.70 ± 0.02 versus 1.98 ± 0.09; p = 0.02)
      • -
        Inverse correlation between RHI and BMI (r = −0.32; p = 0.02), waist circumference (r = −0.31; p = 0.03) and HOMA (r = −0.32; p = 0.04)
      Pareyn et al. (2015) [
      • Pareyn A.
      • Allegaert K.
      • Verhamme P.
      • Vinckx J.
      • Casteels K.
      Impaired endothelial function in adolescents with overweight or obesity measured by peripheral artery tonometry.
      ]
      14.7 (13.0–16.4) years f

      N = 51 (24 ♀)
      • 1
        adolescents with overweight (cut-off defined by Cole et al. [
        • Cole T.J.
        • Bellizzi M.C.
        • Flegal K.M.
        • Dietz W.H.
        Establishing a standard definition for child overweight and obesity worldwide: international survey.
        ]) (n = 27) BMI SDS 2.6 (2.0–3.0)
      • 2
        lean controls (n = 25) BMI SDS 0 [−0.3 to 0.5)
      • -
        ↓RHI in overweight adolescents (1.51 versus 1.88; p = 0.027)
      • -
        ↑baseline pulse amplitude in overweight adolescents (416.3 versus 145.29; p < 0.0001)
      Bartz et al. (2015) [
      • Bartz S.K.
      • Caldas M.C.
      • Tomsa A.
      • Krishnamurthy R.
      • Bacha F.
      Urine albumin-to-creatinine ratio: a marker of early endothelial dysfunction in youth.
      ]
      15.7 ± 0.2 years

      N = 58 (35♀)
      • 1
        normal weight (n = 13) BMI 21.4 ± 0.6
      • 2
        overweightc with normal glucose tolerance (n = 25) BMI 30.8 ± 0.9
      • 3
        overweightc with pre-diabetes (n = 20) BMI 34.7 ± 1.2
      • -
        ↓RHI in overweight adolescents (1.56 ± 0.1 versus 1.84 ± 0.1; p = 0.04)
      • -
        No differences in RHI according to glucose tolerance
      Hudgins et al. (2016) [
      • Hudgins L.C.
      • Annavajjhala V.
      • Kovanlikaya A.
      • Frank M.D.
      • Solomon A.
      • Parker T.S.
      • et al.
      Non-invasive assessment of endothelial function in children with obesity and lipid disorders.
      ]
      13 ± 3 years

      N = 38 (18♀)
      • 1
        children and adolescents with obesityb (n = 15) BMI SDS 2.1 ± 0.3
      • 2
        non-obese, dyslipidemicg children (n = 23) BMI SDS 0.3 ± 0.8
      • -
        ↑RHI with age and its correlates in normal weight, dyslipidemic children
      • -
        ↓ Peak response in obese children and adolescents (1.52 [1.22–1.97] versus 2.04 [1.61–2.46]; p = 0.038)
      • -
        No correlation with RHI and other cardiovascular risk factors
      Tomsa et al. (2016) [
      • Tomsa A.
      • Klinepeter Bartz S.
      • Krishnamurthy R.
      • Bacha F.
      Endothelial function in youth: a biomarker modulated by adiposity-related insulin resistance.
      ]
      15.5 ± 0.2 years

      N = 81 (46♀)
      • 1
        normal weight (n = 21)
      • 2
        overweightc normal glucose tolerance (n = 25)
      • 3
        overweightc impaired glucose tolerance (n = 19)
      • 4
        overweightc type 2 diabetes (n = 16)
      • -
        Inverse correlation between RHI and BMI, % body fat, total, subcutaneous and visceral abdominal fat. Positive correlation between RHI and age and insulin sensitivity.
      • -
        More arterial stiffness in lower RHI tertiles; positively related to % body fat and inversely related to age, insulin sensitivity and inflammatory markers
      Miscellaneous - pathologiesMahmud et al.(2006) [
      • Mahmud F.H.
      • Earing M.G.
      • Lee R.A.
      • Lteif A.N.
      • Driscoll D.J.
      • Lerman A.
      Altered endothelial function in asymptomatic male adolescents with type 1 diabetes.
      ]
      14.2 ± 1.3 years

      N = 40 (16♀)
      • 1
        adolescents with Type 1 diabetes mellitus (n = 20)
      • ♂ BMI 20.6 ± 2.0 & ♀ BMI 24.2 ± .5
      • 2
        Control group (n = 20)
      • -
        ♂: ↓ RHI in adolescents with Type 1 diabetes mellitus (1.61 ± 0.32 versus 1.93 ± 0.28; p < 0.001)
      • -
        Group 1: RHI↓ in ♂ compared to ♀ (1.61 ± 0.32 versus 2.21 ± 0.35; p = 0.001) [♀ more sexually mature]
      • -
        No correlation in RHI and age, BMI or duration of diabetes
      Mahmud et al. (2008) [
      • Mahmud F.H.
      • Van Uum S.
      • Kanji N.
      • Thiessen-Philbrook H.
      • Clarson C.L.
      Impaired endothelial function in adolescents with type 1 diabetes mellitus.
      ]
      14.6 ± 1.75 years

      N = 46 (18 ♀)
      • 1
        adolescents with Type 1 diabetes mellitus (n = 23) BMI 20.3 ± 3.5
      • 2
        Control group (n = 23) BMI 20.8 ± 2.9
      • -
        ↓ RHI in children with type 1 diabetes mellitus (1.78 ± 0.4 versus 2.06 ± 0.4; p = 0.02)
      • -
        ↓ RHI postprandial in both groups (1.45 ± 0.3 and 1.71 ± 0.3; p = 0.01).
      Sivamurthy et al. (2009) [
      • Sivamurthy K.M.
      • Dampier C.
      • MacDermott M.
      • Maureen M.
      • Cahill M.
      • Hsu L.L.
      Peripheral arterial tonometry in assessing endothelial dysfunction in pediatric sickle cell disease.
      ]
      7–20 years

      N = 36
      • 1
        Sickle cell disease – SS (n = 27)
      • 2
        Sickle cell disease – SC (n = 7)
      • 3
        Sickle cell disease – Sβ+thalassemia (n = 2)
      • -
        ↓RHI with frequent Sickle Cell Disease symptoms compared to less symptomatic subjects (1.53 versus 1.71; p = 0 .032)
      • -
        No difference in RHI if treatment with hydroxyurea or chronic transfusion compared to no treatment in group 1.
      • -
        No correlation with hemoglobin level (r = 0.29; p = 0.14).
      Goldstein et al. (2011) [
      • Goldstein B.H.
      • Golbus J.R.
      • Sandelin A.M.
      • Warnke N.
      • Gooding L.
      • King K.K.
      • et al.
      Usefulness of peripheral vascular function to predict functional health status in patients with Fontan circulation.
      ]
      15.0 (10.9–17.8) years f

      N = 73 (27♀)
      • 1
        children and adolescents with Fontan circulation (n = 51)
      • 2
        control group (n = 22)
      • -
        ↓ PAT ratio in subjects with Fontan circulation (0.17 (0.04–0.44)¥ versus 0.50 (0.27–0.74)¥; p = 0.002)
      O'Gorman et al. (2012) [
      • O'Gorman C.S.
      • Syme C.
      • Bradley T.
      • Hamilton J.
      • Mahmud F.H.
      Impaired endothelial function in pediatric patients with turner syndrome and healthy controls: a case-control study.
      ]
      13.5 ± 2.4 years

      N = 30 (30 ♀)
      • 1
        girls with Turner syndrome (n = 15) BMI 21.5 ± 4.5
      • 2
        control group (n = 15) BMI 20.8 ± 3.4
      • -
        ↓ RHI in subjects with Turner syndrome (1.64 ± 0.34 versus 2.08 ± 0.32; p = 0.002)
      • -
        ↑ RHI in subjects with Turner syndrome and growth hormone treatment compared with untreated (1.80 ± 0.36 versus 1.4 + 0.22; p = 0.02)
      • -
        Group 2: positive correlation between RHI and age/systolic BP, and negative correlation with LDL and HDL -cholesterol
      Pareyn et al. (2013) [
      • Pareyn A.
      • Allegaert K.
      • Asscherickx W.
      • Peirsman E.
      • Verhamme P.
      • Casteels K.
      Impaired endothelial function in female adolescents with type 1 diabetes measured by peripheral artery tonometry.
      ]
      15.8 (14.4–16.6) f years

      N = 59 (31♀)
      • 1
        adolescents with Type 1 diabetes mellitus (n = 34) BMI 20.9 (18.9-23.4) f
      • 2
        control group (n = 25) BMI 19.9 (19.3-20.8) f
      • -
        ↓ RHI in group 1 (1.6 (1.3–2.0)¥ versus 1.9(1.7–2.4)¥; p = 0.0154)
      • -
        ↓RHI in♀
      • -
        Positive correlation between RHI and LDL-cholesterol (r = 0.29; p = 0.031)
      Yano et al. (2013) [
      • Yano S.
      • Moseley K.
      • Wong L.
      • Castelnovi C.
      • Azen C.
      • Pavlova Z.
      Glycosaminoglycan metabolism defects and atherosclerosis: frequent association of endothelial dysfunction in patients with Mucopolysaccharidosis.
      ]
      4–50 years (mean 18.1yrs)

      N = 42 (28♀)
      • 1
        children with genetic defects of glycosaminoglycan (GAG) metabolism (n = 30)
      • 2
        control group (n = 12)
      • -
        ↓ RHI in group 1 (1.32 ± 0.59 versus 2.40 ± 0.72; p < 0.0001)
      • -
        No correlation between RHI and age in group 1 (r = 0.19, p = 0.32)
      Scaramuzza et al. (2015) [
      • Scaramuzza A.E.
      • Redaelli F.
      • Giani E.
      • Macedoni M.
      • Giudici V.
      • Gazzarri A.
      • et al.
      Adolescents and young adults with type 1 diabetes display a high prevalence of endothelial dysfunction.
      ]
      16.2 ± 3.5 years

      N = 73 (25♀)
      adolescents with Type 1 diabetes mellitus BMI 20 ± 3
      • -
        76.7% have RHI<1.67 (mean RHI1.26 ± 0.22 versus 2.24 ± 0.48; p < 0.0001)
      • -
        No correlation between RHI and body composition, age, lipid profile and blood pressure
      Goldstein et al. (2016)13.9 ± 4.1 years

      N = 60 (29♀)
      children and adolescents with Fontan circulation (n = 60)
      • -
        Median RHI 1.2 (0.2–4.8)¥
      • -
        ↓ vascular function associated with ↓ functional measures
      Butbul Aviel et al. (2017)

      [
      • Butbul Aviel Y.
      • Dafna L.
      • Pilar G.
      • Brik R.
      Endothelial function in children with a history of henoch schonlein purpura.
      ]
      13.5 ± 3.9 years

      N = 42 (15♀)
      • 1
        children and adolescents with history Henoch Schonlein Purpura (n = 19) BMI 22 ± 6.1
      • 2
        control group (n = 23) BMI 18.8 ± 3.8
      • -
        No differences in RHI between both groups
      • -
        No correlation between RHI and gender/BMI
      • -
        ↑ RHI when > 6 years after diagnosis of Henoch Schonlein Purpura (1.98 ± 0.74 versus 1.38 ± 0.43; p = 0.037)
      a [BMI] >97th percentile.
      b [BMI] > 95th percentile.
      c [BMI] > 85th percentile.
      d Addition of nitroglycerin to FMD described in Methodology.
      e Cross-sectional, baseline comparison.
      f median (Inter Quartile range).
      g LDL-cholesterol >130 mg/dL, triglycerides >150 mg/dL, HDL-cholesterol <40 mg/dL, and/or lipoprotein (a) > 2 fold the upper limit of normal.
      ↑: increased.
      ↓: decreased.
      Additional markers for endothelial cell dysfunction include the urinary Albumin-to-Creatinine ratio, which is an early marker in adolescents as demonstrated by Bartz et al. (71) Serum biomarkers as Interleukin-6, Tumor Necrosis Factor α, high sensitive-CRP offer promising perspectives in addition to the traditional endothelial assessment techniques [
      • Gimbrone M.A.
      • García-Cardeña G.
      Endothelial cell dysfunction and the pathobiology of atherosclerosis.
      ].

      5. Endothelial cell (dys)function: treatment and prevention of adverse cardiovascular programming

      5.1 Interventions during pregnancy

      The pre-conception period and early pregnancy are potential ideal time periods for a health care intervention in order to tackle the endothelial cell dysfunction at its roots.

      5.1.1 Lifestyle intervention in pregnancy

      A wide range of lifestyle interventions have been investigated to minimize adverse metabolic and cardiovascular outcomes in the offspring of pregnant women with obesity. They can be used to improve the dietary habits and/or level of physical activity and subsequently minimize the weight gain or even induce weight loss. These interventions are thought to lower the levels of circulating triglycerides, leptin and insulin [
      • Penfold N.C.
      • Ozanne S.E.
      Developmental programming by maternal obesity in 2015: outcomes, mechanisms, and potential interventions.
      ]. Nevertheless the improvement of maternal metabolic state is mostly obtained after the critical period of fetal programming which is a probable explanation for the conflicting evidence [
      • Catalano P.M.
      • Shankar K.
      Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child.
      ]. Also most studies used a different methodology and studied neonatal outcomes, making it difficult to draw unambiguous conclusions [
      • Flynn A.C.
      • Dalrymple K.
      • Barr S.
      • Poston L.
      • Goff L.M.
      • Rogozinska E.
      • et al.
      Dietary interventions in overweight and obese pregnant women: a systematic review of the content, delivery, and outcomes of randomized controlled trials.
      ]. These drawbacks have been stressed by several comparable, extensive systematic reviews [
      • Tanvig M.
      Offspring body size and metabolic profile - effects of lifestyle intervention in obese pregnant women.
      ,
      • Bogaerts A.
      • Ameye L.
      • Martens E.
      • Devlieger R.
      Weight loss in obese pregnant women and risk for adverse perinatal outcomes.
      ,
      • Muktabhant B.
      • Lawrie T.A.
      • Lumbiganon P.
      • Laopaiboon M.
      Diet or exercise, or both, for preventing excessive weight gain in pregnancy.
      ]. Thus so far no type of intervention has been considered superior to the others, but there seems a probable important role for moderate-intense exercise [
      • Muktabhant B.
      • Lawrie T.A.
      • Lumbiganon P.
      • Laopaiboon M.
      Diet or exercise, or both, for preventing excessive weight gain in pregnancy.
      ]. The different data point in the direction of a favorable effect on neonatal outcomes with less macrosomia and respiratory distress syndrome [
      • Muktabhant B.
      • Lawrie T.A.
      • Lumbiganon P.
      • Laopaiboon M.
      Diet or exercise, or both, for preventing excessive weight gain in pregnancy.
      ]. Follow-up studies on the offspring are scarce and show no clear effects on the metabolic profile in long-term, probably due to insufficient follow-up time [
      • Tanvig M.
      Offspring body size and metabolic profile - effects of lifestyle intervention in obese pregnant women.
      ].

      5.1.2 Bariatric surgery

      Bariatric surgery is widely used when the desired weight loss can not be obtained through a lifestyle intervention. Up to two third of woman undergoing bariatric surgery are in the reproductive age. Two important themes emerge from the studies performed up to now. On the one hand there is a trend towards favorable neonatal outcomes with less excessive fetal growth [
      • Vrebosch L.
      • Bel S.
      • Vansant G.
      • Guelinckx I.
      • Devlieger R.
      Maternal and neonatal outcome after laparoscopic adjustable gastric banding: a systematic review.
      ,
      • Johansson K.
      • Stephansson O.
      • Neovius M.
      Outcomes of pregnancy after bariatric surgery.
      ,
      • Adams T.D.
      • Hammoud A.O.
      • Davidson L.E.
      • Laferrère B.
      • Fraser A.
      • Stanford J.B.
      • et al.
      Maternal and neonatal outcomes for pregnancies before and after gastric bypass surgery.
      ]. On the other hand however, the risk for small-for-gestation-age infants is increasing and micronutrient deficiencies have been reported. They can cause visual, neurological and developmental impairments as well as intracranial hemorrhages and neural tube defects [
      • Jans G.
      • Matthys C.
      • Bogaerts A.
      • Lannoo M.
      • Verhaeghe J.
      • Van der Schueren B.
      • et al.
      Maternal micronutrient deficiencies and related adverse neonatal outcomes after bariatric surgery: a systematic review.
      ]. A certain degree of ambiguity persists considering whether or not there is a genuine increase in congenital malformations and preterm births after bariatric surgery [
      • González I.
      • Lecube A.
      • Rubio M.
      • García-Luna P.P.
      Pregnancy after bariatric surgery: improving outcomes for mother and child.
      ]. Nevertheless the advantages seem to outweigh the disadvantages. The limited available data on long-term show lower prevalence of childhood obesity, a favorable lipid profile, less insulin resistance and less chronic inflammation [
      • González I.
      • Lecube A.
      • Rubio M.
      • García-Luna P.P.
      Pregnancy after bariatric surgery: improving outcomes for mother and child.
      ,
      • Smith J.
      • Cianflone K.
      • Biron S.
      • Hould F.S.
      • Lebel S.
      • Marceau S.
      • et al.
      Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity.
      ]. A suggested underlying altered epigenetic methylation pattern needs to be confirmed [
      • Smith J.
      • Cianflone K.
      • Biron S.
      • Hould F.S.
      • Lebel S.
      • Marceau S.
      • et al.
      Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity.
      ].

      5.2 Interventions during childhood and adolescence

      Once endothelial cell dysfunction is established, different treatment strategies have been proposed in order to reverse this condition. An unfavorable body composition and metabolic profile is expected in the offspring of mothers with obesity. Findings from studies in children or adolescents with overweight or obesity could hypothetically apply to these children as well. An extensive overview of these treatment strategies can be found in Table 3, only including studies published in the last 10 years with non-invasive assessment of the endothelial cell function.
      Table 3Overview of different treatment strategies for endothelial cell dysfunction in children or adolescents with overweight and/or obesity or hypercholesteraemic conditions. Only studies published in the last 10 years and non-invasive measurement of the endothelial cell function were included.
      Study (year)Population (mean age ± SD)N (n ♀)Study groups BMI (kg/m2)InterventionMethodMain findingsEffect on cardiovascular risk factors
      LIFESTYLE AND/OR DIET INTERVENTIONSKaufman et al. (2008) [
      • Kaufman C.L.
      • Kaiser D.R.
      • Kelly A.S.
      • Dengel J.L.
      • Steinberger J.
      • Dengel D.R.
      Diet revision in overweight children: effect on autonomic and vascular function.
      ]
      children with overweightc 11.4 ± 0.5 years15 (9♀)
      • 1
        overweight diet (n = 15) BMI 26.8 ± 4.4
      5-month dietary modification with ShapeDown® program (5–8% weight loss goal)FMD dNo significant changes in FMD

      (trend toward increased peak EID (P = 0.05) and peak EDD (p = 0.08))
      ↓BMI

      ↓ weight

      ↓ body fat %

      ↓CRP
      Kelishadi et al. (2008) [
      • Kelishadi R.
      • Hashemi M.
      • Mohammadifard N.
      • Asgary S.
      • Khavarian N.
      Association of changes in oxidative and proinflammatory states with changes in vascular function after a lifestyle modification trial among obese children.
      ]
      adolescents with obesity b 14.1 ± 2.2 years35 (16 ♀)
      • 1
        obese exercise + diet (n = 35) BMI 25.3 ± 4.06
      Exercise: 6 weeks aerobic training program (30 min fitness & 30 min games + running)

      3 times/week, 60 min/session

      Diet: optimized mixed diet: Kcal based on requirement for height; 30% fat, 15% protein, and 55% carbohydrate
      -FMD d

      -IMT
      ↑FMD 90 s(%)

      (3.3 ± 0.3 before to 3.4 ± 0.3 after intervention, p=0.005)

      No significant changes in IMT
      ↓BMI

      ↓ weight

      ↓ body fat %

      ↓ waist circumference

      ↓fasting insulin, insulin resistance, triglycerides,

      total and LDL cholesterol, CRP
      Farpour-Lambert et al. (2009) [
      • Farpour-Lambert N.J.
      • Aggoun Y.
      • Marchand L.M.
      • Martin X.E.
      • Herrmann F.R.
      • Beghetti M.
      Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children.
      ]
      children with obesitya 8.9 ± 1.5 years66 (44♀)
      • 1
        obese exercise (n = 22) BMI 25.4 ± 4.6
      • 2
        obese control (n = 22) BMI 25.1 ± 4.7
      • 3
        lean control (n = 22) BMI 15.5 ± 1.6
      3 month aerobic training program

      3 times/week, 60 min/session:

      30 min aerobic exercise(fast

      walking, running, ball games, or swimming) (55–65% VO2 max) + 20 min resistance

      +6 months follow-up (exercise 2 times/week)
      -FMD d

      -IMT
      No significant changes in FMD

      After 6 months:

      ↓cIMT (mm) difference

      (-0.02; p = 0.045)
      ↓BMI z-score

      ↓ abdominal and total body fat%

      ↓24h systolic BP

      ↓ diastolic BP
      Murphy et al. (2009) [
      • Murphy E.C.
      • Carson L.
      • Neal W.
      • Baylis C.
      • Donley D.
      • Yeater R.
      Effects of an exercise intervention using Dance Dance Revolution on endothelial function and other risk factors in overweight children.
      ]
      children with overweightc 10.2 ± 1.7 years35 (17♀)
      • 1
        overweight exercise (n = 23) BMI 27.9 ± 4.8
      • 2
        overweight control (n = 12) BMI 31.8 ± 5.0
      12 weeks exercise intervention with active video game (Dance Dance Revolution™)

      5 times/week, 10–30 min/session
      FMD↑FMD (%)

      (4.0  ± 3.2 before to 9.6 ± 4.7 after intervention compared to controls 2.7 ± 3.6 at baseline to 3.0 ± 4.0 at 12 weeks; p < 0.01)
      ↓ Weight

      ↓ MAP
      TjØnna et al. (2009) [
      • Tjønna A.E.
      • Stølen T.O.
      • Bye A.
      • Volden M.
      • Slørdahl S.A.
      • Odegård R.
      • et al.
      Aerobic interval training reduces cardiovascular risk factors more than a multitreatment approach in overweight adolescents.
      ]
      adolescents with overweight and obesity 14 ± 0.3 years54 (28♀)
      • 1
        obese exercise (n = 28) BMI 33.2 ± 6.1
      • 2
        obese control (=standard care) (n = 26) BMI 33.3 ± 4.5
      Exercise: 12 months aerobic interval training: 4 × 4 min intervals (90–95% HR max) (interval separated by 3 min 70% HR) 2 times/week

      Standard care: group meetings every 2 weeks (physician, psychologist, physiotherapist and clinical nutritional physiologist)
      FMDAfter 3 months:
      • -
        ↑ FMD (%) both groups
      • (absolute + 5.1% in exercise group and + 3.9% in standard care group)
      • -
        Exercise group > standard care (p < 0.01)
      After 12 months (compared to baseline):
      • -
        ↑ FMD (%) both groups
      • (absolute + 6.3% in exercise group and + 1.0% in standard care group)
      • -
        Exercise group > standard care (p < 0.01)
      ↓ body fat %

      ↓ BMI

      ↓waist circumference

      ↓systolic and diastolic BP and MAP
      Hansen et al. (2013) [
      • Hansen P.R.
      • Andersen L.J.
      • Rebelo A.N.
      • Brito J.
      • Hornstrup T.
      • Schmidt J.F.
      • et al.
      Cardiovascular effects of 3 months of football training in overweight children examined by comprehensive echocardiography: a pilot study.
      ]
      children with overweight 8–12 years31(7♀)
      • 1
        overweight exercise BMI 23.1 ± 2.9
      • 2
        overweight control BMI 28.0 ± 2.9
      3 months football training program

      4 times/week, 60–90 min/session

      (mean HR > 80% of HRmax)
      EndoPAT 2000®No significant changes in RHI↑systolic BP in group 2
      Giannini et al. (2014) [
      • Giannini C.
      • Diesse L.
      • D'Adamo E.
      • Chiavaroli V.
      • de Giorgis T.
      • Di Iorio C.
      • et al.
      Influence of the Mediterranean diet on carotid intima-media thickness in hypercholesterolaemic children: a 12-month intervention study.
      ]
      Pre-pubertal hypercholesterolaemic children ([total or LDL-cholesterol level] > 75th percentile) 7.5 ± 2.3 years68 (35♀)
      • 1
        hypercholesterolaemic and mediterranean diet (n = 36) BMI SDS 2.88 ± 2.88
      • 2
        Control group (n = 32) BMI SDS 0.73 ± 1.29
      Traditional Mediterranean diet (food pattern typical of southern Italy in the early 1960s)

      Goals total energy: <30% fats (10–15% monounsaturated fats, 10% PUFAs and <10% saturated fats), 12–14% proteins and >55% from carbohydrates. Recommended daily cholesterol intake= <200 mg.
      IMT↓cIMT (mm)

      (mean 0.37 ± 0.04 before to 0.32 ± 0.03 after intervention)
      ↓ total cholesterol

      ↓ LDL &↑ HDL cholesterol

      ↓BMI SDS

      ↓ body fat %

      ↓glucose and insulin resistance
      Bruyndonckx et al. (2015) [
      • Bruyndonckx L.
      • Hoymans V.Y.
      • De Guchtenaere A.
      • Van Helvoirt M.
      • Van Craenenbroeck E.M.
      • Frederix G.
      • et al.
      Diet, exercise, and endothelial function in obese adolescents.
      ]
      adolescents with obesitya 15.4 ± 1.5 years61

      (46♀)
      • 1
        obese residential treatment (n = 33) BMI 36.44 ± 4.82
      • 2
        obese control (=standard care) (n = 28) BMI 36.7 ± 5.8
      Inpatient treatment: dietary restriction (1500–1800 kcal/day), physical activity, and psychological support under medical supervision.

      Physical activity: 2h supervised play/day +3 supervised aerobic and resistance training sessions/week (min 40 min)
      EndoPAT 2000®↑ peak response (AU)

      (Amelioration + 0.59 ± 0.20 compared with + 0.01 ± 0.12 in the control group; p=0.04)
      ↓ BMI and BMI SDS

      ↓ body fat %

      ↓ LDL- & ↑ HDL- cholesterol

      ↓hs CRP
      DIETARY SUPPLEMENTATIONPena et al.

      (2007)

      [
      • Peña A.S.
      • Wiltshire E.
      • Gent R.
      • Piotto L.
      • Hirte C.
      • Couper J.
      Folic acid does not improve endothelial function in obese children and adolescents.
      ]
      Children with obesity (BMI SDS 1.7–3.0) 13.3 ± 2.2 years53 (27♀)RCT-Double-blind parallel
      • 1
        obese intervention (n = 27) BMI SDS 33.2 ± 4.7
      • 2
        obese placebo (n = 26) BMI SDS 33.2 ± 4.9
      8 weeks treatment with oral folic acid (5 mg/day)

      or placebo
      FMD dNo significant changes in FMD↓BMI

      ↓ waist-to-hip ratio
      Dangardt et al. (2010) [
      • Dangardt F.
      • Osika W.
      • Chen Y.
      • Nilsson U.
      • Gan L.M.
      • Gronowitz E.
      • et al.
      Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents.
      ]
      Adolescents with obesity 15.7 ± 1.0 year25 (14♀)RCT – Double-blind, crossover study (6 weeks washout)
      • 1
        Obese intervention (n = 25) BMI 33.8 ± 3.9
      3 months dietary supplementation 10 caps/day:

      - 930 mg eicosapentaenoic aceid (EPA; 20:5n-3) + 290 mg docosahexaenoic acid (DHA; 22:6n-3)+ 100 mg gammalinolenic acid (GLA; 18: 3n-6)+ 18 mg Vitamin E

      or placebo
      EndoPAT 2000®

      IMT
      ↑ RH response

      (Pair-wise compared curves using global fitting; p = 0.01).

      No significant changes in IMT
      < ↓ TNF-α, IL-1β, IL-6

      ↑ IL-2
      Djurica et al. (2016) [
      • Djurica D.
      • Holt R.R.
      • Ren J.
      • Shindel A.W.
      • Hackman R.M.
      • Keen C.L.
      Effects of a dietary strawberry powder on parameters of vascular health in adolescent males.
      ]
      male adolescents with overweight or obesity ([BMI]>75th percentile) 14–18 years25 (0♀)RCT – Double-blind, crossover study (1 week washout)
      • 1
        Obese intervention (n = 25) BMI SDS 1.54 ± 0.5
      1 week treatment with 50 g of freeze-dried strawberry powder once/day

      or control powder
      EndoPAT 2000®No significant changes in RHI

      Subgroup responders (positive 1-week change in fasting plasma nitrate/nitrite):

      ↑ change RHI (AU)

      (0·07 ± 0·67 versus control: −0·45 ± 0·89; p = 0·012)

      ↑change fRHI (AU)

      (0·06 ± 0·42 versus control: −0·17 ± 0·35; p=0·05)
      ↓ LDL- & ↑ HDL- cholesterol
      Javed et al. (2016) [
      • Javed A.
      • Kullo I.J.
      • Balagopal P.B.
      • Kumar S.
      Effect of vitamin D3 treatment on endothelial function in obese adolescents.
      ]
      adolescents with obesity b + vitamin D deficiency (25[OH]D<75 nmol/l)

      15.8 ± 1.7 years
      19
      • 1
        Obese treatment BMI 36.1 ± 6.03
      3 months treatment with once a month oral 100 000 IU vitamin D3 (cholecalciferol, 2 caps 50 000 IU each)FMDNo significant changes in FMD↑ total cholesterol

      ↑ triglycerides
      MEDICATIONYu et al. (2013) [
      • Yu C.C.
      • Li A.M.
      • Chan K.O.
      • Chook P.
      • Kam J.T.
      • Au C.T.
      • et al.
      Orlistat improves endothelial function in obese adolescents: a randomised trial.
      ]
      Adolescents with obesity 11–18 years64 (19♀)
      • 1
        obese diet (n = 20) BMI 30.4 (27.9 to 34.3) f
      • 2
        obese diet + orlistat (n = 21) BMI 31.4 (27.8 to 34.0) f
      • 3
        obese diet + orlistat + exercise (n = 23) BMI 33.2 (30.0 to 35.4) f
      10 week trial:
      • -
        diet: balanced hypocaloric diet (1200–2000 kcals/day): 25–30% fat, 55–65% complex carbohydrate, 15–20%protein.
      • -
        orlistat: 120 mg of Orlistat 3 times/day + multivitamin supplement 1 time/day (5000 IU vitamin A, 400 IU vitamin D, 30 IU vitamin E and 25 mg vitamin K1)
      • -
        Exercise: resistance training, 2 times/week, 70 min/session
      FMD dDiet + Orlistat (+exercise):

      ↑FMD (%)

      (change 1.0 with orlistat treatment versus 0.1 with diet alone; p < 0.001)
      Diet + Orlistat (+exercise):

      ↓ weight

      ↓ BMI

      ↓ waist circumference

      ↓ total and LDL cholesterol

      All groups:

      ↓ insulin

      ↓ triglycerides
      a [BMI] >97th percentile.
      b [BMI] > 95th percentile.
      c [BMI] > 85th percentile.
      d Addition of nitroglycerin to FMD described in Methodology.
      e Cross-sectional, baseline comparison.
      f Median (inter quartile range).
      g LDL-cholesterol >130 mg/dL, triglycerides >150 mg/dL, HDL-cholesterol <40 mg/dL, and/or lipoprotein (a) > 2 fold the upper limit of normal.
      ↑: increased.
      ↓: decreased.
      Intense, aerobic physical activity, several times a week for a minimum of 30–60 min per session for a period of at least 6 weeks improve or even normalize the endothelial cell dysfunction [
      • Skilton M.R.
      • Celermajer D.S.
      Endothelial dysfunction and arterial abnormalities in childhood obesity.
      ,
      • Bruyndonckx L.
      • Hoymans V.Y.
      • Van Craenenbroeck A.H.
      • Vissers D.K.
      • Vrints C.J.
      • Ramet J.
      • et al.
      Assessment of endothelial dysfunction in childhood obesity and clinical use.
      ,
      • Herouvi D.
      • Karanasios E.
      • Karayianni C.
      • Karavanaki K.
      Cardiovascular disease in childhood: the role of obesity.
      ]. The specific nature of the physical activity seems hardly important. This physical activity can be combined with a dietary intervention, but dietary changes alone do not substantially affect the endothelial cell function. It is somewhat surprising that the reported improvements seem independent of concomitant changes in body composition and other cardiovascular risk factors. To maintain the obtained improvements, a regular continuation of the physical activity during childhood and adolescence is of great importance. Treatments with folic acid, Vitamin D and freeze-dried strawberry powder remain controversial [
      • Herouvi D.
      • Karanasios E.
      • Karayianni C.
      • Karavanaki K.
      Cardiovascular disease in childhood: the role of obesity.
      ]. Supplementations with omega-3 fatty acids or antioxidants seem promising, but need further confirmation in larger study populations. Lastly, a medical treatment with Orlistat or Metformin could offer potential. A single study performed by Yu et al., in 2013 shows a favorable result of the addition of Orlistat to a lifestyle intervention. However, studies performed in adults showed no consistency [
      • Bruyndonckx L.
      • Hoymans V.Y.
      • Van Craenenbroeck A.H.
      • Vissers D.K.
      • Vrints C.J.
      • Ramet J.
      • et al.
      Assessment of endothelial dysfunction in childhood obesity and clinical use.
      ].
      Surprisingly, in both diagnosis and treatment of endothelial cell dysfunction no sex nor gender differences were reported. The aforementioned observed premature cardiovascular death in the male offspring of mothers with obesity, did not result in a striking difference in the male endothelial function during childhood or adolescence. In future research however attention should be paid to these gender/sex difference since they might by one of the key factors to the development of individual tailored screening and treatment programs in order to prevent premature cardiovascular death [
      • Spence J.D.
      • Pilote L.
      Importance of sex and gender in atherosclerosis and cardiovascular disease.
      ].

      6. Conclusion

      The offspring of mothers with obesity should be considered a high risk population for the existence of endothelial cell dysfunction and consequent cardiovascular morbidity and mortality in adult life. Novel techniques for early detection and the proven reversibility of this condition make it an excellent treatment target. The fundamental solution to break the vicious cycle seems an intervention before or in early pregnancy. Many questions remain unanswered about the definite underlying programming mechanisms and actual functioning state of the endothelial cells in the offspring of mothers with obesity. Future research is needed to provide a better understanding in order to move the debate forward and tackle some of the most challenging health problems of this century.

      Conflicts of interest

      The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

      Financial support

      The research activities of K. Van De Maele are funded by a doctoral research grant from the Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED) and additional research funding from Wetenschappelijk Fonds Willy Gepts of the UZ Brussel.

      Author contributions

      All authors contributed to the design of the review, to the analysis of the articles and to the writing of the manuscript.

      Acknowledgements

      The authors kindly thank Elke Uyttenhove for drawing the digital version of Fig. 2.

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