Akt signaling as a mediator of cardiac adaptation to low birth weight

Intrauterine insults, such as poor nutrition and placental insufficiency, can alter cardiomyocyte development, and this can have significant long-term implications for heart health. Consequently, epidemiological studies have shown that low-birth-weight babies have an increased risk of death from cardiovascular disease in adult life. In addition, intrauterine growth restriction can result in increased left ventricular hypertrophy, which is the strongest predictor for poor health outcomes in cardiac patients. The mechanisms responsible for these associations are not clear, but a suboptimal intrauterine environment can program alternative expression of genes such as cardiac IGF-2/H19, IGF-2R and AT1R through either an increase or decrease in DNA methylation or histone acetylation at specific loci. Furthermore, hypoxia and other intrauterine insults can also activate the IGF-1 receptor via IGF-1 and IGF-2, and the AT1 receptor via angiotensin signaling pathways; both of which can result in the phosphorylation of Akt and the activation of a range of downstream pathways. In turn, Akt activation can increase cardiac angiogenesis and cardiomyocyte apoptosis and promote a reversion of metabolism in postnatal life to a fetal phenotype, which involves increased reliance on glucose. Cardiac Akt can also be indirectly regulated by microRNAs and conversely can target microRNAs that will eventually affect other specific cardiac genes and proteins. This review aims to discuss our understanding of this complex network of interactions, which may help explain the link between low birth weight and the increased risk of cardiovascular disease in adult life.

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IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00346.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. R627-R635 ◽

Cited By ~ 17

Author(s):

Kimberley C. W. Wang ◽

Darran N. Tosh ◽

Song Zhang ◽

I. Caroline McMillen ◽

Jaime A. Duffield ◽

...

Keyword(s):

Birth Weight ◽

Low Birth Weight ◽

Cardiac Hypertrophy ◽

Histone Acetylation ◽

Troponin I ◽

Adult Life ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Average Birth Weight ◽

Increased Risk

The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.

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Small size at birth predicts decreased cardiomyocyte number in the adult ovine heart

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174417000381 ◽

2017 ◽

Vol 8 (5) ◽

pp. 618-625 ◽

Cited By ~ 11

Author(s):

S. Vranas ◽

G. K. Heinemann ◽

H. Liu ◽

M. J. De Blasio ◽

J. A. Owens ◽

...

Keyword(s):

Body Weight ◽

Birth Weight ◽

Low Birth Weight ◽

Left Ventricle ◽

Disease Risk ◽

Adult Life ◽

Postnatal Life ◽

Intrauterine Growth ◽

Increased Risk ◽

Cardiomyocyte Number

Low birth weight is associated with increased risk of cardiovascular disease in adulthood. Intrauterine growth restriction (IUGR) hearts have fewer CMs in early postnatal life, which may impair postnatal cardiovascular function and hence, explain increased disease risk, but whether the cardiomyocyte deficit persists to adult life is unknown. We therefore studied the effects of experimentally induced placental restriction (PR) on cardiac outcomes in young adult sheep. Heart size, cardiomyocyte number, nuclearity and size were measured in control (n=5) and PR (n=5) male sheep at 1 year of age. PR lambs were 36% lighter at birth (P=0.007), had 38% faster neonatal relative growth rates (P=0.001) and had 21% lighter heart weights relative to body weight as adults (P=0.024) than control lambs. Cardiomyocyte number, nuclearity and size in the left ventricle did not differ between control and PR adults; hearts of both groups contained cardiomyocytes (CM) with between one and four nuclei. Overall, cardiomyocyte number in the adult left ventricle correlated positively with birth weight but not with adult weight. This study is the first to demonstrate that intrauterine growth directly influences the complement of CM in the adult heart. Cardiomyocyte size was not correlated with cardiomyocyte number or birth weight. Our results suggest that body weight at birth affects lifelong cardiac functional reserve. We hypothesise that decreased cardiomyocyte number of low birth weight individuals may impair their capacity to adapt to additional challenges such as obesity and ageing.

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Three interpretations of the association between birth weight and cardiovascular disease

Norsk Epidemiologi ◽

10.5324/nje.v15i1.225 ◽

2009 ◽

Vol 15 (1) ◽

Author(s):

Per Magnus

Keyword(s):

Cardiovascular Disease ◽

Birth Weight ◽

Low Birth Weight ◽

Developmental Plasticity ◽

Epidemiological Studies ◽

Font Size ◽

Spurious Association ◽

Fetal Organ ◽

Organ Systems ◽

Increased Risk

Most epidemiological studies of cardiovascular disease have had a focus on smoking, blood pressure, diet, physical activity and obesity in adulthood as determinants of cardiovascular disease. A few studies from the 1970s and onwards attempted to shed light on the early origins of this disease, and it is now established through cohort studies that there is a fairly strong and consistent relationship between low birth weight and increased risk of later cardiovascular disease. However, the interpretation of this relationship is under discussion. Three alternative interpretations of the association are discussed. The first interpretation, the environmental causal model, claims that the external influences on the growth of fetal organ systems have detrimental biological consequences that predispose the child for cardiovascular disease as an adult. This is the fetal programming hypothesis, which presently more often is called the theory of developmental plasticity, integrating environmental events before and after birth. The second interpretation, the genetic confounding model, says that the association between low birth weight and later cardiovascular disease is not causal. The association is due to confounding by pleiotropic genes, i.e. genes that influence more than one phenotype. The third interpretation, the environmental confounding model, says that lifestyles and general socioeconomic conditions that correlate across generations cause both low birth weight and predisposes for cardiovascular disease, and thereby leads to a spurious association. The conclusion is that, with the studies reported up to now, one cannot dismiss any of these interpretations. By utilizing the large pregnancy cohorts set up in Norway and other countries, these models can be put to critical tests.

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Low birth weight, very low birth weight and extremely low birth weight in African children aged between 0 and 5 years old: a systematic review

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174416000131 ◽

2016 ◽

Vol 7 (4) ◽

pp. 408-415 ◽

Cited By ~ 6

Author(s):

M. E. Tchamo ◽

A. Prista ◽

C. G. Leandro

Keyword(s):

Systematic Review ◽

Birth Weight ◽

Low Birth Weight ◽

Very Low Birth Weight ◽

Neurodevelopmental Outcome ◽

Sub Saharan Africa ◽

Extremely Low Birth Weight ◽

Risk Of Death ◽

African Children ◽

Increased Risk

Low birth weight (LBW<2500), very low birth weight (VLBW<1500), extremely low birth weight (ELBW<1500) infants are at high risk for growth failure that result in delayed development. Africa is a continent that presents high rates of children born with LBW, VLBW and ELBW particularly sub-Saharan Africa. To review the existing literature that explores the repercussions of LBW, VLBW and ELBW on growth, neurodevelopmental outcome and mortality in African children aged 0–5 years old. A systematic review of peer-reviewed articles using Academic Search Complete in the following databases: PubMed, Scopus and Scholar Google. Quantitatives studies that investigated the association between LBW, VLBW, ELBW with growth, neurodevelopmental outcome and mortality, published between 2008 and 2015 were included. African studies with humans were eligible for inclusion. From the total of 2205 articles, 12 articles were identified as relevant and were subsequently reviewed in full version. Significant associations were found between LBW, VLBW and ELBW with growth, neurodevelopmental outcome and mortality. Surviving VLBW and ELBW showed increased risk of death, growth retardation and delayed neurodevelopment. Post-neonatal interventions need to be carried out in order to minimize the short-term effects of VLBW and ELBW.

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Remodeling of the Heart of the Premature Child

Annals of the Russian academy of medical sciences ◽

10.15690/vramn1268 ◽

2020 ◽

Vol 75 (6) ◽

pp. 631-637

Author(s):

O. P. Kovtun ◽

P. B. Tsyvian ◽

T. V. Markova ◽

T. V. Chumarnaya

Keyword(s):

Birth Weight ◽

Preterm Birth ◽

Low Birth Weight ◽

Adult Life ◽

Later Life ◽

Epidemiological Studies ◽

Wall Structure ◽

Early Postnatal Development ◽

Cardiovascular Remodeling ◽

Cardiovascular Morbidity And Mortality

Epidemiological studies consistently have suggested an association between low birth weight and increased rate of cardiovascular morbidity and mortality in adult life. Preterm birth, as one of the leading causes of the low birth weight, is associated with cardiovascular remodeling which consists of changes in heart chambers geometry and contraction-relaxation mode, ventricular hypertrophy, arterial wall structure and density changes. Several types of preterm birth are discussed: prematurity, associated with placental insufficiency and fetal growth restriction, preterm leaking of amniotic fluid, and twin pregnancy. DNA methylation process under the influence of epigenetic factors of the intrauterine and early postnatal development is suggested as a one of the main mechanism of cardiovascular remodeling in preterm infants. The other mechanisms of cardiovascular remodeling are discussed in terms of the modern intrauterine programming concept. The early diagnostics and prevention of cardiovascular diseases in preterm born children are discussed. The treatment during prenatal and early postnatal periods as well as prevention of the remodeling causes could diminish and even reverse the development of the negative cardiovascular events and diseases in later life according to the so called concept of one thousand days opportunities window.

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A CROSS SECTIONAL STUDY: ASSESSMENT OF MATERNAL RISK FACTORS FOUND IN LOW BIRTH WEIGHT NEONATES

10.36106/gjra/2605382 ◽

2020 ◽

pp. 11-13

Author(s):

Nikulkumar Thakkar ◽

Shalini Panday ◽

Nomeeta Gupta

Keyword(s):

Socioeconomic Status ◽

Birth Weight ◽

Low Birth Weight ◽

Adult Life ◽

Cross Sectional Study ◽

Sectional Study ◽

Maternal Factors ◽

Cross Sectional ◽

Maternal Risk ◽

Increased Risk

Introduction Birth weight is one of the important factors for the survival, normal growth and development of a child. LBW is associated with compromised growth, disabilities, hospitalizations, brain damage, and poorer language development, increased risk of cardiovascular and metabolic disorders in adult life. Maternal risk factor that may contribute to LBW include age, stature, socioeconomic status, multiple pregnancies, previous LBW infants and poor nutrition. Method: The present cross-sectional study was carried out in the postnatal care wards and NICU of Janta trust hospital, Patan. All live born babies born at Janta Hopsital with birth weight of less than 2.5kg during July 2019 to June 2020 were included after written consent from parents. The information regarding the study variables was record on predesigned, pretested questionnaire. Result: Out of 65 LBW babies, 46.2% were boys. Percentage of LBW babies was similar in second para and above (52.3%) as compared to primiparous mothers (47.7%). Eighteen babies (18, 27.7%) were born pre term. About 3.1% LBW babies had very low birth weight. The proportion of LBW babies was higher in 20-24 year age group (52.3%). Majority of mothers studied up to primary (84.8%). Total 63.1% had an antenatal registration with in the first trimester. Half of mothers (52.3%) visited adequately during antenatal period. Most common maternal factors found in LBW mothers were anemia (55.4%), PIH (12.0%) followed by UTI (7.7%) fever (6.2%) and APH (6.2%). Conclusion: Maternal factors like teenage pregnancy, illiteracy of the mothers, lower socioeconomic status, short birth spacing, lack of antenatal care were observed higher among low birth weight newborn. There is the need to strengthen the maternal services at community level.

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Sexually dimorphic effects of maternal alcohol intake and adrenalectomy on left ventricular hypertrophy in rat offspring

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00552.2002 ◽

2003 ◽

Vol 285 (1) ◽

pp. E31-E39 ◽

Cited By ~ 22

Author(s):

Jennifer Slone Wilcoxon ◽

Jeff Schwartz ◽

Fraser Aird ◽

Eva E. Redei

Keyword(s):

Cardiovascular Disease ◽

Birth Weight ◽

Low Birth Weight ◽

Left Ventricular Hypertrophy ◽

Ventricular Hypertrophy ◽

Alcohol Exposure ◽

Female Offspring ◽

Left Ventricular ◽

Placental Weight ◽

Mrna Levels

In humans, low birth weight and increased placental weight can be associated with cardiovascular disease in adulthood. Low birth weight and increased placental size are known to occur after fetal alcohol exposure or prenatal glucocorticoid administration. Thus the effects of removing the alcohol-induced increase in maternal corticosterone by maternal adrenalectomy on predictors of cardiovascular disease in adulthood were examined in rats. Alcohol exposure of dams during the last 2 wk of gestation resulted in significantly decreased fetal weight and increased placental weight on gestational day 21. Adult female, but not male, offspring of alcohol-consuming mothers exhibited left ventricular hypertrophy. Placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2) mRNA levels, measured by Northern blot, were decreased in females but not males. Adrenalectomy of alcohol-consuming dams reversed the increase in placental weight and the decrease in female placental 11β-HSD-2 expression and eliminated the left ventricular hypertrophy of adult female offspring. These data suggest that alcohol-induced changes in placental 11β-HSD-2 mRNA levels and left ventricular weight are coupled in female offspring only and depend on maternal adrenal status.

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Impact of maternal undernutrition on diabetes and cardiovascular disease risk in adult offspring

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y09-006 ◽

2009 ◽

Vol 87 (3) ◽

pp. 161-179 ◽

Cited By ~ 38

Author(s):

Caroline Le Clair ◽

Tina Abbi ◽

Heather Sandhu ◽

Paramjit S. Tappia

Keyword(s):

Cardiovascular Disease ◽

Birth Weight ◽

Low Birth Weight ◽

Maternal Nutrition ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Adult Life ◽

Adult Disease ◽

Maternal Undernutrition ◽

The Impact

Epidemiological, clinical, and experimental observations have led to the hypothesis that the risk of developing chronic diseases in adulthood is influenced not only by genetic and adult lifestyle factors, but also by environmental factors during early life. Low birth weight, a marker of intrauterine stress, has been linked to predisposition to cardiovascular disease (CVD) and diabetes. The compelling animal evidence and significant human data to support this conclusion are reviewed. Specifically, the review discusses the role of maternal nutrition before and during pregnancy, placental insufficiencies and epigenetic changes in the increased predisposition to diabetes and CVD in adult life. The impact of low birth weight and catch-up growth as they pertain to risk of disease in adult life is also discussed. In addition, adult disease risk in the overnourished fetus is also mentioned. Reference is made to some of the mechanisms of the induction of diabetes and CVD phenotype. It is proposed that fetal nutrition, growth and development through efficient maternal nutrition before and during pregnancy could constitute the basis for nutritional strategies for the primary prevention of diabetes and CVD.

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Parathyroid adenomas and cardiovascular risk.

Endocrine Related Cancer ◽

10.1677/erc.0.0100309 ◽

2003 ◽

pp. 309-322 ◽

Cited By ~ 45

Author(s):

N Garcia de la Torre ◽

J A H Wass ◽

H E Turner

Keyword(s):

Cardiovascular Disease ◽

Glucose Metabolism ◽

Vascular Reactivity ◽

Renal Involvement ◽

Cardiovascular Disorder ◽

Left Ventricular ◽

Cardiac Conduction ◽

Impaired Glucose Metabolism ◽

Risk Of Death ◽

Increased Risk

In recent decades, primary hyperparathyroidism (pHPT) has changed its clinical presentation from a disease with bone and renal involvement to a frequently asymptomatic disorder detected on routine biochemistry. Nevertheless, it remains unclear whether patients with untreated mild asymptomatic hyperparathyroidism are at risk for other complications such as increased morbidity and mortality from cardiovascular diseases. There are limited data on the incidence of cardiovascular abnormalities in mild pHPT. However, pHPT has been associated with increased risk of death from cardiovascular disease, hypertension, left ventricular hypertrophy (LVH), valvular and myocardial calcifications, impaired vascular reactivity, alterations in cardiac conduction, impaired glucose metabolism, dyslipidaemia, and alterations in body composition. The nature of some of these associations is in question, because cure of pHPT does not lead to improvement of the cardiovascular disorder e.g. hypertension. In contrast, currently available data suggest that LVH, impaired glucose metabolism and dyslipidaemia may improve after surgery and that successful parathyroidectomy could decrease the excess mortality in patients with pHPT due to cardiovascular disease.

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Prenatal glucocorticoids and long-term programming

Acta Endocrinologica ◽

10.1530/eje.0.151u049 ◽

2004 ◽

Vol 151 (Suppl_3) ◽

pp. U49-U62 ◽

Cited By ~ 503

Author(s):

Keyword(s):

Birth Weight ◽

Low Birth Weight ◽

Prenatal Exposure ◽

Hpa Axis ◽

Molecular Mechanisms ◽

Adult Life ◽

Gene Mutations ◽

Increased Risk ◽

Low Birth Weight Babies ◽

Physiological Variations

Epidemiological evidence suggests that low birth weight is associated with an increased risk of cardiovascular, metabolic and neuroendocrine disorders in adult life. Glucocorticoid administration during pregnancy reduces offspring birth weight and alters the maturation of the lung and other organs. We hypothesised that prenatal exposure to excess glucocorticoids or stress might represent a mechanism linking foetal growth with adult pathophysiology. In rats, birth weight is reduced following prenatal exposure to the synthetic steroid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental 'barrier' to maternal glucocorticoids. As adults, the offspring exhibit permanent hypertension, hyperglycaemic, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behaviour reminiscent of anxiety. Physiological variations in placental 11beta-HSD2 activity correlate directly with foetal weight. In humans, 11beta-HSD2 gene mutations cause low birth weight. Moreover, low-birth-weight babies have higher plasma cortisol levels throughout adult life, indicating HPA axis programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors, key among which is the glucocorticoid receptor (GR) itself. The differential programming of the GR in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the GR gene. Overall, the data suggest that both pharmacological and physiological exposure prenatally to excess glucocorticoids programmes cardiovascular, metabolic and neuroendocrine disorders in adult life.

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