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

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

Journal of Endocrinology ◽

10.1530/joe-17-0039 ◽

2017 ◽

Vol 233 (2) ◽

pp. R81-R94 ◽

Cited By ~ 10

Author(s):

Kimberley C W Wang ◽

Kimberley J Botting ◽

Song Zhang ◽

I Caroline McMillen ◽

Doug A Brooks ◽

...

Keyword(s):

Cardiovascular Disease ◽

Birth Weight ◽

Low Birth Weight ◽

Adult Life ◽

Epidemiological Studies ◽

Left Ventricular ◽

Postnatal Life ◽

Risk Of Death ◽

Expression Of Genes ◽

Increased Risk

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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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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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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Leptin-Independent Programming of Adult Body Weight and Adiposity in Mice

Endocrine Reviews ◽

10.1210/edrv.32.1.zef152c ◽

2011 ◽

Vol 32 (1) ◽

pp. 152-153

Author(s):

Elizabeth C. Cottrell ◽

Malgorzata S. Martin-Gronert ◽

Denise S. Fernandez-Twinn ◽

Jian'an Luan ◽

Lindsey M. Berends ◽

...

Keyword(s):

Body Weight ◽

Birth Weight ◽

Low Birth Weight ◽

Energy Homeostasis ◽

Adult Life ◽

Subsequent Development ◽

Critical Factor ◽

Additive Risk ◽

Adult Body Weight ◽

Postnatal Weight Gain

Abstract Low birth weight and rapid postnatal weight gain are independent and additive risk factors for the subsequent development of metabolic disease. Despite an abundance of evidence for these associations, mechanistic data are lacking. The hormone leptin has received significant interest as a potential programming factor, because differences in the profile of leptin in early life have been associated with altered susceptibility to obesity. Whether leptin alone is a critical factor for programming obesity has, until now, remained unclear. Using the leptin-deficient ob/ob mouse, we show that low birth weight followed by rapid catch-up growth during lactation (recuperated offspring) leads to a persistent increase in body weight in adult life, both in wild-type and ob/ob animals. Furthermore, recuperated offspring are hyperphagic and epididymal fat pad weights are significantly increased, reflecting greater adiposity. These results show definitively that factors other than leptin are crucial in the programming of energy homeostasis in this model and are powerful enough to alter adiposity in a genetically obese strain.

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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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Leptin-Independent Programming of Adult Body Weight and Adiposity in Mice

Endocrinology ◽

10.1210/en.2010-0911 ◽

2011 ◽

Vol 152 (2) ◽

pp. 476-482 ◽

Cited By ~ 20

Author(s):

Elizabeth C. Cottrell ◽

Malgorzata S. Martin-Gronert ◽

Denise S. Fernandez-Twinn ◽

Jian'an Luan ◽

Lindsey M. Berends ◽

...

Keyword(s):

Body Weight ◽

Birth Weight ◽

Low Birth Weight ◽

Energy Homeostasis ◽

Adult Life ◽

Subsequent Development ◽

Critical Factor ◽

Additive Risk ◽

Adult Body Weight ◽

Postnatal Weight Gain

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miRNAs, target genes expression and morphological analysis on the heart in gestational protein-restricted offspring

10.1101/507038 ◽

2018 ◽

Author(s):

José A.R. Gontijo ◽

Heloisa Balan Assalin ◽

Patrícia Aline Boer

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Birth Weight ◽

Low Birth Weight ◽

Left Ventricle ◽

Systolic Blood Pressure ◽

Target Genes ◽

Protein Restriction ◽

Protein Diet ◽

Genes Expression

BACKGROUND Gestational protein restriction was associated with low birth weight, hypertension and higher prevalence of cardiac disorders in adults. Several mechanisms, including epigenetics, could be related with the cardiovascular phenotype on protein-restricted offspring. Thus, we investigated the morphological cardiac effects of gestational protein restriction and left ventricle miRNAs and target genes expression pattern in both 12-day and 16-week old gestational protein-restricted male offspring. METHODS Pregnant Wistar rats were allocated into two groups, according to protein supply during pregnancy: NP (normal protein diet- 17%) or LP (low protein diet - 6%). The study evaluates the effects of maternal protein restriction on food consumption and body weight of both pregnant dams and offspring, systolic blood pressure in 16-wk old offspring and on cardiac morphometric and molecular parameters in both 12-d and 16-wk old offspring. RESULTS: Dams on the gestational protein-restricted diet had lower body weight gain and higher food intake. Gestational protein-restricted offspring had low birth weight, followed by rapidly body weight recovery, hypertension, and increased myocytes cross-sectional area and collagen fraction at 16-week old age. At 12-days old, miR-184, miR-192, miR-376c, miR-380-3p, miR-380-5p, miR-451, and miR-582-3p had increased expression, and miR-547 and miR-743a had decreased expression in the gestational protein-restricted left ventricle. At 16-week old, let-7b, miR-125a-3p, miR-142-3p, miR-182 and miR-188-5p had increased expression and let-7g, miR-107, miR-127, miR-181a, miR-181c, miR-184, miR-324-5p, miR-383, miR-423-5p and miR-484 had decreased expression in gestational protein-restricted left ventricle. Target predicted gene expression analysis shown higher expression of Dnmt3a, Oxct1, Rictor and Trps1 and lower expression of Bbs1 and Calml3 in 12-day old protein-restricted offspring. 16-week old protein-restricted offspring had higher expression of Adrbk1, Bbs1, Dnmt3a, Gpr22, Inppl1, and Oxct1 genes. CONCLUSION: Gestational protein restriction leads to offspring low birth weight, increased systolic blood pressure and morphological heart alterations that could be related to early heart miRNA expression changes that perpetuate into adulthood and which are associated with the regulation of essential genes involved in cardiovascular development, heart morphology, function, and metabolism.

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